Method of treating cancer using subcutaneous administration of mosnetuzumab as monotherapy or in combination with lenalidomide

Abstract

Provided herein are methods of treating a subject having a CD20 - positive cell-proliferative disorder (e.g., a B-cell proliferative disorder, e.g., non-Hodgkin's lymphoma or chronic lymphocytic leukaemia).SOLUTION: The present invention provides the treatment of a subject having a B-cell proliferative disorder by subcutaneous administration of mosnetuzumab as monotherapy or in combination with lenalidomide.SELECTED DRAWING: Figure 10

Description

[Technical Field]

[0001] Sequence Listing This application contains a Sequence Listing that has been submitted electronically in XML format and is incorporated herein by reference in its entirety. The XML copy, created on June 20, 2025, is named 50474-355JP5_Sequence_Listing_6_20_25.xml and is 34,026 bytes in size.

[0002] The present invention relates to the treatment of CD20-positive cell proliferative disorders. More particularly, the present invention relates to the treatment of subjects with CD20-positive cell proliferative disorders by subcutaneous administration of mosunetuzumab alone or in combination with lenalidomide. [Background technology]

[0003] Cancer is characterized by the uncontrolled proliferation of a subpopulation of cells. It is the leading cause of death in developed countries and the second leading cause of death in developing countries, with over 14 million new cancer cases diagnosed and over 8 million cancer deaths occurring each year. Cancer care therefore represents a significant and growing societal burden.

[0004] CD20-positive cell proliferative disorders, such as B-cell proliferative disorders, are a leading cause of cancer-related deaths. For example, non-Hodgkin's lymphoma (NHL) progresses rapidly and is fatal if untreated. In the United States, B-cell lymphomas account for approximately 80%–85% of all NHL cases. Diffuse large B-cell lymphoma (DLBCL) is the most common type of NHL, accounting for approximately 30%–40% of all NHL diagnoses, followed by follicular lymphoma (FL; 20%–25% of all NHL diagnoses) and mantle cell lymphoma (MCL; 6%–10% of all NHL diagnoses). B-cell chronic lymphocytic leukemia (CLL) is the most common leukemia in adults, with approximately 15,000 new cases occurring annually in the United States (American Cancer Society 2015).

[0005] Bispecific antibodies are capable of simultaneously binding to cell surface antigens on cytotoxic cells (e.g., T cells, by binding to cluster of differentiation 3 (CD3)) and cancer cells (e.g., B cells, by binding to CD20), with the intention that the bound cytotoxic cells will destroy the bound cancer cells. However, such antibody-based immunotherapies can be limited by undesirable effects, including cytokine-driven toxicity (e.g., cytokine release syndrome (CRS)), infusion-related reactions (IRR), severe tumor lysis syndrome (TLS), and central nervous system (CNS) toxicity.

[0006] Thus, there is an unmet need in the art for the development of therapeutic bispecific antibodies (e.g., mosunetuzumab) that achieve a more favorable benefit-risk profile for the treatment of CD20-positive cell proliferative disorders, such as B-cell proliferative disorders (e.g., non-Hodgkin's lymphoma (NHL) (e.g., previously untreated (1L) NHL, diffuse large B-cell lymphoma (DLBCL) (e.g., 1L DLBCL, relapsed and / or refractory DLBCL, or Richter's transformation), follicular lymphoma (FL) (e.g., 1L FL, relapsed and / or refractory FL, or transformed FL), mantle cell lymphoma (MCL), high-grade B-cell lymphoma, or primary mediastinal (thymic) large B-cell lymphoma (PMLBCL)), or chronic lymphocytic leukemia (CLL). Summary of the Invention

[0007] The present invention relates to methods of treating a subject with a CD20-positive cell proliferative disorder (e.g., a B-cell proliferative disorder) with subcutaneous administration of mosunetuzumab as monotherapy or in combination with lenalidomide, wherein the treatment comprising subcutaneous administration of mosunetuzumab as monotherapy or in combination with lenalidomide exhibits non-inferior outcomes or improved outcomes compared to intravenous administration of mosunetuzumab as monotherapy or in combination with lenalidomide, respectively, as measured using pharmacokinetics (PK), efficacy, safety, or a combination thereof.

[0008] In one aspect, the invention features a method for treating follicular lymphoma (FL) in a subject in need thereof, the method comprising administering to the subject a combination treatment comprising subcutaneously administered mosunetuzumab and orally administered lenalidomide, wherein administering the combination treatment to the plurality of subjects results in a non-inferior or improved efficacy response in the plurality of subjects compared to a reference efficacy response, where the reference efficacy response is the efficacy response of the plurality of subjects who received a control treatment comprising intravenously administered mosunetuzumab and orally administered lenalidomide, and the efficacy response is complete response rate (CRR), objective response rate (ORR), duration of response (DOR), duration of complete response (DOCR), overall survival (OS), or progression-free survival (PFS).

[0009] In some embodiments, the efficacy response is a CRR, where the CRR or reference CRR is the proportion of subjects receiving the corresponding treatment whose best overall response is a complete response (CR).

[0010] In some embodiments, the improved response in CRR is an increase in CRR compared to a reference CRR of 1% to 25% (e.g., 5% to 25%, 10% to 25%, 15% to 25%, 20% to 25%, 5% to 10%, 5% to 15%, 5% to 20%, 10% to 20%, 10% to 15%, or 15% to 20%; e.g., about 1%, 5%, 10%, 15%, 20%, or 25%). In some embodiments, the efficacy response in CRR is non-inferior to the reference CRR.

[0011] In some embodiments, the efficacy response is ORR, where ORR or reference ORR is the proportion of subjects receiving the corresponding treatment whose best overall response is CR or partial response (PR). In some embodiments, an improvement in response in ORR is an increase in ORR compared to the reference ORR of 1% to 24% (e.g., 5% to 24%, 10% to 24%, 15% to 24%, 20% to 24%, 5% to 10%, 5% to 15%, 5% to 20%, 10% to 20%, 10% to 15%, or 15% to 20%; e.g., about 1%, 5%, 10%, 15%, 20%, or 24%). In some embodiments, the efficacy response in ORR is non-inferior to the reference ORR.

[0012] In some embodiments, the efficacy response is DOR, and the DOR or reference DOR is measured starting from the first occurrence of documented CR or PR until disease progression or recurrence or death from any cause, whichever occurs first. In some embodiments, the DOR or reference DOR is the median DOR of multiple human patients receiving the corresponding treatment. In some embodiments, the improvement in median DOR is an increase in DOR compared to the reference DOR at 1 to 22 months (e.g., 1 to 5 months, 5 to 22 months, 10 to 22 months, 15 to 22 months, 5 to 10 months, 5 to 15 months, 10 to 22 months, 10 to 15 months, or 15 to 22 months; e.g., about 1 month, 5 months, 10 months, 15 months, 20 months, or 22 months). In some embodiments, the efficacy response in DOR is non-inferior to the reference DOR.

[0013] In some embodiments, the efficacy response is DOCR, and the DOCR or reference DOCR is measured starting from the first occurrence of a documented CR until disease progression or recurrence or death from any cause, whichever occurs first. In some embodiments, the DOCR or reference DOCR is the median DOCR of multiple human patients receiving the corresponding treatment. In some embodiments, the improvement in median DOCR is an increase in DOCR compared to the reference DOCR over 1 to 22 months (e.g., 1 to 5 months, 5 to 22 months, 10 to 22 months, 15 to 22 months, 5 to 10 months, 5 to 15 months, 10 to 22 months, 10 to 15 months, or 15 to 22 months; e.g., about 1 month, 5 months, 10 months, 15 months, 20 months, or 22 months). In some embodiments, the efficacy response in DOCR is non-inferior to the reference DOCR.

[0014] In some embodiments, CR or PR is determined by PET / CT. In some embodiments, CR or PR is determined based on the Lugano response criteria for malignant lymphoma (Cheson et al., 2014).

[0015] In some embodiments, the efficacy response is OS, and the OS or reference OS is measured starting from the first treatment (e.g., the first dose of mosunetuzumab or the first dose of lenalidomide; e.g., day 1 of dosing cycle 1) until death from any cause. In some embodiments, the OS or reference OS is the median OS of multiple human patients receiving the corresponding treatment. In some embodiments, the improvement in median OS is an increase in OS compared to a reference OS of 1 to 28 months (e.g., 1 to 5 months, 5 to 28 months, 10 to 28 months, 15 to 28 months, 20 to 28 months, 25 to 28 months, 5 to 10 months, 5 to 15 months, 5 to 20 months, 5 to 25 months, 10 to 20 months, 10 to 25 months, 10 to 15 months, 15 to 25 months, or 20 to 28 months; e.g., about 1 month, 5 months, 10 months, 15 months, 20 months, 25 months, or 28 months). In some embodiments, the efficacy response in OS is non-inferior to the reference OS.

[0016] In some embodiments, the efficacy response is PFS, and the PFS or reference PFS is measured from the first treatment (e.g., the first dose of mosunetuzumab or the first dose of lenalidomide; e.g., day 1 of dosing cycle 1) to the first occurrence of disease progression or death from any cause. In some embodiments, the PFS or reference PFS is the median PFS of multiple human patients receiving the corresponding treatment. In some embodiments, the improvement in median PFS is an increase in PFS compared to a reference PFS of 1 to 26 months (e.g., 1 to 5 months, 5 to 26 months, 10 to 26 months, 15 to 26 months, 5 to 10 months, 5 to 15 months, 10 to 26 months, 10 to 15 months, 15 to 20 months, or 20 to 26 months; e.g., about 1 month, 5 months, 10 months, 15 months, 20 months, or 26 months). In some embodiments, the efficacy response in PFS is non-inferior compared to the reference PFS.

[0017] In another aspect, the invention features a method for treating follicular lymphoma (FL) in a subject in need thereof, the method comprising administering to the subject a combination treatment comprising subcutaneously administered mosunetuzumab and orally administered lenalidomide, wherein administering the combination treatment to the plurality of subjects results in a non-inferior or improved safety response in the plurality of subjects compared to a reference safety response, where the reference safety response is the safety response of the plurality of subjects who received a control treatment comprising intravenously administered mosunetuzumab and orally administered lenalidomide, and the safety response is an incidence of adverse events (AEs), an incidence of cytokine release syndrome (CRS), or an incidence of serious AEs (SAEs).

[0018] In some embodiments, the safety response is the incidence of an AE, and the prior incidence of an AE or the reference incidence of an AE is the incidence of the AE in multiple subjects receiving the corresponding treatment. In some embodiments, the safety response in the incidence of an AE is non-inferior to the reference AE.

[0019] In some embodiments, the safety response is the incidence of CRS, and the incidence of CRS or reference incidence of CRS is the incidence of CRS in multiple subjects receiving a corresponding treatment. In some embodiments, the improved incidence of CRS is a reduction in the incidence of CRS compared to a reference incidence of CRS of 7% to 17% (e.g., 7% to 12%, 12% to 17%, or 10% to 14%; e.g., about 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, or 17%). In some embodiments, the improved incidence of CRS is a reduction in the incidence of CRS compared to a reference incidence of CRS of about 12%. In some embodiments, the incidence of CRS is the incidence of Grade 1 or 2 CRS in multiple patients receiving a corresponding treatment. In some embodiments, the incidence of Grade 3+ CRS is non-inferior to the reference incidence of Grade 3+ CRS. In some embodiments, CRS is graded based on the American Society of Transplantation and Cellular Therapy (ASTCT) consensus grading for cytokine release syndrome (Lee et al., 2019).

[0020] In some embodiments, the safety response is the incidence of SAE, and the incidence of SAE or the reference incidence of SAE is the incidence of SAE in multiple subjects receiving the corresponding treatment. In some embodiments, the safety response in the incidence of SAE is non-inferior to the reference SAE.

[0021] In another aspect, the present invention provides a method for treating follicular lymphoma (FL) in a subject in need thereof, comprising administering to the subject a combination treatment comprising subcutaneously administered mosunetuzumab and orally administered lenalidomide according to a dosing regimen comprising an initial 21-day dosing cycle and three 28-day dosing cycles, wherein administering the combination treatment to the plurality of subjects results in a non-inferiority pharmacokinetic (PK) endpoint for the plurality of subjects compared to a reference PK endpoint, wherein the PK endpoint is an observed dosing cycle 2 serum trough concentration (scConc). トラフCYC2-OBS ) or cumulative area under the concentration-time curve (scAUC) over 0 to 77 days 0~77 ); the reference PK endpoint is a PK endpoint in subjects receiving a control treatment comprising intravenously administered mosunetuzumab and orally administered lenalidomide according to a dosing regimen comprising an initial 21-day dosing cycle and three 28-day dosing cycles, and the reference PK endpoint is the observed dosing cycle 2 serum trough concentration (ivConc トラフCYC2-OBS ) or cumulative area under the concentration-time curve (ivAUC 0~77 ) is a method.

[0022] In some embodiments, the scAUC 0~77 and ivAUC 0~77 One or both of the above are determined using population PK (popPK) model-predicted individual empirical Bayes estimates (EBE).

[0023] In some embodiments, the combination treatment comprises subcutaneous administration of mosunetuzumab and oral administration of lenalidomide according to a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein the first dosing cycle is a 21-day dosing cycle and the second dosing cycle is a 28-day dosing cycle, and (a) the first dosing cycle comprises a first subcutaneous administration (scC1D1), a second subcutaneous administration (scC1D2), and a third subcutaneous administration (scC1D3) of mosunetuzumab administered on days 1, 8, and 15, respectively, of the first dosing cycle, wherein scC1D1 is about 5 mg (e.g., 5 mg ± 10%; 5 mg ± 0.5 mg) and scC1D2 is about (b) a second dosing cycle comprising: (i) a first subcutaneous administration (scC2D1) of mosunetuzumab administered on day 1 of the second dosing cycle, wherein the scC2D1 is about 45 mg (e.g., 45 mg ± 10%; 45 mg ± 4.5 mg); and (ii) 21 oral doses of lenalidomide administered on days 1-21 of the second dosing cycle, wherein each oral dose of lenalidomide is about 20 mg (e.g., 20 mg ± 10%; 20 mg ± 2 mg).In certain embodiments, the combination treatment comprises subcutaneous administration of mosunetuzumab and oral administration of lenalidomide according to a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein the first dosing cycle is a 21-day dosing cycle and the second dosing cycle is a 28-day dosing cycle, and wherein (a) the first dosing cycle comprises a first subcutaneous administration (scC1D1), a second subcutaneous administration (scC1D2), and a third subcutaneous administration (scC1D3), administered on days 1, 8, and 15, respectively, of the first dosing cycle. (b) a second dosing cycle comprising (i) a first subcutaneous administration (scC2D1) of mosunetuzumab administered on day 1 of the second dosing cycle, where scC2D1 is 45 mg; and (ii) 21 oral doses of lenalidomide administered on days 1-21 of the second dosing cycle, where each oral dose of lenalidomide is 20 mg.

[0024] In some embodiments, the combination treatment dosing regimen further comprises one or more additional 28-day dosing cycles, hi some embodiments, the combination treatment dosing regimen comprises ten additional 28-day dosing cycles.

[0025] In some embodiments, each additional dosing cycle comprises: (a) a subcutaneous dose of mosunetuzumab administered on day 1 of the additional dosing cycle, wherein the subcutaneous dose of mosunetuzumab is about 45 mg (e.g., 45 mg ± 10%; 45 mg ± 4.5 mg); and (b) 21 oral doses of lenalidomide administered on days 1-21 of the additional dosing cycle, wherein each oral dose of lenalidomide is about 20 mg (e.g., 20 mg ± 10%; 20 mg ± 2 mg). In certain embodiments, each additional dosing cycle comprises: (i) mosunetuzumab administered subcutaneously on day 1 of the additional dosing cycle, wherein each subcutaneous dose of mosunetuzumab is 45 mg; and (b) 21 oral doses of lenalidomide administered on days 1-21 of the additional dosing cycle, wherein each oral dose of lenalidomide is 20 mg.

[0026] In some embodiments, the combination treatment dosing regimen further comprises 1 to 9 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9) subcutaneous maintenance administrations of mosunetuzumab.

[0027] In another aspect, a method for treating follicular lymphoma (FL) in a subject in need thereof comprises administering to the subject a combination treatment comprising subcutaneously administered mosunetuzumab and orally administered lenalidomide, wherein the combination treatment comprises administering mosunetuzumab subcutaneously and administering lenalidomide orally according to a dosing regimen comprising a first dosing cycle and a second dosing cycle, wherein the first dosing cycle is a 21-day dosing cycle and the second dosing cycle is a 28-day dosing cycle; and ten additional 28-day dosing cycles. and 1 to 9 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9) subcutaneous maintenance administrations of mosunetuzumab, wherein (a) a first dosing cycle comprises a first subcutaneous administration (scC1D1), a second subcutaneous administration (scC1D2), and a third subcutaneous administration (scC1D3) of mosunetuzumab administered on days 1, 8, and 15, respectively, of the first dosing cycle, wherein scC1D1 is about 5 mg (e.g., 5 mg ± 10%; 5 mg ± 0.5 mg) and scC1D2 is about 45 mg (e.g., 45 mg ± 10%; 45 mg ± 4.5 mg), and scC1 (b) a second dosing cycle comprising: (i) a first subcutaneous administration (scC2D1) of mosunetuzumab administered on day 1 of the second dosing cycle, wherein scC2D1 is about 45 mg (e.g., 45 mg ± 10%; 45 mg ± 4.5 mg); and (ii) 21 oral doses of lenalidomide administered on days 1-21 of the second dosing cycle, wherein each oral dose of lenalidomide is about 20 mg (e.g., 20 mg ± 10%; 20 mg ± 2 mg). and (c) 10 additional dosing cycles each comprising: (i) a first subcutaneous dose (scC3D1-scC12D1) of mosunetuzumab administered on day 1 of each additional dosing cycle, where scC3D1 to scC12D1 is about 45 mg (e.g., 45 mg ± 10%; 45 mg ± 4.5 mg); and (ii) 21 oral doses of lenalidomide administered on days 1-21 of each additional dosing cycle, where each oral dose of lenalidomide is about 20 mg (e.g., 20 mg ± 10%; 20 mg ± 2 mg).

[0028] In some embodiments, the combination treatment dosing regimen further comprises nine subcutaneous maintenance doses of mosunetuzumab.

[0029] In some embodiments, one to nine (e.g., one, two, three, four, five, six, seven, eight, or nine) subcutaneous maintenance doses of mosunetuzumab are administered every eight weeks, starting eight weeks after day 1 of a tenth additional 28-day dosing cycle. In some embodiments, each maintenance dose is about 45 mg (e.g., 45 mg ± 10%; 45 mg ± 4.5 mg). In certain embodiments, each maintenance dose is 45 mg.

[0030] In some embodiments, the control treatment comprises intravenously administering mosunetuzumab and orally administering lenalidomide according to a dosing regimen comprising at least a first 21-day dosing cycle and a second 28-day dosing cycle, wherein (a) the first dosing cycle comprises a first intravenous administration (ivC1D1), a second intravenous administration (ivC1D2), and a third intravenous administration (ivC1D3) of mosunetuzumab administered on days 1, 8, and 15, respectively, of the first dosing cycle, wherein ivC1D1 is about 1 mg (e.g., 1 mg ± 10%) and ivC1D2 is about 2 mg. g (e.g., 2 mg ± 10%) and ivC1D3 is about 30 mg (e.g., 30 mg ± 10%); (b) a second dosing cycle comprising: (i) a first intravenous administration (ivC2D1) of mosunetuzumab administered on day 1 of the second dosing cycle, wherein ivC2D1 is about 30 mg (e.g., 30 mg ± 10%); and (ii) 21 oral doses of lenalidomide administered on days 1-21 of the second dosing cycle, wherein each oral dose of lenalidomide is about 20 mg (e.g., 20 mg ± 10%; 20 mg ± 2 mg). In certain embodiments, the control treatment comprises intravenously administering mosunetuzumab and orally administering lenalidomide according to a dosing regimen comprising at least a first 21-day dosing cycle and a second 28-day dosing cycle, wherein (a) the first dosing cycle comprises a first intravenous administration (ivC1D1), a second intravenous administration (ivC1D2), and a third intravenous administration (ivC1D3) of mosunetuzumab administered on days 1, 8, and 15, respectively, of the first dosing cycle. (b) a second dosing cycle comprising: (i) a first intravenous administration (ivC2D1) of mosunetuzumab administered on day 1 of the second dosing cycle, wherein ivC2D1 is 1 mg, ivC1D2 is 2 mg, and ivC1D3 is 30 mg; and (ii) 21 oral doses of lenalidomide administered on days 1-21 of the second dosing cycle, wherein each oral dose of lenalidomide is 20 mg. In some embodiments, the control treatment dosing regimen further comprises one or more additional 28-day dosing cycles.In some embodiments, the control treatment dosing regimen includes 10 additional 28-day dosing cycles, in which each additional dosing cycle includes: (a) intravenous mosunetuzumab administered on day 1 of the additional dosing cycle, where the intravenous dose of mosunetuzumab is about 30 mg (e.g., 30 mg ± 10%); and (b) 21 oral doses of lenalidomide administered on days 1-21 of the additional dosing cycle, where each oral dose of lenalidomide is about 20 mg (e.g., 20 mg ± 10%; 20 mg ± 2 mg). In certain embodiments, each additional dosing cycle comprises: (a) intravenous mosunetuzumab administered on day 1 of the additional dosing cycle, wherein the intravenous dose of mosunetuzumab is 30 mg; and (b) 21 oral doses of lenalidomide administered on days 1-21 of the additional dosing cycle, wherein each oral dose of lenalidomide is 20 mg.

[0031] In some embodiments, the subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2. In some embodiments, the subject has not been previously treated for FL. In some embodiments, the subject has relapsed after or is refractory to one or more prior lines of systemic therapy. In some embodiments, the one or more prior lines of systemic therapy comprise immunotherapy or chemoimmunotherapy. In some embodiments, the one or more prior lines of systemic therapy comprise an anti-CD20 antibody. In some embodiments, the anti-CD20 antibody is rituximab.

[0032] In some embodiments, the FL is grade 1, 2, or 3a.

[0033] In another aspect, the invention features a method for treating non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL) in a subject in need thereof, the method including administering to the subject a treatment comprising subcutaneously administered mosunetuzumab, wherein administering the treatment to the plurality of subjects results in a non-inferior or improved efficacy response in the plurality of subjects compared to a reference efficacy response, where the reference efficacy response is the efficacy response of the plurality of subjects who received a control treatment comprising intravenously administered mosunetuzumab, and the efficacy response is complete response rate (CRR), objective response rate (ORR), duration of response (DOR), duration of complete response (DOCR), progression-free survival (PFS), or overall survival (OS).

[0034] In some embodiments, the efficacy response is a CRR, and the CRR or reference CRR is the proportion of subjects receiving the corresponding treatment whose best overall response is a complete response (CR). In some embodiments, an improved response in CRR is an increase in CRR compared to the reference CRR of 1% to 20% (e.g., 5% to 20%, 10% to 20%, 15% to 20%, 1% to 15%, 1% to 10%, 1% to 5%, 5% to 15%, or 10% to 20%; e.g., about 1%, about 5%, about 10%, about 15%, or about 20%). In some embodiments, the efficacy response in CRR is non-inferior to the reference CRR rate.

[0035] In some embodiments, the efficacy response is ORR, where ORR or reference ORR is the proportion of subjects receiving the corresponding treatment whose best overall response is CR or partial response (PR). In some embodiments, an improvement in response in ORR is an increase in ORR compared to a reference ORR of 1% to 13% (e.g., 1% to 5%, 5% to 13%, or 3% to 10%; e.g., about 1%, about 5%, about 10%, or 13%). In some embodiments, the efficacy response in ORR is non-inferior to the reference ORR.

[0036] In some embodiments, the efficacy response is DOR, and the DOR or reference DOR is measured starting from the first occurrence of documented CR or PR until disease progression or recurrence or death from any cause, whichever occurs first. In some embodiments, the DOR or reference DOR is the median DOR of multiple human patients receiving the corresponding treatment. In some embodiments, the median improvement in DOR is an increase in DOR compared to the reference DOR of 1 to 13 months (e.g., 1 to 5 months, 5 to 13 months, or 3 to 10 months; e.g., about 1 month, 5 months, 10 months, or 13 months). In some embodiments, the efficacy response in DOR is non-inferior to the reference DOR. In some embodiments, the improved DOR is an increase in the 12-month DOR rate compared to a 12-month reference DOR rate of 1% to 31% (e.g., 1% to 25%, 1% to 20%, 1% to 15%, 1% to 10%, 1% to 5%, 5% to 10%, 5% to 15%, 5% to 20%, 5% to 25%, 5% to 31%, 1% to 10%, 10% to 20%, 20% to 31%, 15% to 31%, 1% to 20%, or 10% to 31%; e.g., about 1%, 5%, 10%, 15%, 20%, 25%, or 31%). In some embodiments, the improved DOR is an increase in the 12-month DOR rate compared to a 12-month reference DOR rate of about 8%.

[0037] In some embodiments, the efficacy response is a DOCR, and the DOCR or reference DOCR is measured starting from the first occurrence of a documented CR until disease progression or recurrence or death from any cause, whichever occurs first. In some embodiments, the DOCR or reference DOCR is the median DOCR of multiple human patients receiving the corresponding treatment. In some embodiments, the improvement in DOCR is an increase in the 12-month DOCR rate compared to the 12-month reference DOCR rate of 1% to 27% (e.g., 1% to 25%, 1% to 20%, 1% to 15%, 1% to 10%, 1% to 5%, 5% to 10%, 5% to 15%, 5% to 20%, 5% to 25%, 5% to 27%, 1% to 10%, 10% to 20%, 20% to 27%, 15% to 27%, 1% to 20%, or 10% to 27%; e.g., about 1%, 5%, 10%, 15%, 20%, 25%, or 27%). In some embodiments, the efficacy response in DOCR is non-inferior to the reference DOCR.

[0038] In some embodiments, CR or PR is determined by PET / CT. In some embodiments, CR or PR is determined based on the revised response criteria for malignant lymphoma (Cheson et al., 2007).

[0039] In some embodiments, the efficacy response is PFS, and the PFS or reference PFS is measured from the first treatment (e.g., the first dose of mosunetuzumab or the first dose of lenalidomide; e.g., day 1 of dosing cycle 1) to the first occurrence of disease progression or death from any cause. In some embodiments, the PFS or reference PFS is the median PFS of multiple human patients receiving the corresponding treatment. In some embodiments, the improvement in median PFS is an increase in PFS compared to a reference PFS of 1 to 14 months (e.g., between 1 to 5 months, 5 to 14 months, or 3 to 10 months; e.g., about 1 month, 5 months, 10 months, or 14 months). In some embodiments, the efficacy response in PFS is non-inferior to the reference PFS. In some embodiments, an improvement in PFS is an increase in the rate of PFS compared to a 12-month reference PFS rate of 1% to 26% (e.g., 1% to 20%, 1% to 15%, 1% to 10%, 1% to 5%, 5% to 10%, 5% to 15%, 5% to 20%, 5% to 26%, 1% to 10%, 10% to 20%, 20% to 26%, 15% to 26%, 1% to 20%, or 10% to 26%; e.g., about 1%, 5%, 10%, 15%, 20% or 26%). In some embodiments, an improvement in PFS is an increase in the rate of PFS compared to a 12-month reference PFS rate of about 5%.

[0040] In some embodiments, the efficacy response is OS, where OS or reference OS is measured starting from the first treatment (e.g., the first dose of mosunetuzumab or the first dose of lenalidomide; e.g., day 1 of dosing cycle 1) until death from any cause. In some embodiments, an improvement in OS is an increase in the OS rate compared to a 12-month reference OS rate of 1% to 9% (e.g., about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, or 9%). In some embodiments, the efficacy response in OS is non-inferior to the reference OS.

[0041] In another aspect, the invention features a method for treating non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL) in a subject in need thereof, the method including administering to the subject a treatment comprising subcutaneously administered mosunetuzumab, wherein administering the treatment to the plurality of subjects results in a non-inferior or improved safety response in the plurality of subjects compared to a reference safety response, where the reference safety response is the safety response of the plurality of subjects who received a control treatment comprising intravenously administered mosunetuzumab, and the safety response is an incidence of adverse events (AEs), an incidence of cytokine release syndrome (CRS), or an incidence of serious AEs (SAEs).

[0042] In some embodiments, the safety response is the incidence of an AE, and the incidence of an AE or reference incidence of an AE is the incidence of an AE in multiple subjects receiving a corresponding treatment. In some embodiments, the safety response in incidence of an AE is non-inferior compared to the reference AE. In some embodiments, the improved incidence of an AE is a reduction in the incidence of Grade 3 or 4 AEs by 11% to 21% (e.g., 11% to 16%, 16% to 21%, or 13% to 19%; e.g., about 11%, about 16%, or about 21%) compared to the reference incidence of Grade 3 or 4 AEs. In some embodiments, the improved incidence of an AE is a reduction in the incidence of Grade 3 or 4 AEs by about 16% compared to the reference incidence of Grade 3 or 4 AEs. In some embodiments, the incidence of an AE is the incidence of Grade 5 AEs in multiple subjects receiving a corresponding treatment, and the incidence of an AE is non-inferior compared to the reference incidence of AEs. In some embodiments, the grade of the AE is determined based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), v4.0.

[0043] In some embodiments, the safety response is the incidence of SAEs, and the incidence of SAEs or reference incidence of SAEs is the incidence of SAEs in multiple subjects receiving the corresponding treatment. In some embodiments, the improved safety response in incidence of SAEs is a reduction in the incidence of SAEs of 9% to 19% (e.g., 9% to 14%, 14% to 19%, or 11% to 17%, e.g., about 9%, about 14%, or about 19%) compared to the reference incidence of SAEs. In some embodiments, the improved safety response in incidence of SAEs is a reduction in the incidence of SAEs of about 14% compared to the reference incidence of SAEs.

[0044] In some embodiments, the safety response is the incidence of CRS, and the incidence of CRS or reference incidence of CRS is the incidence of CRS in multiple subjects receiving the corresponding treatment. In some embodiments, the improved incidence of CRS is a reduction in the incidence of CRS of 9% to 19% (e.g., 9% to 14%, 14% to 19%, or 11% to 17%, e.g., about 9%, about 14%, or about 19%) compared to the reference incidence of CRS. In some embodiments, the improved incidence of CRS is a reduction in the incidence of CRS compared to a reference incidence of about 14%. In some embodiments, the improved incidence of CRS is a reduction in the incidence of Grade 2+ CRS of 3% to 13% (e.g., 3% to 8%, 8% to 13%, or 5% to 11%; e.g., about 3%, about 8%, or about 13%) compared to the reference incidence of Grade 2+ CRS. In some embodiments, the improved incidence of CRS is an approximately 8% reduction in the incidence of Grade 2+ CRS compared to a reference incidence of Grade 2+ CRS. In some embodiments, the grade of CRS is determined based on the Modified Cytokine Release Syndrome Grading System (Lee et al., 2014).

[0045] In another aspect, the present invention provides a method for treating non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL) in a subject in need thereof, comprising administering to the subject a treatment comprising subcutaneously administered mosunetuzumab according to a dosing regimen comprising four 21-day dosing cycles, wherein administering the combination treatment to the plurality of subjects results in a non-inferiority or improved pharmacokinetic (PK) endpoint for the plurality of subjects compared to a reference PK endpoint, wherein the PK endpoint is an observed dosing cycle 3 serum trough concentration (scConc). トラフCYC3-OBS ) or cumulative area under the concentration-time curve (scAUC) over 0 to 84 days 0~84 ), where the reference PK endpoint is a PK endpoint in multiple subjects receiving a control treatment containing intravenously administered mosunetuzumab according to a dosing regimen comprising four 21-day dosing cycles, and the reference PK endpoint is the observed dosing cycle 3 serum trough concentration (ivConc トラフCYC3-OBS ) or cumulative area under the concentration-time curve (ivAUC 0~84 ) is a method.

[0046] In some embodiments, the scAUC 0~84 and ivAUC 0~84 One or more of the following are determined using a population PK (popPK) model predictive individual empirical Bayes estimate (EBE).

[0047] In some embodiments, the treatment comprises subcutaneously administering mosunetuzumab according to a dosing regimen comprising at least a first 21-day dosing cycle and a second 21-day dosing cycle, wherein (a) the first dosing cycle comprises a first subcutaneous administration (scC1D1), a second subcutaneous administration (scC1D2), and a third subcutaneous administration (scC1D3) of mosunetuzumab administered on days 1, 8, and 15, respectively, of the first dosing cycle, wherein scC1D1 is about 5 mg (e.g., 5 mg ± 10%; 5 mg ± 0.5 mg); (b) a second dosing cycle comprises a first subcutaneous administration (scC2D1) of mosunetuzumab administered on day 1 of the second dosing cycle, wherein scC2D1 is about 45 mg (e.g., 45 mg ± 10%; 45 mg ± 4.5 mg). In certain embodiments, scC1D2 is about 45 mg (e.g., 45 mg ± 10%; 45 mg ± 4.5 mg). In certain embodiments, the treatment comprises subcutaneously administering mosunetuzumab according to a dosing regimen comprising at least a first 21-day dosing cycle and a second 21-day dosing cycle, wherein (a) the first dosing cycle comprises a first subcutaneous administration (scC1D1), a second subcutaneous administration (scC1D2), and a third subcutaneous administration (scC1D3) of mosunetuzumab administered on days 1, 8, and 15, respectively, of the first dosing cycle, where scC1D1 is 5 mg, scC1D2 is 15 mg or 45 mg, and scC1D3 is 45 mg; and (b) the second dosing cycle comprises a first subcutaneous administration (scC2D1) of mosunetuzumab administered on day 1 of the second dosing cycle, where scC2D1 is 45 mg. In certain embodiments, scC1D2 is 45 mg.

[0048] In some embodiments, the treatment dosing regimen further comprises one or more additional 21-day dosing cycles. In some embodiments, the treatment dosing regimen comprises 6, 15, or 23 additional 21-day dosing cycles. In some embodiments, each additional dosing cycle comprises subcutaneous mosunetuzumab administered on day 1 of the additional dosing cycle, wherein the subcutaneous mosunetuzumab is about 45 mg (e.g., 45 mg ± 10%; 45 mg ± 4.5 mg). In certain embodiments, each additional dosing cycle comprises subcutaneous mosunetuzumab administered on day 1 of the additional dosing cycle, wherein the subcutaneous mosunetuzumab is 45 mg.

[0049] In some embodiments, the control treatment comprises administering mosunetuzumab intravenously according to a dosing regimen comprising at least a first 21-day dosing cycle and a second 21-day dosing cycle, wherein (a) the first dosing cycle comprises a first intravenous administration (ivC1D1), a second intravenous administration (ivC1D2), and a third intravenous administration (ivC1D3) of mosunetuzumab administered on days 1, 8, and 15, respectively, of the first dosing cycle. (b) a second dosing cycle comprising a first intravenous dose (ivC2D1) of mosunetuzumab administered on day 1 of the second dosing cycle, wherein ivC2D1 is about 1 mg (e.g., 1 mg ± 10%), ivC1D2 is about 2 mg (e.g., 2 mg ± 10%), and ivC1D3 is about 60 mg (e.g., 60 mg ± 10%); (b) a second dosing cycle comprising a first intravenous dose (ivC2D1) of mosunetuzumab administered on day 1 of the second dosing cycle, wherein ivC2D1 is 60 mg (e.g., 60 mg ± 10%). In certain embodiments, the control treatment comprises administering mosunetuzumab intravenously according to a dosing regimen comprising at least a first 21-day dosing cycle and a second 21-day dosing cycle, wherein (a) the first dosing cycle comprises a first intravenous administration (ivC1D1), a second intravenous administration (ivC1D2), and a third intravenous administration (ivC1D3) of mosunetuzumab administered on days 1, 8, and 15, respectively, of the first dosing cycle, wherein ivC1D1 is 1 mg, ivC1D2 is 2 mg, and ivC1D3 is 60 mg; and (b) the second dosing cycle comprises a first intravenous administration (ivC2D1) of mosunetuzumab administered on day 1 of the second dosing cycle, wherein ivC2D1 is 60 mg. In some embodiments, the control treatment dosing regimen further comprises one or more additional 21-day dosing cycles. In some embodiments, the control treatment dosing regimen comprises 6, 15, or 23 additional 21-day dosing cycles. In some embodiments, each additional dosing cycle comprises intravenous mosunetuzumab administered on day 1 of the additional dosing cycle, wherein the intravenous mosunetuzumab is about 30 mg (e.g., 30 mg ± 10%). In certain embodiments, each additional dosing cycle comprises intravenous mosunetuzumab administered on day 1 of the additional dosing cycle, wherein the intravenous mosunetuzumab is about 30 mg.

[0050] In some embodiments, the subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. In some embodiments, the subject has relapsed after or is refractory to one or more prior lines of systemic therapy. In some embodiments, the subject has relapsed after or is refractory to two or more prior lines of systemic therapy. In some embodiments, the one or more prior lines of systemic therapy comprise an anti-CD20 antibody, an alkylating agent, a Bruton's tyrosine kinase (BTK) inhibitor, an anthracycline, or a combination thereof.

[0051] In some embodiments, the NHL is follicular lymphoma (FL), marginal zone lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), transformed FL (trFL), high-grade B-cell lymphoma (HGBL), primary mediastinal B-cell lymphoma (PMLBCL), transformed indolent NHL, mantle cell lymphoma (MCL), Richter's transformed, or small lymphocytic lymphoma (SLL). In some embodiments, the NHL is FL, and the FL is grade 1-3b FL or transformed FL. In some embodiments, the FL is grade 1-3a FL, and the subject has relapsed after or is refractory to two or more prior lines of systemic therapy, including an anti-CD20 antibody and an alkylating agent. In some embodiments, the NHL is DLBCL or trFL. In some embodiments, the NHL is DLBCL or trFL, and the subject has relapsed after or is refractory to two or more prior lines of systemic therapy including an anthracycline and an anti-CD20 antibody. In some embodiments, the NHL is Richter transformed. In some embodiments, the NHL is Richter transformed, and the subject has relapsed after or is refractory to one or more prior lines of systemic therapy including an anthracycline and an anti-CD20 antibody. In some embodiments, the anti-CD20 antibody is rituximab. In some embodiments, the NHL is MCL. In some embodiments, the NHL is MCL, and the subject has relapsed after or is refractory to one or more prior lines of systemic therapy including a BTK inhibitor.

[0052] In some embodiments, the method includes administering an additional therapeutic agent. In some embodiments, the additional therapeutic agent includes a corticosteroid, an antihistamine, an antipyretic, or an IL-6R antagonist. In some embodiments, the additional therapeutic agent is a corticosteroid, and the corticosteroid includes prednisone, methylprednisolone, or dexamethasone. In some embodiments, the additional therapeutic agent is an antihistamine, and the antihistamine includes diphenhydramine hydrochloride or an equivalent. In some embodiments, the additional therapeutic agent is an antipyretic, and the antipyretic is acetaminophen. In some embodiments, the additional therapeutic agent is an IL-6R antagonist, and the IL-6R antagonist is tocilizumab.

[0053] In one aspect, the invention features use of mosunetuzumab in combination with lenalidomide to treat follicular lymphoma (FL) in a subject in need of such treatment, wherein mosunetuzumab is administered subcutaneously and lenalidomide is administered orally as a combination treatment, and the administration of the combination treatment to the plurality of subjects results in a non-inferior or improved efficacy response in the plurality of subjects compared to a reference efficacy response, wherein the reference efficacy response is the efficacy response of the plurality of subjects who received a control treatment comprising mosunetuzumab administered intravenously and lenalidomide administered orally, and the efficacy response is complete response rate (CRR), objective response rate (ORR), duration of response (DOR), duration of complete response (DOCR), overall survival (OS), or progression-free survival (PFS).

[0054] In one aspect, the invention features use of lenalidomide in combination with mosunetuzumab to treat follicular lymphoma (FL) in a subject in need thereof, wherein the combination treatment comprises mosunetuzumab administered subcutaneously and lenalidomide administered orally, and the combination treatment is administered to the plurality of subjects, resulting in a non-inferior or improved efficacy response in the plurality of subjects compared to a reference efficacy response, where the reference efficacy response is the efficacy response of the plurality of subjects who received a control treatment comprising mosunetuzumab administered intravenously and lenalidomide administered orally, and the efficacy response is complete response rate (CRR), objective response rate (ORR), duration of response (DOR), duration of complete response (DOCR), overall survival (OS), or progression-free survival (PFS).

[0055] In one aspect, the invention features use of mosunetuzumab and lenalidomide to treat follicular lymphoma (FL) in a subject in need of such treatment, wherein mosunetuzumab is administered subcutaneously and lenalidomide is administered orally as a combination treatment, and the administration of the combination treatment to the plurality of subjects results in a non-inferior or improved efficacy response in the plurality of subjects compared to a reference efficacy response, where the reference efficacy response is the efficacy response of the plurality of subjects who received a control treatment comprising mosunetuzumab administered intravenously and lenalidomide administered orally, and the efficacy response is complete response rate (CRR), objective response rate (ORR), duration of response (DOR), duration of complete response (DOCR), overall survival (OS), or progression-free survival (PFS).

[0056] In one aspect, the invention features use of mosunetuzumab in the manufacture of a medicament for use in combination with lenalidomide to treat follicular lymphoma (FL) in a subject in need of such treatment, wherein mosunetuzumab is administered subcutaneously and lenalidomide is administered orally as a combination treatment, and the administration of the combination treatment to the plurality of subjects results in a non-inferior or improved efficacy response in the plurality of subjects compared to a reference efficacy response, wherein the reference efficacy response is the efficacy response of the plurality of subjects who received a control treatment comprising mosunetuzumab administered intravenously and lenalidomide administered orally, and the efficacy response is complete response rate (CRR), objective response rate (ORR), duration of response (DOR), duration of complete response (DOCR), overall survival (OS), or progression-free survival (PFS).

[0057] In one aspect, the invention features use of lenalidomide in the manufacture of a medicament for use in combination with mosunetuzumab to treat follicular lymphoma (FL) in a subject in need of such treatment, wherein mosunetuzumab is administered subcutaneously and lenalidomide is administered orally as a combination treatment, and the combination treatment is administered to the plurality of subjects, resulting in a non-inferior or improved efficacy response in the plurality of subjects compared to a reference efficacy response, wherein the reference efficacy response is the efficacy response of the plurality of subjects who received a control treatment comprising mosunetuzumab administered intravenously and lenalidomide administered orally, and the efficacy response is complete response rate (CRR), objective response rate (ORR), duration of response (DOR), duration of complete response (DOCR), overall survival (OS), or progression-free survival (PFS).

[0058] In one aspect, the invention features use of mosunetuzumab and lenalidomide in the manufacture of a medicament for treating follicular lymphoma (FL) in a subject in need of such treatment, wherein mosunetuzumab is administered subcutaneously and lenalidomide is administered orally as a combination treatment, and the administration of the combination treatment to the plurality of subjects results in a non-inferior or improved efficacy response in the plurality of subjects compared to a reference efficacy response, where the reference efficacy response is the efficacy response of the plurality of subjects who received a control treatment comprising mosunetuzumab administered intravenously and lenalidomide administered orally, and the efficacy response is complete response rate (CRR), objective response rate (ORR), duration of response (DOR), duration of complete response (DOCR), overall survival (OS), or progression-free survival (PFS).

[0059] In one aspect, the invention features mosunetuzumab for use in combination with lenalidomide for treating follicular lymphoma (FL) in a subject in need thereof, wherein the combination treatment comprises mosunetuzumab administered subcutaneously and lenalidomide administered orally, and the combination treatment is administered to the plurality of subjects, resulting in a non-inferior or improved efficacy response in the plurality of subjects compared to a reference efficacy response, wherein the reference efficacy response is the efficacy response of the plurality of subjects who received a control treatment comprising mosunetuzumab administered intravenously and lenalidomide administered orally, and the efficacy response is complete response rate (CRR), objective response rate (ORR), duration of response (DOR), duration of complete response (DOCR), overall survival (OS), or progression-free survival (PFS).

[0060] In one aspect, the invention features use of lenalidomide in combination with mosunetuzumab to treat follicular lymphoma (FL) in a subject in need of such treatment, wherein mosunetuzumab is administered subcutaneously and lenalidomide is administered orally as a combination treatment, wherein administering the combination treatment to the plurality of subjects results in a non-inferior or improved efficacy response in the plurality of subjects compared to a reference efficacy response, wherein the reference efficacy response is the efficacy response of the plurality of subjects who received a control treatment comprising mosunetuzumab administered intravenously and lenalidomide administered orally, and the efficacy response is complete response rate (CRR), objective response rate (ORR), duration of response (DOR), duration of complete response (DOCR), overall survival (OS), or progression-free survival (PFS).

[0061] In one aspect, the invention features mosunetuzumab and lenalidomide for use in treating follicular lymphoma (FL) in a subject in need of such treatment, wherein mosunetuzumab is administered subcutaneously and lenalidomide is administered orally as a combination treatment, wherein administering the combination treatment to the plurality of subjects results in a non-inferior or improved efficacy response in the plurality of subjects compared to a reference efficacy response, wherein the reference efficacy response is the efficacy response of the plurality of subjects who received a control treatment comprising mosunetuzumab administered intravenously and lenalidomide administered orally, and the efficacy response is complete response rate (CRR), objective response rate (ORR), duration of response (DOR), duration of complete response (DOCR), overall survival (OS), or progression-free survival (PFS).

[0062] In one aspect, the invention features use of mosunetuzumab in combination with lenalidomide to treat follicular lymphoma (FL) in a subject in need of such treatment, wherein mosunetuzumab is administered subcutaneously and lenalidomide is administered orally as a combination treatment, and the combination treatment is administered to a plurality of subjects, resulting in a non-inferior or improved safety response in the plurality of subjects compared to a reference safety response, where the reference safety response is the safety response of a plurality of subjects who received a control treatment comprising mosunetuzumab administered intravenously and lenalidomide administered orally, and the safety response is an incidence of adverse events (AEs), an incidence of cytokine release syndrome (CRS), or an incidence of serious AEs (SAEs).

[0063] In one aspect, the invention features use of lenalidomide in combination with mosunetuzumab to treat follicular lymphoma (FL) in a subject in need thereof, wherein mosunetuzumab is administered subcutaneously and lenalidomide is administered orally as a combination treatment, and the combination treatment is administered to the plurality of subjects, resulting in a non-inferior or improved safety response in the plurality of subjects compared to a reference safety response, where the reference safety response is the safety response of the plurality of subjects who received a control treatment comprising mosunetuzumab administered intravenously and lenalidomide administered orally, and the safety response is an incidence of adverse events (AEs), an incidence of cytokine release syndrome (CRS), or an incidence of serious AEs (SAEs).

[0064] In one aspect, the invention features use of mosunetuzumab and lenalidomide to treat follicular lymphoma (FL) in a subject in need of such treatment, wherein mosunetuzumab is administered subcutaneously and lenalidomide is administered orally as a combination treatment, and the combination treatment is administered to a plurality of subjects, resulting in a non-inferior or improved safety response in the plurality of subjects compared to a reference safety response, where the reference safety response is the safety response of a plurality of subjects who received a control treatment comprising mosunetuzumab administered intravenously and lenalidomide administered orally, and the safety response is an incidence of adverse events (AEs), an incidence of cytokine release syndrome (CRS), or an incidence of serious AEs (SAEs).

[0065] In one aspect, the invention features use of mosunetuzumab in the manufacture of a medicament for use in combination with lenalidomide to treat follicular lymphoma (FL) in a subject in need of such treatment, wherein mosunetuzumab is administered subcutaneously and lenalidomide is administered orally as a combination treatment, and the combination treatment is administered to the plurality of subjects, resulting in a non-inferior or improved safety response in the plurality of subjects compared to a reference safety response, where the reference safety response is the safety response of the plurality of subjects receiving a control treatment comprising mosunetuzumab administered intravenously and lenalidomide administered orally, and the safety response is an incidence of adverse events (AEs), an incidence of cytokine release syndrome (CRS), or an incidence of serious AEs (SAEs).

[0066] In one aspect, the invention features use of lenalidomide in the manufacture of a medicament for use in combination with mosunetuzumab to treat follicular lymphoma (FL) in a subject in need of such treatment, wherein mosunetuzumab is administered subcutaneously and lenalidomide is administered orally as a combination treatment, and the combination treatment is administered to a plurality of subjects, resulting in a non-inferior or improved safety response in the plurality of subjects compared to a reference safety response, where the reference safety response is the safety response of a plurality of subjects receiving a control treatment comprising mosunetuzumab administered intravenously and lenalidomide administered orally, and the safety response is an incidence of adverse events (AEs), an incidence of cytokine release syndrome (CRS), or an incidence of serious AEs (SAEs).

[0067] In one aspect, the invention features use of mosunetuzumab and lenalidomide in the manufacture of a medicament for treating follicular lymphoma (FL) in a subject in need of such treatment, wherein mosunetuzumab is administered subcutaneously and lenalidomide is administered orally as a combination treatment, and the combination treatment is administered to the plurality of subjects, resulting in a non-inferior or improved safety response in the plurality of subjects compared to a reference safety response, where the reference safety response is the safety response of the plurality of subjects who received a control treatment comprising mosunetuzumab administered intravenously and lenalidomide administered orally, and the safety response is an incidence of adverse events (AEs), an incidence of cytokine release syndrome (CRS), or an incidence of serious AEs (SAEs).

[0068] In one aspect, the invention features mosunetuzumab for use in combination with lenalidomide for treating follicular lymphoma (FL) in a subject in need of such treatment, wherein mosunetuzumab is administered subcutaneously and lenalidomide is administered orally as a combination treatment, and the combination treatment is administered to the plurality of subjects, resulting in a non-inferior or improved safety response in the plurality of subjects compared to a reference safety response, wherein the reference safety response is the safety response of the plurality of subjects receiving a control treatment comprising mosunetuzumab administered intravenously and lenalidomide administered orally, and the safety response is an incidence of adverse events (AEs), an incidence of cytokine release syndrome (CRS), or an incidence of serious AEs (SAEs).

[0069] In one aspect, the invention features lenalidomide for use in combination with mosunetuzumab to treat follicular lymphoma (FL) in a subject in need thereof, wherein the combination treatment comprises mosunetuzumab administered subcutaneously and lenalidomide administered orally, and wherein the combination treatment is administered to the plurality of subjects, resulting in a non-inferior or improved safety response in the plurality of subjects compared to a reference safety response, wherein the reference safety response is the safety response of the plurality of subjects receiving a control treatment comprising mosunetuzumab administered intravenously and lenalidomide administered orally, and the safety response is an incidence of adverse events (AEs), an incidence of cytokine release syndrome (CRS), or an incidence of serious AEs (SAEs).

[0070] In one aspect, the invention features mosunetuzumab and lenalidomide for use in treating follicular lymphoma (FL) in a subject in need of such treatment, wherein mosunetuzumab is administered subcutaneously and lenalidomide is administered orally as a combination treatment, and the administration of the combination treatment to the plurality of subjects results in a non-inferior or improved safety response in the plurality of subjects compared to a reference safety response, where the reference safety response is the safety response of the plurality of subjects receiving a control treatment comprising mosunetuzumab administered intravenously and lenalidomide administered orally, and the safety response is an incidence of adverse events (AEs), an incidence of cytokine release syndrome (CRS), or an incidence of serious AEs (SAEs).

[0071] In one aspect, the present invention provides a use of mosunetuzumab in combination with lenalidomide to treat follicular lymphoma (FL) in a subject in need thereof, wherein the combination treatment comprises mosunetuzumab administered subcutaneously and lenalidomide administered orally, and the combination treatment is administered to a plurality of subjects, whereby a non-inferior pharmacokinetic (PK) endpoint is achieved in a plurality of subjects compared to a reference PK endpoint, and the PK endpoint is observed dosing cycle 2 serum trough concentration (scConc トラフCYC2-OBS ) or cumulative area under the concentration-time curve (scAUC) over 0 to 77 days 0~77 ), where the reference PK endpoint is a PK endpoint in subjects receiving a control treatment comprising intravenously administered mosunetuzumab and orally administered lenalidomide according to a dosing regimen comprising an initial 21-day dosing cycle and three 28-day dosing cycles, and the reference PK endpoint is the observed dosing cycle 2 serum trough concentration (ivConc トラフCYC2-OBS ) or cumulative area under the concentration-time curve (ivAUC 0~77 ) and is characterized by its use.

[0072] In one aspect, the present invention provides a use of lenalidomide in combination with mosunetuzumab to treat follicular lymphoma (FL) in a subject in need thereof, wherein the combination treatment comprises mosunetuzumab administered subcutaneously and lenalidomide administered orally, and the combination treatment is administered to a plurality of subjects, resulting in a non-inferiority pharmacokinetic (PK) endpoint for the plurality of subjects compared to a reference PK endpoint, wherein the PK endpoint is observed dosing cycle 2 serum trough concentration (scConc トラフCYC2-OBS ) or cumulative area under the concentration-time curve (scAUC) over 0 to 77 days 0~77 ), where the reference PK endpoint is a PK endpoint in subjects receiving a control treatment comprising intravenously administered mosunetuzumab and orally administered lenalidomide according to a dosing regimen comprising an initial 21-day dosing cycle and three 28-day dosing cycles, and the reference PK endpoint is the observed dosing cycle 2 serum trough concentration (ivConc トラフCYC2-OBS ) or cumulative area under the concentration-time curve (ivAUC 0~77 ) and is characterized by its use.

[0073] In one aspect, the present invention provides a use of mosunetuzumab and lenalidomide for treating follicular lymphoma (FL) in a subject in need thereof, wherein the combination treatment comprises mosunetuzumab administered subcutaneously and lenalidomide administered orally, and the combination treatment is administered to a plurality of subjects, whereby a non-inferior pharmacokinetic (PK) endpoint is achieved in a plurality of subjects compared to a reference PK endpoint, and the PK endpoint is observed dosing cycle 2 serum trough concentration (scConc). トラフCYC2-OBS ) or cumulative area under the concentration-time curve (scAUC) over 0 to 77 days 0~77 ), where the reference PK endpoint is a PK endpoint in subjects receiving a control treatment comprising intravenously administered mosunetuzumab and orally administered lenalidomide according to a dosing regimen comprising an initial 21-day dosing cycle and three 28-day dosing cycles, and the reference PK endpoint is the observed dosing cycle 2 serum trough concentration (ivConc トラフCYC2-OBS) or cumulative area under the concentration-time curve (ivAUC 0~77 ) and is characterized by its use.

[0074] In one aspect, the invention provides a use of mosunetuzumab in the manufacture of a medicament for use in combination with lenalidomide for treating follicular lymphoma (FL) in a subject in need thereof, wherein the combination treatment comprises mosunetuzumab administered subcutaneously and lenalidomide administered orally, and wherein administering the combination treatment to a plurality of subjects results in a non-inferiority pharmacokinetic (PK) endpoint compared to a reference PK endpoint, wherein the PK endpoint is observed dosing cycle 2 serum trough concentration (scConc トラフCYC2-OBS ) or cumulative area under the concentration-time curve (scAUC) over 0 to 77 days 0~77 ), where the reference PK endpoint is a PK endpoint in subjects receiving a control treatment comprising intravenously administered mosunetuzumab and orally administered lenalidomide according to a dosing regimen comprising an initial 21-day dosing cycle and three 28-day dosing cycles, and the reference PK endpoint is the observed dosing cycle 2 serum trough concentration (ivConc トラフCYC2-OBS ) or cumulative area under the concentration-time curve (ivAUC 0~77 ) and is characterized by its use.

[0075] In one aspect, the invention provides a use of lenalidomide in the manufacture of a medicament for use in combination with mosunetuzumab for treating follicular lymphoma (FL) in a subject in need thereof, wherein the combination treatment comprises mosunetuzumab administered subcutaneously and lenalidomide administered orally, and the combination treatment is administered to a plurality of subjects, whereby a non-inferiority pharmacokinetic (PK) endpoint is achieved in the plurality of subjects compared to a reference PK endpoint, and the PK endpoint is observed dosing cycle 2 serum trough concentration (scConc トラフCYC2-OBS ) or cumulative area under the concentration-time curve (scAUC) over 0 to 77 days 0~77), where the reference PK endpoint is a PK endpoint in subjects receiving a control treatment comprising intravenously administered mosunetuzumab and orally administered lenalidomide according to a dosing regimen comprising an initial 21-day dosing cycle and three 28-day dosing cycles, and the reference PK endpoint is the observed dosing cycle 2 serum trough concentration (ivConc トラフCYC2-OBS ) or cumulative area under the concentration-time curve (ivAUC 0~77 ) and is characterized by its use.

[0076] In one aspect, the invention provides a use of mosunetuzumab and lenalidomide in the manufacture of a medicament for treating follicular lymphoma (FL) in a subject in need thereof, wherein the combination treatment comprises mosunetuzumab administered subcutaneously and lenalidomide administered orally, and the combination treatment is administered to a plurality of subjects, whereby a non-inferior pharmacokinetic (PK) endpoint is achieved in the plurality of subjects compared to a reference PK endpoint, and the PK endpoint is observed dosing cycle 2 serum trough concentration (scConc). トラフCYC2-OBS ) or cumulative area under the concentration-time curve (scAUC) over 0 to 77 days 0~77 ), where the reference PK endpoint is a PK endpoint in subjects receiving a control treatment comprising intravenously administered mosunetuzumab and orally administered lenalidomide according to a dosing regimen comprising an initial 21-day dosing cycle and three 28-day dosing cycles, and the reference PK endpoint is the observed dosing cycle 2 serum trough concentration (ivConc トラフCYC2-OBS ) or cumulative area under the concentration-time curve (ivAUC 0~77 ) and is characterized by its use.

[0077] In one aspect, the present invention provides mosunetuzumab for use in combination with lenalidomide for treating follicular lymphoma (FL) in a subject in need thereof, wherein the combination treatment comprises mosunetuzumab administered subcutaneously and lenalidomide administered orally, and the combination treatment is administered to a plurality of subjects to achieve a non-inferiority pharmacokinetic (PK) endpoint compared to a reference PK endpoint, wherein the PK endpoint is observed dosing cycle 2 serum trough concentration (scConc). トラフCYC2-OBS ) or cumulative area under the concentration-time curve (scAUC) over 0 to 77 days 0~77 ), where the reference PK endpoint is a PK endpoint in subjects receiving a control treatment comprising intravenously administered mosunetuzumab and orally administered lenalidomide according to a dosing regimen comprising an initial 21-day dosing cycle and three 28-day dosing cycles, and the reference PK endpoint is the observed dosing cycle 2 serum trough concentration (ivConc トラフCYC2-OBS ) or cumulative area under the concentration-time curve (ivAUC 0~77 ) and is characterized by mosunetuzumab.

[0078] In one aspect, the invention provides lenalidomide for use in combination with mosunetuzumab for treating follicular lymphoma (FL) in a subject in need thereof, wherein the combination treatment comprises mosunetuzumab administered subcutaneously and lenalidomide administered orally, and wherein administering the combination treatment to the plurality of subjects results in a non-inferiority pharmacokinetic (PK) endpoint compared to a reference PK endpoint, and the PK endpoint is observed dosing cycle 2 serum trough concentration (scConc トラフCYC2-OBS ) or cumulative area under the concentration-time curve (scAUC) over 0 to 77 days 0~77 ), where the reference PK endpoint is a PK endpoint in subjects receiving a control treatment comprising intravenously administered mosunetuzumab and orally administered lenalidomide according to a dosing regimen comprising an initial 21-day dosing cycle and three 28-day dosing cycles, and the reference PK endpoint is the observed dosing cycle 2 serum trough concentration (ivConc トラフCYC2-OBS) or cumulative area under the concentration-time curve (ivAUC 0~77 ) and is characterized by lenalidomide.

[0079] In one aspect, the present invention provides mosunetuzumab and lenalidomide for use in treating follicular lymphoma (FL) in a subject in need thereof, wherein the combination treatment comprises mosunetuzumab administered subcutaneously and lenalidomide administered orally, and wherein administering the combination treatment to the plurality of subjects results in a non-inferiority pharmacokinetic (PK) endpoint compared to a reference PK endpoint, and the PK endpoint is observed dosing cycle 2 serum trough concentration (scConc). トラフCYC2-OBS ) or cumulative area under the concentration-time curve (scAUC) over 0 to 77 days 0~77 ), where the reference PK endpoint is a PK endpoint in subjects receiving a control treatment comprising intravenously administered mosunetuzumab and orally administered lenalidomide according to a dosing regimen comprising an initial 21-day dosing cycle and three 28-day dosing cycles, and the reference PK endpoint is the observed dosing cycle 2 serum trough concentration (ivConc トラフCYC2-OBS ) or cumulative area under the concentration-time curve (ivAUC 0~77 ), and features mosunetuzumab and lenalidomide.

[0080] In one aspect, the present invention provides a use of mosunetuzumab in combination with lenalidomide for treating follicular lymphoma (FL) in a subject in need thereof, wherein mosunetuzumab is administered subcutaneously and lenalidomide is administered orally as combination treatment, according to a dosing regimen comprising a first dosing cycle and a second dosing cycle, wherein the first dosing cycle is a 21-day dosing cycle and the second dosing cycle is a 28-day dosing cycle; 10 additional 28-day dosing cycles; and 1 to 9 subcutaneous maintenance doses of mosunetuzumab; (a) a first dosing cycle comprises a first subcutaneous administration (scC1D1), a second subcutaneous administration (scC1D2), and a third subcutaneous administration (scC1D3) of mosunetuzumab administered on days 1, 8, and 15, respectively, of the first dosing cycle, wherein scC1D1 is about 5 mg, scC1D2 is about 45 mg, and scC1D3 is about 45 mg; (b) the second dosing cycle is (i) a first subcutaneous administration (scC2D1) of mosunetuzumab administered on day 1 of a second dosing cycle, wherein the scC2D1 is about 45 mg; and (ii) 21 oral doses of lenalidomide administered on days 1-21 of a second dosing cycle, wherein each oral dose of lenalidomide is about 20 mg. Including, (c) 10 additional dosing cycles, each (i) a first subcutaneous administration (scC3D1 through scC12D1) of mosunetuzumab administered on day 1 of each additional dosing cycle, wherein each of scC3D1 through scC12D1 is about 45 mg; and (ii) 21 oral doses of lenalidomide administered on days 1-21 of each additional dosing cycle, wherein each oral dose of lenalidomide is about 20 mg. The present invention is characterized by the use of

[0081] In one aspect, the present invention provides a use of lenalidomide in combination with mosunetuzumab for treating follicular lymphoma (FL) in a subject in need thereof, wherein the combination treatment comprises a dosing regimen comprising a first dosing cycle and a second dosing cycle, wherein mosunetuzumab is administered subcutaneously and lenalidomide is administered orally, wherein the first dosing cycle is a 21-day dosing cycle and the second dosing cycle is a 28-day dosing cycle; 10 additional 28-day dosing cycles; and 1 to 9 subcutaneous maintenance doses of mosunetuzumab; (a) a first dosing cycle comprises a first subcutaneous administration (scC1D1), a second subcutaneous administration (scC1D2), and a third subcutaneous administration (scC1D3) of mosunetuzumab administered on days 1, 8, and 15, respectively, of the first dosing cycle, wherein scC1D1 is about 5 mg, scC1D2 is about 45 mg, and scC1D3 is about 45 mg; (b) the second dosing cycle is (i) a first subcutaneous administration (scC2D1) of mosunetuzumab administered on day 1 of a second dosing cycle, wherein the scC2D1 is about 45 mg; and (ii) 21 oral doses of lenalidomide administered on days 1-21 of a second dosing cycle, wherein each oral dose of lenalidomide is about 20 mg. Including, (c) 10 additional dosing cycles, each (i) a first subcutaneous administration (scC3D1 through scC12D1) of mosunetuzumab administered on day 1 of each additional dosing cycle, wherein each of scC3D1 through scC12D1 is about 45 mg; and (ii) 21 oral doses of lenalidomide administered on days 1-21 of each additional dosing cycle, wherein each oral dose of lenalidomide is about 20 mg. The present invention is characterized by the use of

[0082] In one aspect, the present invention provides a use of mosunetuzumab and lenalidomide for treating follicular lymphoma (FL) in a subject in need thereof, wherein mosunetuzumab is administered subcutaneously and lenalidomide is administered orally as combination treatment, according to a dosing regimen comprising a first dosing cycle and a second dosing cycle, wherein the first dosing cycle is a 21-day dosing cycle and the second dosing cycle is a 28-day dosing cycle; 10 additional 28-day dosing cycles; and 1 to 9 subcutaneous maintenance doses of mosunetuzumab; (a) a first dosing cycle comprises a first subcutaneous administration (scC1D1), a second subcutaneous administration (scC1D2), and a third subcutaneous administration (scC1D3) of mosunetuzumab administered on days 1, 8, and 15, respectively, of the first dosing cycle, wherein scC1D1 is about 5 mg, scC1D2 is about 45 mg, and scC1D3 is about 45 mg; (b) the second dosing cycle is (i) a first subcutaneous administration (scC2D1) of mosunetuzumab administered on day 1 of a second dosing cycle, wherein the scC2D1 is about 45 mg; and (ii) 21 oral doses of lenalidomide administered on days 1-21 of a second dosing cycle, wherein each oral dose of lenalidomide is about 20 mg. Including, (c) 10 additional dosing cycles, each (i) a first subcutaneous administration (scC3D1 through scC12D1) of mosunetuzumab administered on day 1 of each additional dosing cycle, wherein each of scC3D1 through scC12D1 is about 45 mg; and (ii) 21 oral doses of lenalidomide administered on days 1-21 of each additional dosing cycle, wherein each oral dose of lenalidomide is about 20 mg. The present invention is characterized by the use of

[0083] In one aspect, the invention provides use of mosunetuzumab in the manufacture of a medicament for use in combination with lenalidomide for treating follicular lymphoma (FL) in a subject in need thereof, wherein mosunetuzumab is administered subcutaneously and lenalidomide is administered orally as the combination treatment, according to a dosing regimen comprising a first dosing cycle and a second dosing cycle, wherein the first dosing cycle is a 21-day dosing cycle and the second dosing cycle is a 28-day dosing cycle; 10 additional 28-day dosing cycles; and 1 to 9 subcutaneous maintenance doses of mosunetuzumab; (a) a first dosing cycle comprises a first subcutaneous administration (scC1D1), a second subcutaneous administration (scC1D2), and a third subcutaneous administration (scC1D3) of mosunetuzumab administered on days 1, 8, and 15, respectively, of the first dosing cycle, wherein scC1D1 is about 5 mg, scC1D2 is about 45 mg, and scC1D3 is about 45 mg; (b) the second dosing cycle is (i) a first subcutaneous administration (scC2D1) of mosunetuzumab administered on day 1 of a second dosing cycle, wherein the scC2D1 is about 45 mg; and (ii) 21 oral doses of lenalidomide administered on days 1-21 of a second dosing cycle, wherein each oral dose of lenalidomide is about 20 mg. Including, (c) 10 additional dosing cycles, each (i) a first subcutaneous administration (scC3D1 through scC12D1) of mosunetuzumab administered on day 1 of each additional dosing cycle, wherein each of scC3D1 through scC12D1 is about 45 mg; and (ii) 21 oral doses of lenalidomide administered on days 1-21 of each additional dosing cycle, wherein each oral dose of lenalidomide is about 20 mg. The present invention is characterized by the use of

[0084] In one aspect, the invention provides a use of lenalidomide in the manufacture of a medicament for use in combination with mosunetuzumab for treating follicular lymphoma (FL) in a subject in need thereof, wherein mosunetuzumab is administered subcutaneously and lenalidomide is administered orally as the combination treatment, according to a dosing regimen comprising a first dosing cycle and a second dosing cycle, wherein the first dosing cycle is a 21-day dosing cycle and the second dosing cycle is a 28-day dosing cycle; 10 additional 28-day dosing cycles; and 1 to 9 subcutaneous maintenance doses of mosunetuzumab; (a) a first dosing cycle comprises a first subcutaneous administration (scC1D1), a second subcutaneous administration (scC1D2), and a third subcutaneous administration (scC1D3) of mosunetuzumab administered on days 1, 8, and 15, respectively, of the first dosing cycle, wherein scC1D1 is about 5 mg, scC1D2 is about 45 mg, and scC1D3 is about 45 mg; (b) the second dosing cycle is (i) a first subcutaneous administration (scC2D1) of mosunetuzumab administered on day 1 of a second dosing cycle, wherein the scC2D1 is about 45 mg; and (ii) 21 oral doses of lenalidomide administered on days 1-21 of a second dosing cycle, wherein each oral dose of lenalidomide is about 20 mg. Including, (c) 10 additional dosing cycles, each (i) a first subcutaneous administration (scC3D1 through scC12D1) of mosunetuzumab administered on day 1 of each additional dosing cycle, wherein each of scC3D1 through scC12D1 is about 45 mg; and (ii) 21 oral doses of lenalidomide administered on days 1-21 of each additional dosing cycle, wherein each oral dose of lenalidomide is about 20 mg. The present invention is characterized by the use of

[0085] In one aspect, the invention provides a use of mosunetuzumab and lenalidomide in the manufacture of a medicament for treating follicular lymphoma (FL) in a subject in need thereof, wherein mosunetuzumab is administered subcutaneously and lenalidomide is administered orally as combination treatment, according to a dosing regimen comprising a first dosing cycle and a second dosing cycle, wherein the first dosing cycle is a 21-day dosing cycle and the second dosing cycle is a 28-day dosing cycle; 10 additional 28-day dosing cycles; and 1 to 9 subcutaneous maintenance doses of mosunetuzumab; (a) a first dosing cycle comprises a first subcutaneous administration (scC1D1), a second subcutaneous administration (scC1D2), and a third subcutaneous administration (scC1D3) of mosunetuzumab administered on days 1, 8, and 15, respectively, of the first dosing cycle, wherein scC1D1 is about 5 mg, scC1D2 is about 45 mg, and scC1D3 is about 45 mg; (b) the second dosing cycle is (i) a first subcutaneous administration (scC2D1) of mosunetuzumab administered on day 1 of a second dosing cycle, wherein the scC2D1 is about 45 mg; and (ii) 21 oral doses of lenalidomide administered on days 1-21 of a second dosing cycle, wherein each oral dose of lenalidomide is about 20 mg. Including, (c) 10 additional dosing cycles, each (i) a first subcutaneous administration (scC3D1 through scC12D1) of mosunetuzumab administered on day 1 of each additional dosing cycle, wherein each of scC3D1 through scC12D1 is about 45 mg; and (ii) 21 oral doses of lenalidomide administered on days 1-21 of each additional dosing cycle, wherein each oral dose of lenalidomide is about 20 mg. The present invention is characterized by the use of

[0086] In one aspect, the invention provides mosunetuzumab for use in combination with lenalidomide for treating follicular lymphoma (FL) in a subject in need thereof, wherein the combination treatment comprises mosunetuzumab administered subcutaneously and lenalidomide administered orally, according to a dosing regimen comprising a first dosing cycle and a second dosing cycle, wherein the first dosing cycle is a 21-day dosing cycle and the second dosing cycle is a 28-day dosing cycle; 10 additional 28-day dosing cycles; and 1 to 9 subcutaneous maintenance doses of mosunetuzumab; (a) a first dosing cycle comprises a first subcutaneous administration (scC1D1), a second subcutaneous administration (scC1D2), and a third subcutaneous administration (scC1D3) of mosunetuzumab administered on days 1, 8, and 15, respectively, of the first dosing cycle, wherein scC1D1 is about 5 mg, scC1D2 is about 45 mg, and scC1D3 is about 45 mg; (b) the second dosing cycle is (i) a first subcutaneous administration (scC2D1) of mosunetuzumab administered on day 1 of a second dosing cycle, wherein the scC2D1 is about 45 mg; and (ii) 21 oral doses of lenalidomide administered on days 1-21 of a second dosing cycle, wherein each oral dose of lenalidomide is about 20 mg. Including, (c) 10 additional dosing cycles, each (i) a first subcutaneous administration (scC3D1 through scC12D1) of mosunetuzumab administered on day 1 of each additional dosing cycle, wherein each of scC3D1 through scC12D1 is about 45 mg; and (ii) 21 oral doses of lenalidomide administered on days 1-21 of each additional dosing cycle, wherein each oral dose of lenalidomide is about 20 mg. The present invention features mosunetuzumab, including

[0087] In one aspect, the invention provides lenalidomide for use in combination with mosunetuzumab for treating follicular lymphoma (FL) in a subject in need thereof, wherein the combination treatment comprises a dosing regimen comprising a first dosing cycle and a second dosing cycle, wherein mosunetuzumab is administered subcutaneously and lenalidomide is administered orally, wherein the first dosing cycle is a 21-day dosing cycle and the second dosing cycle is a 28-day dosing cycle; 10 additional 28-day dosing cycles; and 1 to 9 subcutaneous maintenance doses of mosunetuzumab; (a) a first dosing cycle comprises a first subcutaneous administration (scC1D1), a second subcutaneous administration (scC1D2), and a third subcutaneous administration (scC1D3) of mosunetuzumab administered on days 1, 8, and 15, respectively, of the first dosing cycle, wherein scC1D1 is about 5 mg, scC1D2 is about 45 mg, and scC1D3 is about 45 mg; (b) the second dosing cycle is (i) a first subcutaneous administration (scC2D1) of mosunetuzumab administered on day 1 of a second dosing cycle, wherein the scC2D1 is about 45 mg; and (ii) 21 oral doses of lenalidomide administered on days 1-21 of a second dosing cycle, wherein each oral dose of lenalidomide is about 20 mg. Including, (c) 10 additional dosing cycles, each (i) a first subcutaneous administration (scC3D1 through scC12D1) of mosunetuzumab administered on day 1 of each additional dosing cycle, wherein each of scC3D1 through scC12D1 is about 45 mg; and (ii) 21 oral doses of lenalidomide administered on days 1-21 of each additional dosing cycle, wherein each oral dose of lenalidomide is about 20 mg. The present invention features lenalidomide, comprising:

[0088] In one aspect, the present invention provides mosunetuzumab and lenalidomide for use in treating follicular lymphoma (FL) in a subject in need thereof, wherein mosunetuzumab is administered subcutaneously and lenalidomide is administered orally as combination treatment, according to a dosing regimen comprising a first dosing cycle and a second dosing cycle, wherein the first dosing cycle is a 21-day dosing cycle and the second dosing cycle is a 28-day dosing cycle; 10 additional 28-day dosing cycles; and 1 to 9 subcutaneous maintenance doses of mosunetuzumab; (a) a first dosing cycle comprises a first subcutaneous administration (scC1D1), a second subcutaneous administration (scC1D2), and a third subcutaneous administration (scC1D3) of mosunetuzumab administered on days 1, 8, and 15, respectively, of the first dosing cycle, wherein scC1D1 is about 5 mg, scC1D2 is about 45 mg, and scC1D3 is about 45 mg; (b) the second dosing cycle is (i) a first subcutaneous administration (scC2D1) of mosunetuzumab administered on day 1 of a second dosing cycle, wherein the scC2D1 is about 45 mg; and (ii) 21 oral doses of lenalidomide administered on days 1-21 of a second dosing cycle, wherein each oral dose of lenalidomide is about 20 mg. Including, (c) 10 additional dosing cycles, each (i) a first subcutaneous administration (scC3D1 through scC12D1) of mosunetuzumab administered on day 1 of each additional dosing cycle, wherein each of scC3D1 through scC12D1 is about 45 mg; and (ii) 21 oral doses of lenalidomide administered on days 1-21 of each additional dosing cycle, wherein each oral dose of lenalidomide is about 20 mg. The present invention features mosunetuzumab and lenalidomide, including:

[0089] In one aspect, the invention features use of mosunetuzumab to treat non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL) in a subject in need of such treatment, wherein mosunetuzumab is administered subcutaneously as a treatment, and the administration of the treatment to a plurality of subjects results in a non-inferior or improved efficacy response in the plurality of subjects compared to a reference efficacy response, where the reference efficacy response is the efficacy response of a plurality of subjects who received a control treatment comprising mosunetuzumab administered intravenously, and the efficacy response is complete response rate (CRR), objective response rate (ORR), duration of response (DOR), duration of complete response (DOCR), progression-free survival (PFS), or overall survival (OS).

[0090] In one aspect, the invention features the use of mosunetuzumab in the manufacture of a medicament for treating non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL) in a subject in need of such treatment, wherein mosunetuzumab is administered subcutaneously as a treatment, and the administration of the treatment to the plurality of subjects results in a non-inferior or improved efficacy response in the plurality of subjects compared to a reference efficacy response, where the reference efficacy response is the efficacy response of the plurality of subjects who received a control treatment comprising mosunetuzumab administered intravenously, and the efficacy response is complete response rate (CRR), objective response rate (ORR), duration of response (DOR), duration of complete response (DOCR), progression-free survival (PFS), or overall survival (OS).

[0091] In one aspect, the invention features mosunetuzumab for use in treating non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL) in a subject in need thereof, wherein the mosunetuzumab is administered subcutaneously as a treatment, and the administration of the treatment to a plurality of subjects results in a non-inferior or improved efficacy response in the plurality of subjects compared to a reference efficacy response, wherein the reference efficacy response is the efficacy response of a plurality of subjects who received a control treatment comprising mosunetuzumab administered intravenously, and the efficacy response is complete response rate (CRR), objective response rate (ORR), duration of response (DOR), duration of complete response (DOCR), progression-free survival (PFS), or overall survival (OS).

[0092] In one aspect, the invention features use of mosunetuzumab to treat non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL) in a subject in need of such treatment, wherein mosunetuzumab is administered subcutaneously as a treatment, and the administration of the treatment to a plurality of subjects results in a non-inferior or improved safety response in the plurality of subjects compared to a reference safety response, where the reference safety response is the safety response of a plurality of subjects who received a control treatment comprising mosunetuzumab administered intravenously, and the safety response is the incidence of adverse events (AEs), the incidence of cytokine release syndrome (CRS), or the incidence of serious AEs (SAEs).

[0093] In one aspect, the invention features use of mosunetuzumab in the manufacture of a medicament for treating non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL) in a subject in need of such treatment, wherein mosunetuzumab is administered subcutaneously as a treatment, and the administration of the treatment to the plurality of subjects results in a non-inferior or improved safety response in the plurality of subjects compared to a reference safety response, where the reference safety response is the safety response of the plurality of subjects who received a control treatment comprising mosunetuzumab administered intravenously, and the safety response is the incidence of adverse events (AEs), the incidence of cytokine release syndrome (CRS), or the incidence of serious AEs (SAEs).

[0094] In one aspect, the invention features mosunetuzumab for treating non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL) in a subject in need of such treatment, wherein the mosunetuzumab is administered subcutaneously as a treatment, and the administration of the treatment to the plurality of subjects results in a non-inferior or improved safety response in the plurality of subjects compared to a reference safety response, wherein the reference safety response is the safety response of the plurality of subjects who received a control treatment comprising mosunetuzumab administered intravenously, and the safety response is an incidence of adverse events (AEs), an incidence of cytokine release syndrome (CRS), or an incidence of serious AEs (SAEs).

[0095] In one aspect, the present invention provides a use of mosunetuzumab to treat non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL) in a subject in need thereof, wherein the treatment comprises mosunetuzumab administered subcutaneously according to a dosing regimen comprising four 21-day dosing cycles, and the administration of the combination treatment to the plurality of subjects results in non-inferiority or improved pharmacokinetic (PK) endpoints compared to a reference PK endpoint, wherein the PK endpoint is observed dosing cycle 3 serum trough concentration (scConc トラフCYC3-OBS) or cumulative area under the concentration-time curve (scAUC) over 0 to 84 days 0~84 ), where the reference PK endpoint is a PK endpoint in multiple subjects receiving a control treatment containing intravenously administered mosunetuzumab according to a dosing regimen comprising four 21-day dosing cycles, and the reference PK endpoint is the observed dosing cycle 3 serum trough concentration (ivConc トラフCYC3-OBS ) or cumulative area under the concentration-time curve (ivAUC 0~84 ) and is characterized by its use.

[0096] In one aspect, the invention provides a use of mosunetuzumab in the manufacture of a medicament for treating non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL) in a subject in need thereof, wherein the treatment comprises mosunetuzumab administered subcutaneously according to a dosing regimen comprising four 21-day dosing cycles, and the combination treatment is administered to the plurality of subjects, resulting in non-inferiority or improved pharmacokinetic (PK) endpoints compared to a reference PK endpoint, wherein the PK endpoint is observed dosing cycle 3 serum trough concentration (scConc). トラフCYC3-OBS ) or cumulative area under the concentration-time curve (scAUC) over 0 to 84 days 0~84 ), where the reference PK endpoint is a PK endpoint in multiple subjects receiving a control treatment containing intravenously administered mosunetuzumab according to a dosing regimen comprising four 21-day dosing cycles, and the reference PK endpoint is the observed dosing cycle 3 serum trough concentration (ivConc トラフCYC3-OBS ) or cumulative area under the concentration-time curve (ivAUC 0~84 ) and is characterized by its use.

[0097] In one aspect, the present invention provides mosunetuzumab for the treatment of non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL) in a subject in need thereof, wherein the treatment comprises mosunetuzumab administered subcutaneously according to a dosing regimen comprising four 21-day dosing cycles, and the combination treatment is administered to the plurality of subjects, resulting in a non-inferiority or improved pharmacokinetic (PK) endpoint compared to a reference PK endpoint in the plurality of subjects, wherein the PK endpoint is observed dosing cycle 3 serum trough concentration (scConc トラフCYC3-OBS ) or cumulative area under the concentration-time curve (scAUC) over 0 to 84 days 0~84 ), where the reference PK endpoint is a PK endpoint in multiple subjects receiving a control treatment containing intravenously administered mosunetuzumab according to a dosing regimen comprising four 21-day dosing cycles, and the reference PK endpoint is the observed dosing cycle 3 serum trough concentration (ivConc トラフCYC3-OBS ) or cumulative area under the concentration-time curve (ivAUC 0~84 ) and is characterized by mosunetuzumab.

[0098] In some embodiments, administering a combination treatment comprising subcutaneously administered mosunetuzumab and orally administered lenalidomide to subjects with FL results in an ORR of about 81% to about 99% (e.g., 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) in the subjects. In some embodiments, the ORR is about 90%. In some embodiments, administering the combination treatment to a plurality of subjects with FL results in a CRR of about 79% to about 97% (e.g., 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, or 97%) in the plurality of subjects. In some embodiments, the CRR is about 88%. In some embodiments, administering the combination treatment to a plurality of subjects with FL results in a 12-month event-free rate of DOR of about 86% to about 100% (e.g., 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) in the plurality of subjects. In some embodiments, the 12-month event-free rate of DOR is about 94%. In some embodiments, administering the combination treatment to subjects with FL results in a 12-month event-free rate of DOCR of about 86% to about 100% (e.g., 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) in the subjects. In some embodiments, the 12-month event-free rate of DOCR is about 94%. In some embodiments, administering the combination treatment to subjects with FL results in a 12-month event-free PFS rate of about 76% to about 98% (e.g., 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, or 98%) in the subjects. In some embodiments, the 12-month event-free PFS rate is about 87%.In some embodiments, administering the combination treatment to subjects with FL results in a 12-month event-free rate of OS of about 92% to about 100% (e.g., 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) in the subjects. In some embodiments, the 12-month event-free rate of OS is about 97%. In some embodiments, the FL is previously untreated (1L) FL.

[0099] In some embodiments, administering a treatment comprising subcutaneous mosunetuzumab to subjects with R / R FL results in an ORR of about 66% to about 85% (e.g., 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, or 85%). In some embodiments, the ORR is about 77%. In some embodiments, administering treatment to subjects with R / R FL results in a CRR of about 51% to about 72% (e.g., 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, or 72%) in the subjects. In some embodiments, the CRR is about 62%. In some embodiments, administering the treatment to a plurality of subjects with R / R FL results in an 18-month event-free rate of DOCR of about 57% to about 83% (e.g., 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, or 83%) in the plurality of subjects. In some embodiments, the 18-month event-free rate of DOCR is about 70%. In some embodiments, administering the treatment to a plurality of subjects with R / R FL results in a median DOCR of at least about 20 months (e.g., 20, 24, 28, 32, 36, 40, 44, 48, 60, 72 months or longer) in the plurality of subjects. In some embodiments, the median DOCR is about 35 months. In some embodiments, administering treatment to a plurality of subjects with R / R FL results in an 18-month event-free PFS rate of about 46% to about 68% (e.g., 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, or 68%) in the plurality of subjects. In some embodiments, the 18-month event-free PFS rate is about 57%.In some embodiments, administering treatment to a plurality of subjects with R / R FL results in a median PFS of at least 14 months (e.g., 14, 18, 22, 24, 28, 30, 34, 38, 42 months or longer) in the plurality of subjects. In some embodiments, the median PFS is about 24 months.

[0100] In some embodiments, administering a treatment comprising subcutaneous mosunetuzumab to multiple subjects with 1L FL results in an ORR of about 76% to about 96% (e.g., 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, or 96%). In some embodiments, the ORR is about 87%. In some embodiments, administering a treatment to multiple subjects with 1L FL results in a CRR of about 55% to about 67% (e.g., 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, or 67%) in the multiple subjects. In some embodiments, the CRR is about 61%. In some embodiments, administering the treatment to a plurality of subjects with 1L FL results in a 12-month event-free rate of PFS of about 73% to about 90% (e.g., 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, or 90%) in the plurality of subjects. In some embodiments, the 12-month event-free rate of PFS is about 83%. In some embodiments, administering the treatment to a plurality of subjects with 1L FL results in a median time to response (TTR) of about 1 month to about 6 months (e.g., about 1, 2, 3, 4, 5, or 6 months) in the plurality of subjects who respond. In some embodiments, the median TTR is about 3 months. In some embodiments, a plurality of subjects have high tumor burden according to the Groupe d'Etude des Lymphomes Folliculaires (GELF) criteria.

[0101] In some embodiments, administering a treatment comprising subcutaneous mosunetuzumab to subjects with 1L MZL results in an ORR of about 58% to about 88% (e.g., 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, or 88%). In some embodiments, the ORR is about 75%. In some embodiments, administering the treatment to a plurality of subjects with 1L MZL results in a CRR of about 44% to about 77% (e.g., 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, or 77%) in the plurality of subjects. In some embodiments, the CRR is about 61%. In some embodiments, administering the treatment to a plurality of subjects with 1L MZL results in a median TTR of about 2 months to about 6 months (e.g., about 2, 3, 4, 5, or 6 months) in the plurality of responding subjects. In some embodiments, the median TTR is about 3 months. [Brief explanation of the drawings]

[0102] [Figure 1] Figure 1 is a schematic diagram showing the design of the dose escalation portion of the GO29781 study in Example 1. Initially, mosunetuzumab is given as a single, unfractionated intravenous (IV) dose on day 1 of each cycle (Group A). ​​Cycle 1 dosing is then altered to stop dose escalation for Group A and perform mosunetuzumab dose escalation as follows: Group B: mosunetuzumab dose escalation utilizing a cycle 1 step-up IV administration scheme; Group D: mosunetuzumab dose escalation utilizing a cycle 1 unfractionated subcutaneous (SC) dosing scheme; Group F: mosunetuzumab dose escalation utilizing a cycle 1 step-up SC dosing scheme. C = cycle; D = day; DL = dose level; MAD = maximum assessed dose. [Figure 2]Figure 2 is a schematic diagram illustrating the design of the non-Hodgkin's lymphoma (NHL) expansion cohort and chronic lymphocytic leukemia (CLL) dose escalation / expansion cohort for the GO29781 study. DLBCL = diffuse large B-cell lymphoma; FL = follicular lymphoma; MCL = mantle cell lymphoma; NHL = non-Hodgkin's lymphoma; RP2D = recommended phase II dose; R / R = relapsed / refractory; trFL = transformed follicular lymphoma. a Multiple expansion cohorts based on dose escalation of arms A, B, D, and F may be tested. b Expansion cohorts in R / R DLBCL / trFL will enroll a maximum of approximately 80 patients, except for expansion cohorts based on the arm B RP2D, which will enroll a maximum of approximately 20 patients. c Expansion cohorts in R / R FL will enroll a maximum of approximately 80 patients, except for expansion cohorts based on the arm B RP2D, which will enroll a maximum of approximately 20 patients. Expansion cohorts based on dB group dose escalation only will be studied. e Dose escalation was performed as for NHL (see Figure 1). f Multiple expansion cohorts based on dose escalation of groups B, D, and F may be studied. [Figure 3] FIG. 3 is a schematic diagram showing the evaluation window in Arm B of the GO29781 study. [Figure 4] Figure 4 is a schematic diagram showing the duration of initial study treatment and options for retreatment or continuation study treatment in the GO29781 study. CR = complete response; PD = progressive disease; PR = partial response; SD = stable disease. a Additional rounds of retreatment are possible according to the treatment trajectory for initial treatment. b Scans should be scheduled to avoid / minimize any dose delays between cycle 8 and cycle 9 whenever possible. [Figure 5] 5 is a schematic diagram of the dosing regimen described in Example 2 for the dosing regimen of IV mosunetuzumab and lenalidomide combination therapy. Mosunetuzumab is administered subcutaneously by infusion and lenalidomide is administered orally. Len = lenalidomide; Cycle = dosing cycle. [Figure 6]6 is a schematic diagram of the dosing regimen described in Example 2 for SC mosunetuzumab and lenalidomide combination therapy. Mosunetuzumab is administered subcutaneously by injection, and lenalidomide is administered orally. Len = lenalidomide; Cycle = dosing cycle. [Figure 7] FIG. 7 is a graph and accompanying statistical analysis of duration of response results comparing patients in the B11 (mosunetuzumab IV) and F2 (mosunetuzumab SC) cohorts. [Figure 8] FIG. 8 is a graph and accompanying statistical analysis of duration of complete response outcomes comparing patients in the B11 (mosunetuzumab IV) and F2 (mosunetuzumab SC) cohorts. [Figure 9] FIG. 9 is a graph and accompanying statistical analysis of progression-free survival results comparing patients in the B11 (mosunetteuzumab IV) and F2 (mosunetteuzumab SC) cohorts. [Figure 10] FIG. 10 is a graph and accompanying statistical analysis of overall survival results comparing patients in the B11 (mosunetteuzumab IV) and F2 (mosunetteuzumab SC) cohorts. [Figure 11] Figure 11 summarizes the demographics and baseline characteristics of Arm A (IV mosun+len) and Arm B (SC mosun+len) patients. [Figure 12] Figure 12 summarizes the previously administered treatments for Arm A (IV mosun+len) and Arm B (SC mosun+len) patients. [Figure 13] Figure 13 summarizes the baseline disease characteristics and FL history of Arm A (IV mosun+len) and Arm B (SC mosun+len) patients. [Figure 14] Figure 14 summarizes the complete response analysis results for various patient subgroups in Arm A (IV mosun+len) and Arm B (SC mosun+len) patients. [Figure 15]Figure 15 summarizes the overall response analysis results for various patient subgroups in Arm A (IV mosun+len) and Arm B (SC mosun+len) patients. [Figure 16] Figure 16 is a Kaplan-Meier plot and summary table showing duration of complete response results for Arm A (IV mosun+len) and Arm B (SC mosun+len) patients. [Figure 17] Figure 17 is a Kaplan-Meier plot and summary table showing duration of complete response results for Arm A (IV mosun+len) and Arm B (SC mosun+len) patients treated with two or more (2L+) prior lines of therapy. [Figure 18] Figure 18 is a Kaplan-Meier plot and summary table showing duration of response results for Arm A (IV mosun+len) and Arm B (SC mosun+len) patients. [Figure 19] Figure 19 is a Kaplan-Meier plot and summary table showing duration of response results for Arm A (IV mosun+len) and Arm B (SC mosun+len) patients treated with two or more (2L+) prior lines of therapy. [Figure 20] Figure 20 is a Kaplan-Meier plot and summary table showing overall survival results for Arm A (IV mosun+len) and Arm B (SC mosun+len) patients. [Figure 21] Figure 21 is a Kaplan-Meier plot and summary table showing overall survival results for Arm A (IV mosun+len) and Arm B (SC mosun+len) patients treated with two or more (2L+) prior lines of therapy. [Figure 22] Figure 22 is a Kaplan-Meier plot and summary table showing progression-free survival results for patients in Arm A (IV mosun+len) and Arm B (SC mosun+len). [Figure 23]Figure 23 is a Kaplan-Meier plot and summary table showing progression-free survival results for Arm A (IV mosun+len) and Arm B (SC mosun+len) patients treated with two or more (2L+) prior lines of therapy. [Figure 24] Figure 24 summarizes the overall safety results for Arm A (IV mosun+len) patients and Arm B (SC mosun+len). [Figure 25] Figure 25 summarizes the overall safety results for Arm A (IV mosun+len) and Arm B (SC mosun+len) in patients who had received two or more prior lines of therapy. [Figure 26] Figure 26 shows the breakdown of grade 5 adverse events in Arm A (IV mosun+len) and Arm B (SC mosun+len). [Figure 27] Figure 27 summarizes CRS events that occurred in Arm A (IV mosun+len) and Arm B (SC mosun+len), as well as the time to onset and duration of CRS events, and a summary of CRS events by dose / cycle. [Figure 28] Figure 28 summarizes the rates of adverse events of interest for Arm A (IV mosun+len) and Arm B (SC mosun+len) patients. [Figure 29] Figure 29 shows the effectiveness of SC or IV mosun+len compared to other therapies in treating patients with FL who have been treated with two or more prior lines of therapy. [Figure 30] Figure 30 shows the safety of SC or IV mosun+len compared to other therapies in treating patients with FL who have been treated with two or more prior lines of therapy. [Figure 31] Figure 31 is a Swimlane plot of individual responses to Mosun SC treatment in patients with 1L MZL. 1L, Column 1; Mosun, mosunetuzumab; MZL, marginal zone lymphoma; PET, positron emission tomography; SC, subcutaneous. [Figure 32]Figure 32 is a bar graph showing the complete metabolic response rates (CMR rate or complete response (CR) rate) and partial metabolic response rates (PMR rate or partial response (PR) rate) for patients described in Example 7, broken down by patient / subject subgroup. The overall response rate (ORR) is indicated by the number above each bar. Patients were stratified by age (≥65 years or <65 years); Follicular Lymphoma International Prognostic Index (FLIPI) score (0 or 1, 2, or 3-5); elevated lactate dehydrogenase (LDH) (yes or no); B syndrome (yes or no); bulky disease (yes or no); or FL grade (1-2 or 3a). DETAILED DESCRIPTION OF THE INVENTION

[0103] The present invention relates to the treatment of CD20-positive cell proliferative disorders, such as B-cell proliferative disorders (e.g., non-Hodgkin's lymphoma (NHL) (e.g., previously untreated (1L) NHL), diffuse large B-cell lymphoma (DLBCL) (e.g., 1L DLBCL, relapsed and / or refractory DLBCL, or Richter's transformed), follicular lymphoma (FL) (e.g., 1L and / or a combination thereof, as compared to intravenous administration of mosunetuzumab as monotherapy or in combination with lenalidomide.

[0104] I. General techniques The techniques and procedures described or referenced herein are generally well understood and commonly employed by those skilled in the art using conventional methodologies, such as, for example, widely used methodologies described in: Sambrook et al., Molecular Cloning: A Laboratory Manual 3rd edition (2001) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; Current Protocols in Molecular Biology (F.M.A.usubel, et al. eds., (2003)); the series Methods in Enzymology (Academic Press, Inc.): PCR 2: A Practical Approach (M.J. MacPherson, B.D. Hames and G.R. Taylor eds. (1995)), Harlow and Lane, eds. (1988) Antibodies, A Laboratory Manual, and Animal Cell Culture (R.I. Freshney, ed. (1987)); Oligonucleotide Synthesis (M.J. Gait, ed., 1984); Methods in Molecular Biology, Humana Press; Cell Biology: A Laboratory Notebook(JECellis,ed.,1998)Academic Press;Animal Cell Culture(RIFreshney),ed.,1987);Introduction to Cell and Tissue Culture(JPMather and PERoberts,1998)Plenum Press;Cell and Tissue Culture:Laboratory Procedures(A.Doyle,JBGriffiths,and DGNewell,eds.,1993-8)J.Wiley and Sons; Handbook of Experimental Immunology (DM Weir and CC Blackwell, eds.);Gene Transfer Vectors for Mammalian Cells(JMMiller and MPCalos,eds.,1987);PCR: The Polymerase Chain Reaction,(Mullis et al.,eds.,1994);Current Protocols in Immunology(JEColigan et al.,eds.,1991);Short Protocols in Molecular Biology(Wiley and Sons, 1999); Immunobiology (CA Janeway and P. Travers, 1997); Antibodies (P. Finch, 1997); Press,2000);Using Antibodies:A Laboratory Manual(E.Harlow and D.Lane(Cold Spring Harbor Laboratory Press, 1999); The Antibodies (M. Zanetti and JDCapra, eds., Harwood Academic Publishers, 1995); and Cancer: Principles and Practice of Oncology (VTDeVita et al., eds., JBLippincott Company, 1993). .

[0105] II. Definition It will be understood that aspects and embodiments of the invention described herein include "comprising," "consisting of," and "consisting essentially of" aspects and embodiments.

[0106] As used herein, the singular forms "a," "an," and "the" include plural references unless otherwise indicated.

[0107] The term "about" as used herein refers to the normal error range for each value, which is readily understood by one of ordinary skill in the art. Reference herein to "about" a value or parameter includes (and describes) embodiments that are directed to the value or parameter itself. In some embodiments, the term "about" a value or parameter refers to the value or parameter ±10%.

[0108] The terms "cancer" and "cancerous" refer to or describe a physiological condition in mammals that is typically characterized by uncontrolled cell proliferation. Examples of cancer include, but are not limited to, hematological cancers such as mature B-cell cancers, such as Hodgkin's lymphoma, but also non-Hodgkin's lymphoma (NHL), such as diffuse large B-cell lymphoma (DLBCL), which may be relapsed or refractory DLBCL or Richter's transformation. Other specific examples of cancer include germinal center B-cell-like (GCB) diffuse large B-cell lymphoma (DLBCL), activated B-cell-like (ABC) DLBCL, follicular lymphoma (FL), transformed FL, mantle cell lymphoma (MCL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), marginal zone lymphoma (MZL), transformed MZL, high-grade B-cell lymphoma, primary mediastinal (thymic) large B-cell lymphoma (PMLBCL), small lymphocytic leukemia (SLL), lymphoplasmacytic lymphoma (LL), transformed LL, Waldenstrom's hypergammaglobulinemia (WM), Central nervous system lymphoma (CNSL), Burkitt lymphoma (BL), B-cell prolymphocytic leukemia, splenic marginal zone lymphoma, hairy cell leukemia, splenic lymphoma / leukemia, unclassifiable, diffuse red pulp small B-cell lymphoma, hairy cell leukemia variant, heavy chain disease, alpha heavy chain disease, gamma heavy chain disease, mu heavy chain disease, plasma cell myeloma, isolated bone plasmacytoma, extraskeletal plasmacytoma, extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma), nodal marginal zone lymphoma, pediatric nodal marginal zone lymphoma, pediatric follicular lymphoma, primary cutaneous follicle center lymphoma, T-cell / histiocyte-rich large B-cell lymphoma, primary CNS DLBCL, primary cutaneous DLBCL, lower extremity type, EBV-positive DLBCL of the elderly, chronic inflammation-associated DLBCL, lymphomatoid granulomatosis, intravascular large B-cell lymphoma, ALK-positive large B-cell lymphoma, plasmablastic lymphoma, large B-cell lymphoma due to HHV8-associated multicentric Castleman disease, primary effusion lymphoma; unclassifiable B-cell lymphoma with features intermediate between DLBCL and Burkitt lymphoma; and unclassifiable B-cell lymphoma with features intermediate between DLBCL and classical Hodgkin lymphoma.In addition, examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and lymphoid malignancies, including leukemia or B-cell lymphoma.More specific examples of such cancer include, but are not limited to, multiple myeloma (MM); low-grade / follicular NHL; small lymphocytic (SL) NHL; intermediate-grade / follicular NHL; intermediate-grade diffuse NHL; high-grade immunoblastic NHL; high-grade lymphoblastic NHL; high-grade small non-cleaved cell NHL; large mass disease NHL; AIDS-related lymphoma; and acute lymphoblastic leukemia (ALL); chronic myeloblastic leukemia; and post-transplant lymphoproliferative disorder (PTLD).

[0109] "Tumor," as used herein, refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all pre-cancerous and cancerous cells and tissues. The terms "cancer," "cancerous," "cell proliferative disorder," "proliferative disorder," and "tumor" are not mutually exclusive when referred to herein.

[0110] A "disorder" is any condition for which treatment would be beneficial, including, but not limited to, chronic and acute disorders or diseases, including pathological conditions that predispose a mammal to the disorder in question.

[0111] The terms "cell proliferative disorder" and "proliferative disorder" refer to disorders associated with some degree of abnormal cell proliferation. In one embodiment, the cell proliferative disorder is cancer. In another embodiment, the cell proliferative disorder is a tumor.

[0112] The term "B-cell proliferative disorder" or "B-cell malignancy" refers to diseases associated with some degree of abnormal B-cell proliferation, including, for example, lymphoma, leukemia, myeloma, and myelodysplastic syndrome. In one embodiment, the B-cell proliferative disorder is a lymphoma, such as, for example, non-Hodgkin's lymphoma (NHL), including diffuse large B-cell lymphoma (DLBCL) (e.g., relapsed or refractory DLBCL or Richter's transformation), FL (e.g., relapsed and / or refractory FL or transformed FL), MCL, high-grade B-cell lymphoma, or PMLBCL. In another embodiment, the B-cell proliferative disorder is a leukemia, such as chronic lymphocytic leukemia (CLL). In some cases, subjects with relapsed or refractory disease have relapsed after or are refractory to two or more prior lines of systemic therapy. In some embodiments, the FL is previously untreated FL. In certain embodiments, subjects with previously untreated FL were determined based on the Groupe d'Etude des Lymphomes Folliculaires (GELF) criteria (Brice et al. J Clin Oncol. 15(3):1110-1117, 1997), which determined that subjects require systemic therapy to treat previously untreated FL.

[0113] The terms "Groupe d'Etude des Lymphomes Folliculaires criteria" and "GELF criteria" refer to criteria for determining whether immediate treatment is required for follicular lymphoma. In particular, subjects or individuals who meet one or more GELF criteria are determined to require treatment. GELF criteria include: (i) any lymph node or extranodal tumor mass ≥7 cm in diameter; (ii) at least three lymph node sites of metastasis, each with a diameter greater than 3 cm; (iii) the presence of B symptoms (e.g., fever, night sweats, and weight loss); (iv) splenomegaly (greater than 16 cm on computed tomography (CT) scan); (v) risk of local compression symptoms that may result in organ damage; (vi) pleural effusion or ascites; (vii) leukemia stage (>5×10 9 / L of circulating malignant cells); and (viii) cytopenia (granulocyte count <1 × 10 9 / L and / or platelets <100 × 10 9 / L). See Brice et al. J Clin Oncol. 15(3):1110-1117, 1997. In some embodiments, subjects who meet one or more GELF criteria are considered to have a high tumor burden.

[0114] The term "B symptoms" refers to systemic symptoms associated with Hodgkin's lymphoma and some NHLs. B symptoms may serve as prognostic factors for certain lymphomas. B symptoms include night sweats (wetness); unexplained fever (above 38°C); and unexplained weight loss (generally, e.g., more than 10% of body weight in the 6 months prior to hospitalization (for lymphoma)). See North American Association of Central Cancer Registries (NAACCR) Data Dictionary, Data Item #3812: B symptoms (cancer.gov).

[0115] "Follicular Lymphoma International Prognostic Index" or "FLIPI" refers to a scoring system or index for determining the prognostic risk of a patient (e.g., with cancer; e.g., NHL; e.g., follicular lymphoma (FL)). The FLIPI score ranges from 0 to 5, depending on how many of the following five symptoms or risk factors the patient may have: (i) age 60 years or older; (ii) Ann Arbor stage III-IV; hemoglobin level ≤ 120 g / L; serum lactate dehydrogenase (LDH) concentration ≥ upper limit of normal (ULN) (e.g., > 280 units / L); (v) number of nodal sites > 4. FLIPI risk groups are defined as follows: (a) 0 or 1 FLIPI risk factor = low risk group; (b) 2 FLIPI risk factors = intermediate risk group; and (c) 3 to 5 FLIPI risk factors = high risk group. See, for example, Table 4 of Solal-Celigny et al. Blood. 2004;104(5):1258-1265.

[0116] As used herein, the term "Ann Arbor staging" or "Ann Arbor stage" refers to a system for classifying the stage of lymphoma (e.g., NHL). Lymphoma (e.g., NHL) can be classified as one of four Ann Arbor stages. Stage I refers to lymphoma with metastasis to a single lymph node region or a single extralymphatic organ or site. Stage II refers to lymphoma with metastasis to two or more lymph node regions on the same side of the diaphragm. Stage III refers to lymphoma with metastasis to lymph node regions on both sides of the diaphragm (III), which may also involve localized metastasis to an extralymphatic organ or site, or splenic metastasis, or both. Stage IV refers to lymphoma with diffuse or disseminated metastasis to one or more extralymphatic organs or tissues, with or without associated lymphadenopathy. Liver metastasis is always considered diffuse and therefore always considered Ann Arbor Stage IV. Lymphatic structures include lymph nodes, thymus, spleen, appendix, Waldeyer's rings, and Peyer's patches. See Carbone, PP et al., Cancer Res. 1971, 31(11):1860-1861.

[0117] As used herein, "treatment" (and grammatical variations thereof, such as "treat" or "treating") refers to a clinical intervention in an attempt to alter the natural course of the subject being treated and may be performed for prophylaxis or during the course of a clinical condition. Desirable effects of treatment include, but are not limited to, preventing the onset or recurrence of disease, alleviating symptoms, reducing the direct or indirect pathological consequences of disease, preventing metastasis, reducing the incidence of disease progression, ameliorating or alleviating disease symptoms, and achieving remission or improving prognosis. In some embodiments, the antibodies of the invention are used to delay the onset of disease or to slow the progression of disease.

[0118] As used herein, "delaying the progression" of a disorder or disease means postponing, preventing, slowing down, retarding, stabilizing, and / or delaying the development of a disease or disorder (e.g., a CD20-positive cell proliferative disorder, e.g., a B-cell proliferative disorder, e.g., NHL, e.g., DLBCL or FL). This delay can be of various lengths of time, depending on the disease being treated and / or the individual's medical history. As will be apparent to those skilled in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop the disease. For example, late-stage cancer, such as the development of metastasis, can be delayed.

[0119] "Reducing" or "inhibiting" refers to the ability to produce an overall decrease, e.g., of 20% or more, 50% or more, or 75%, 85%, 90%, 95%, or more. In certain embodiments, reduction or inhibition refers to a reduction or inhibition of undesirable events, such as cytokine-driven toxicity (e.g., cytokine release syndrome (CRS)), infusion reaction (IRR), macrophage activation syndrome (MAS), neurotoxicity, severe tumor lysis syndrome (TLS), neutropenia, thrombocytopenia, elevated liver enzymes, and / or central nervous system (CNS) toxicity, following treatment with mosunetuzumab alone or in combination with lenalidomide using the methods described herein. In other embodiments, reduction or inhibition can refer to antibody effector functions mediated by the antibody Fc region, including, specifically, complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis (ADCP). In other embodiments, reduction or inhibition may refer to symptoms of the disorder being treated (e.g., a CD20-positive cell proliferative disorder (e.g., a B-cell proliferative disorder (e.g., NHL (e.g., previously untreated (1L) NHL, DLBCL (e.g., 1L DLBCL, relapsed and / or refractory DLBCL, or Richter's transformation), FL (e.g., 1L FL, relapsed and / or refractory FL, or transformed FL), MCL, high-grade B-cell lymphoma or PMLBCL) or CLL)), the presence or size of metastases, or the size of the primary tumor.

[0120] As used herein, "administering" refers to a method of providing a subject with a dosage of a compound (e.g., mosunetuzumab or lenalidomide) or composition (e.g., a pharmaceutical composition, e.g., a pharmaceutical composition comprising mosunetuzumab and / or lenalidomide). The compounds and / or compositions utilized in the methods described herein may be administered subcutaneously (e.g., by subcutaneous injection; e.g., mosunetuzumab), intravenously (e.g., by intravenous infusion; e.g., mosunetuzumab), or orally (e.g., lenalidomide).

[0121] A "fixed" or "constant" dose of a therapeutic agent (e.g., mosunetuzumab or lenalidomide) herein refers to a dose administered to a patient without regard to the patient's weight or body surface area (BSA). Thus, a fixed or flat dose is expressed as a mg / kg dose or a mg / m 2 It is not provided as a dose, but as an absolute amount (eg, mg) of therapeutic agent.

[0122] A "subject" or "individual" is a mammal. Mammals include, but are not limited to, primates (e.g., humans and non-human primates, such as monkeys), livestock (e.g., cows, sheep, cats, dogs, and horses), rabbits, and rodents (e.g., mice and rats). In certain embodiments, the subject or individual is a human.

[0123] An "individual response" or "response" can be assessed using any endpoint that indicates a benefit to the subject, including, but not limited to, (1) some inhibition (including slowing and complete halting) of disease progression (e.g., B-cell proliferative disorder; e.g., NHL or CLL progression); (2) reduction in tumor size; (3) inhibition (i.e., reduction, slowing, or complete halt) of cancer cell invasion into adjacent peripheral organs and / or tissues; (4) inhibition (i.e., reduction, slowing, or complete halt) of metastasis; (5) some alleviation of one or more symptoms associated with the B-cell proliferative disorder (e.g., NHL or CLL); (6) increased or prolonged survival, including overall survival and progression-free survival; and / or (9) a reduction in mortality at some point after treatment. In some embodiments, the response to treatment (e.g., complete response (CR) or partial response (PR)) of a CD20-positive cell proliferative disorder (e.g., a B-cell proliferative disorder; e.g., NHL or CLL) is determined based on the Revised Response Criteria for Malignant Lymphoma (Cheson et al., 2007). In some embodiments, the response to treatment (e.g., CR or PR) of a CD20-positive cell proliferative disorder (e.g., a B-cell proliferative disorder; e.g., NHL or CLL) is evaluated using the Lugano Response Criteria for Malignant Lymphoma (Cheson BD, et al. J Clin Oncol 2014;32:1-9).

[0124] As used herein, "complete response" or "CR" refers to the disappearance of all target lesions (i.e., all evidence of disease). In some cases, the target lymph node / nodal mass shrinks to 1.5 cm or less in its longest diameter. In some cases, the complete response is a complete metabolic response.

[0125] As used herein, "partial response" or "PR" refers to at least a 50% reduction in the sum of the products of the diameters (SPD) of target lesions, e.g., up to six measurable target lymph nodes and extranodal sites, relative to the baseline SPD. In some cases, the partial response is a partial metabolic response.

[0126] As used herein, "objective response rate" (ORR) refers to the sum of the complete response (CR) rate and the partial response (PR) rate.

[0127] As used herein, "duration of objective response" (DOR) is defined as the time from the first occurrence of documented objective response to disease progression, recurrence, or death from any cause, whichever occurs first.

[0128] As used herein, "duration of complete response" (DOCR) is defined as the time from the first occurrence of documented complete response to disease progression, relapse, or death from any cause (whichever occurs first).

[0129] "Sustained response" refers to the persistent effect of reducing tumor growth after treatment is stopped.For example, tumor size can remain the same or become smaller compared to the size at the beginning of the administration phase.In some embodiments, the sustained response has a duration at least equal to the treatment period, or at least 1.5 times, 2.0 times, 2.5 times or 3.0 times the treatment period.

[0130] A subject's "effective response" or subject's "responsiveness" to treatment with a pharmaceutical agent, and similar phrases, refers to a clinical or therapeutic benefit conferred on a subject at risk for or suffering from a disease or disorder, such as cancer. In one embodiment, such benefit includes one or more of extending survival (including overall survival and progression-free survival), producing an objective response (including a complete or partial response), or ameliorating signs or symptoms of cancer.

[0131] A subject who "does not have an effective response" to treatment refers to a subject who does not have any one of the following: an extension of survival (including overall survival and progression-free survival), an objective response (including a complete or partial response), or an improvement in signs or symptoms of cancer.

[0132] As used herein, "survival" refers to the patient remaining alive, and includes overall survival and progression-free survival.

[0133] As used herein, "overall survival" (OS) refers to the time or duration from the first study treatment administered to death from any cause.

[0134] As used herein, "progression-free survival" (PFS) refers to the length of time during and after treatment that the disease being treated (e.g., a CD20-positive cell proliferative disorder (e.g., a B-cell proliferative disorder (e.g., an NHL (e.g., previously untreated (1L) NHL, DLBCL (e.g., 1L DLBCL, relapsed and / or refractory DLBCL, or Richter's transformation), FL (e.g., 1L FL, relapsed and / or refractory FL, or transformed FL), MCL, high-grade B-cell lymphoma or PMLBCL) or CLL)) does not worsen. Progression-free survival can include the amount of time a patient experiences a complete response or a partial response, and the amount of time a patient experiences stable disease. In some cases, PFS refers to the time or duration from the first study treatment administered to disease progression or death from any cause, whichever occurs first.

[0135] As used herein, "stable disease" or "SD" refers to neither sufficient shrinkage of target lesions to qualify as PR nor sufficient increase to qualify as PD, with reference to the smallest SLD since treatment initiation. In some cases, stable disease refers to a less than 50% reduction in SPD from baseline, e.g., up to six major measurable lymph nodes and extranodal sites.

[0136] As used herein, "progressive disease" or "PD" refers to an increase in the SLD of any previously identified lesion by at least 50% from the smallest SLD, or an increase in the SPD of a target lesion by at least 50% from the smallest SPD, or the presence of one or more new lesions recorded since the start of treatment.

[0137] As used herein, "delaying progression" of a disorder or disease means postponing, preventing, delaying, stabilizing, and / or postponing the onset of a disease or disorder (e.g., a CD20-positive cell proliferative disorder (e.g., a B-cell proliferative disorder (e.g., NHL (e.g., previously untreated (1L) NHL, DLBCL (e.g., 1L DLBCL, relapsed and / or refractory DLBCL, or Richter's transformation), FL (e.g., 1L FL, relapsed and / or refractory FL, or transformed FL), MCL, high-grade B-cell lymphoma or PMLBCL) or CLL)). This delay can be of varying duration depending on the disease history and / or the subject being treated. As will be apparent to one of skill in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the subject does not develop the disease. For example, in end-stage cancer, the development of central nervous system (CNS) metastases can be delayed.

[0138] As used herein, the term "reducing or inhibiting cancer recurrence" means reducing or inhibiting the recurrence of a tumor or cancer, or the progression of a tumor or cancer.

[0139] "Prolonging survival" means increasing overall survival or progression-free survival in a treated patient compared to an untreated patient (e.g., compared to a patient not treated with a pharmaceutical agent), or compared to a patient who does not express a biomarker at a specified level, and / or compared to a patient treated with an approved anti-tumor agent. Objective response refers to a measurable response, including a complete response (CR) or partial response (PR).

[0140] The term "antibody" as used herein is used in the broadest sense and encompasses a variety of antibody structures, including, but not limited to, monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments, so long as they exhibit the desired antigen-binding activity.

[0141] The terms "full length antibody," "intact antibody," and "whole antibody" are used interchangeably herein to refer to an antibody having a heavy chain that has a structure substantially similar to a native antibody structure or that contains an Fc region as defined herein.

[0142] "Binding domain" refers to a portion of a compound or molecule that specifically binds to a target epitope, antigen, ligand, or receptor. Binding domains include, but are not limited to, antibodies (e.g., monoclonal, polyclonal, recombinant, humanized, and chimeric antibodies), antibody fragments or portions thereof (e.g., Fab fragments, Fab'2, scFv antibodies, SMIPs, domain antibodies, diabodies, minibodies, scFv-Fc, affibodies, nanobodies, and antibody VH and / or VL domains), receptors, ligands, aptamers, and other molecules with identified binding partners.

[0143] The term "Fc region" is used herein to define the C-terminal region of an immunoglobulin heavy chain containing at least a portion of the constant region. This term includes native sequence Fc regions and variant Fc regions. In one embodiment, a human IgG heavy chain Fc region extends from Cys226 or Pro230 to the carboxyl terminus of the heavy chain. However, the C-terminal lysine (Lys447) of the Fc region may or may not be present. Unless otherwise specified herein, the numbering of amino acid residues within the Fc region or constant region follows EU numbering, also known as the EU index, as described by Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991.

[0144] The "class" of an antibody refers to the type of constant domain or constant region carried by its heavy chain. There are five major classes of antibodies: IgA, IgD, IgE, IgG, and IgM, some of which can be further divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy-chain constant domains that correspond to the different classes of immunoglobulins are called α, δ, ε, γ, and μ, respectively.

[0145] As used herein, the term IgG "isotype" or "subclass" means any of the subclasses of immunoglobulins defined by the chemical and antigenic properties of their constant regions.

[0146] "Framework" or "FR" refers to variable domain residues other than hypervariable region (HVR) residues. The FR of a variable domain generally consists of four FR domains: FR1, FR2, FR3, and FR4. Thus, the HVR and FR sequences generally appear in VH (or VL) in the following order: FR1-H1(L1)-FR2-H2(L2)-FR3-H3(L3)-FR4.

[0147] A "human consensus framework" is a framework that represents the most commonly occurring amino acid residues in a selection of human immunoglobulin VL or VH framework sequences. Generally, the selection of human immunoglobulin VL or VH sequences is derived from a subgroup of variable domain sequences. Generally, the subgroup of sequences is as described in Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, NIH Publication 91-3242, Bethesda, MD (1991), vols. 1-3. In one embodiment, for VL, the subgroup is subgroup kappa I in Kabat et al., supra. In one embodiment, for VH, the subgroup is subgroup III in Kabat et al., supra.

[0148] An "acceptor human framework," as used herein, is a framework that comprises the amino acid sequence of a light chain variable domain (VL) framework or a heavy chain variable domain (VH) framework derived from a human immunoglobulin framework or a human consensus framework, as defined below. An acceptor human framework "derived from" a human immunoglobulin framework or a human consensus framework may comprise the same amino acid sequence or may contain amino acid sequence changes. In some embodiments, the number of amino acid changes is 10 or less, 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 or less, 3 or less, or 2 or less. In some embodiments, the VL acceptor human framework is identical in sequence to the VL human immunoglobulin framework sequence or the human consensus framework sequence.

[0149] A "humanized" antibody refers to a chimeric antibody comprising amino acid residues derived from non-human HVRs and human FRs. In certain embodiments, a humanized antibody comprises substantially all of at least one, and typically two, variable domains, with all or substantially all of the HVRs (e.g., CDRs) corresponding to those of a non-human antibody and all or substantially all of the FRs corresponding to those of a human antibody. A humanized antibody may optionally comprise at least a portion of an antibody constant region derived from a human antibody. A "humanized form" of an antibody, e.g., a non-human antibody, refers to an antibody that has undergone humanization.

[0150] A "human antibody" is an antibody having an amino acid sequence corresponding to an antibody produced by a human or human cell, or an antibody of non-human origin using human antibody-encoding sequences, such as the human antibody repertoire. This definition of a human antibody specifically excludes humanized antibodies containing non-human antigen-binding residues. Human antibodies can be generated using various techniques known in the art, including phage display libraries. Hoogenboom and Winter, J. Mol. Biol., 227:381 (1991); Marks et al., J. Mol. Biol., 222:581 (1991). Human monoclonal antibodies can also be prepared using the methods described in Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77 (1985); Boerner et al., J. Immunol., 147(1):86-95 (1991). See also van Dijk and van de Winkel, Curr. Opin. Pharmacol., 5:368-74 (2001). Human antibodies can be prepared by administering antigen to transgenic animals, e.g., immunized xenomouse, which have been engineered to produce such antibodies in response to antigen challenge, but whose endogenous gene loci have been disabled (e.g., XENOMOUSE (商標)(See U.S. Patent Nos. 6,075,181 and 6,150,584 for related techniques.) See also, e.g., Li et al., Proc. Natl. Acad. Sci. USA, 103:3557-3562 (2006), regarding human antibodies produced by human B-cell hybridoma technology.

[0151] The term "variable region" or "variable domain" refers to the domain of an antibody heavy or light chain that is involved in binding the antibody (i.e., mosunetuzumab) to an antigen. The variable domains of the heavy and light chains (VH and VL, respectively) of native antibodies generally have similar structures, with each domain containing four conserved framework regions (FR) and three hypervariable regions (HVR). (See, e.g., Kindt et al., Kuby Immunology, 6 th (See, e.g., W.H. Freeman and Co., page 91 (2007)). A single VH or VL domain may be sufficient to confer antigen-binding specificity. Moreover, antibodies that bind to a specific antigen may be isolated by using the VH or VL domain of an antibody that binds the antigen to screen a library of complementary VL or VH domains, respectively. See, e.g., Portolano et al., J. Immunol. 150:880-887 (1993); Clarkson et al., Nature 352:624-628 (1991).

[0152] As used herein, the term "hypervariable region" or "HVR" refers to each region of an antibody variable domain that is hypervariable in sequence ("complementarity determining region" or "CDR") and / or forms structurally defined loops ("hypervariable loops") and / or contains residues that contact the antigen ("antigen contacts"). Generally, antibodies contain six HVRs, three in the VH (H1, H2, H3) and three in the VL (L1, L2, L3). Exemplary HVRs herein include the following: (a) Hypervariable loops present at amino acid residues 26–32 (L1), 50–52 (L2), 91–96 (L3), 26–32 (H1), 53–55 (H2), and 96–101 (H3) (Chothia and Lesk, J. Mol. Biol. 196:901–917 (1987)); (b) CDRs located at amino acid residues 24–34 (L1), 50–56 (L2), 89–97 (L3), 31–35b (H1), 50–65 (H2), and 95–102 (H3) (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991)); (c) antigenic contacts occurring at amino acid residues 27c-36 (L1), 46-55 (L2), 89-96 (L3), 30-35b (H1), 47-58 (H2), and 93-101 (H3) (MacCallum et al. J. Mol. Biol. 262:732-745 (1996)); and (d) A combination of (a), (b) and / or (c) comprising HVR amino acid residues 46-56 (L2), 47-56 (L2), 48-56 (L2), 49-56 (L2), 26-35 (H1), 26-35b (H1), 49-65 (H2), 93-102 (H3) and 94-102 (H3).

[0153] Unless otherwise indicated, HVR residues and other residues in the variable domain (e.g., FR residues) are numbered herein according to Kabat et al., supra.

[0154] An "immunoconjugate" is an antibody conjugated to one or more heterologous molecules, including, but not limited to, cytotoxic agents.

[0155] As used herein, the term "monoclonal antibody" refers to an antibody obtained from a substantially homogeneous population of antibodies (i.e., the individual antibodies comprising the population are identical and / or bind to the same epitope). This excludes possible variant antibodies, including, for example, naturally occurring mutations or arising during the production of a monoclonal antibody preparation; such variants are generally present in minor amounts. In contrast to polyclonal antibody preparations, which typically contain different antibodies directed against different determinants (epitopes), each monoclonal antibody of a monoclonal antibody preparation is directed against a single determinant on an antigen. Thus, the modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies and should not be construed as requiring production of the antibody by any particular method. For example, monoclonal antibodies used in accordance with the present invention can be produced by a variety of techniques, including, but not limited to, hybridoma methods, recombinant DNA methods, phage display methods, and methods utilizing transgenic animals containing all or part of the human immunoglobulin loci; these and other exemplary methods for producing monoclonal antibodies are described herein.

[0156] "Affinity" refers to the strength of the sum of non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless otherwise indicated, as used herein, "binding affinity" refers to the intrinsic binding affinity that reflects a 1:1 interaction between members of a binding pair (e.g., an antibody and an antigen). The affinity of a molecule X for its partner Y can generally be represented by the dissociation constant (Kd). Affinity can be measured by methods common in the art, including those described herein. Specific illustrative and exemplary embodiments for measuring binding affinity are described below.

[0157] An "affinity matured" antibody refers to an antibody that has one or more alterations in one or more hypervariable regions (HVRs) compared to a parent antibody that does not possess such alterations, which alterations improve the affinity of the antibody for antigen.

[0158] The terms "anti-CD3 antibody" and "antibody that binds to CD3" refer to an antibody that is capable of binding to CD3 with sufficient affinity such that the antibody is useful as a diagnostic and / or therapeutic agent in targeting CD3. In one embodiment, the extent of binding of an anti-CD3 antibody to an unrelated, non-CD3 protein is less than about 10% of the binding of the antibody to CD3, as measured, for example, by radioimmunoassay (RIA). In certain embodiments, an antibody that binds to CD3 has an affinity of ≦1 μM, ≦100 nM, ≦10 nM, ≦1 nM, ≦0.1 nM, ≦0.01 nM, or ≦0.001 nM (e.g., 10 -8 M or less, e.g. 10 -8 ~10 -13 M, e.g. 10 -9 M~10 -13 Dissociation constant (K D In certain embodiments, the anti-CD3 antibody binds to an epitope of CD3 that is conserved among CD3 from different species.

[0159] The term "cluster of differentiation 3" or "CD3," as used herein, unless otherwise indicated, refers to any native CD3 from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), including, for example, the CD3ε, CD3γ, CD3α, and CD3β chains. The term encompasses "full-length" unprocessed CD3 (e.g., unprocessed or unmodified CD3ε or CD3γ) as well as any form of CD3 resulting from intracellular processing. The term also encompasses naturally occurring variants of CD3, including, for example, splice variants or allelic variants. CD3 includes, for example, the human CD3ε protein, which is 207 amino acids long (NCBI Reference SEQ ID NO: NP_000724), and the human CD3γ protein, which is 182 amino acids long (NCBI Reference SEQ ID NO: NP_000064).

[0160] The terms "anti-CD20 antibody" and "antibody that binds to CD20" refer to an antibody that can bind to CD20 with sufficient affinity such that the antibody is useful as a diagnostic and / or therapeutic agent targeting CD20. In one embodiment, the binding of an anti-CD20 antibody to an unrelated, non-CD20 protein is less than about 10% of the binding of the antibody to CD20, as measured, for example, by radioimmunoassay (RIA). In certain embodiments, an antibody that binds to CD20 has an affinity of ≦1 μM, ≦100 nM, ≦10 nM, ≦1 nM, ≦0.1 nM, ≦0.01 nM, or ≦0.001 nM (e.g., ≦10 -8 M or less, e.g. 10 -8 M~10 -13 M, e.g. 10 -9 M~10 -13 M) In certain embodiments, the anti-CD20 antibody binds to an epitope of CD20 that is conserved among CD20 from different species.

[0161] The term "cluster of differentiation 20" or "CD20," as used herein, unless otherwise indicated, refers to any native CD20 from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats). The term encompasses "full-length," unprocessed CD20, as well as any form of CD20 resulting from processing within a cell. The term also encompasses naturally occurring variants of CD20, including, for example, splice variants or allelic variants. CD20 includes, for example, the human CD20 protein (see, e.g., NCBI Reference SEQ ID NOs: NP_068769.2 and NP_690605.1), which is 297 amino acids in length and can be produced, for example, from a variant mRNA transcript lacking a portion of the 5'UTR (see, e.g., NCBI Reference SEQ ID NO: NM_021950.3) or a longer variant mRNA transcript (see, e.g., NCBI Reference SEQ ID NO: NM_152866.2).

[0162] The terms "anti-CD20 / anti-CD3 bispecific antibody," "bispecific anti-CD20 / anti-CD3 antibody," and "antibody that binds to CD20 and CD3," or variations thereof, refer to mosunetuzumab.

[0163] As used herein, the term "mosunetuzumab" refers to an anti-CD20 / anti-CD3 bispecific antibody having International Nonproprietary Names (INN) List 117 (WHO Drug Information, Vol. 31, No. 2, 2017, pp. 304-305) or CAS Registry Number 1905409-39-3. Furthermore, the term "mosunetuzumab," as used herein, is understood to encompass any biosimilar versions approved by regulatory authorities, such as the U.S. FDA or the European EMA. Furthermore, mosunetuzumab may refer to a bispecific anti-CD3 / anti-CD20 bispecific antibody comprising the HVR sequences, VH and VL sequences, and / or heavy and light chain sequences set forth in Table 1 below, as well as any variants thereof, including post-translational modifications.

[0164] As used herein, the term "lenalidomide" refers to the compound having CAS Registry Number 191732-72-6 and IUPAC name (3RS)-3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione. Lenalidomide is also known by trade names including REVLIMID®, linamide, and lenalid. Lenalidomide has DrugBank Accession Number DB00480, PubChem CID 216326, and the chemical formula C 13 H 13 It has N3O3.

[0165] As used herein, the terms "bind," "specifically bind to," or "specific for" refer to a measurable and reproducible interaction, such as binding, between a target and an antibody, which is determinative of the presence of the target in the presence of a heterogeneous population of molecules, including biomolecules. For example, an antibody that specifically binds to a target (which may be an epitope) is one that binds to this target with higher affinity, avidity, more readily, and / or with a longer duration than it binds to other targets. In one embodiment, the extent to which an antibody binds to an unrelated target is less than about 10% of the binding of the antibody to the target, as measured, for example, by radioimmunoassay (RIA). In certain embodiments, an antibody that specifically binds to a target has a dissociation constant (K) of 1 μM or less, 100 nM or less, 10 nM or less, 1 nM or less, or 0.1 nM or less. D In certain embodiments, the antibody specifically binds to an epitope on a protein that is conserved among proteins from different species. In another embodiment, specific binding can include, but does not require, exclusive binding. As used herein, the term "specific binding" refers to an epitope that is conserved among proteins from different species, e.g., 10 -4 M or less, or 10 -5 M or less, or 10 -6 M or less, or 10 -7 M or less, or 10 -8 M or less, or 10 -9 M or less, or 10 -10 M or less, or 10 -11 M or less, or 10 -12 K against targets less than or equal to M D , or 10 -4 M~10 -6 M or 10 -6 M~10 -10 M or 10 -7 M~10 -9 K in the M range D As will be appreciated by those skilled in the art, affinity and K D The values ​​are inversely correlated: a high affinity for the antigen corresponds to a low K DIn one embodiment, the term "specific binding" refers to binding of a molecule to a particular polypeptide or an epitope on a particular polypeptide without substantially binding to any other polypeptides or polypeptide epitopes.

[0166] The term "pharmaceutical formulation" refers to a preparation that is in a form such that the biological activity of the active ingredients contained in the preparation is effective and that does not contain additional components that are unacceptably toxic to the subject to which the formulation is administered.

[0167] A "pharmaceutically acceptable carrier" refers to an ingredient in a pharmaceutical formulation, other than an active ingredient, that is non-toxic to a subject. Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers, or preservatives.

[0168] As used herein, the term "chemotherapeutic agent" refers to a compound useful in the treatment of cancer, such as a CD20-positive cell proliferative disorder (e.g., a B-cell proliferative disorder (e.g., a relapsed or refractory B-cell proliferative disorder), e.g., non-Hodgkin's lymphoma (NHL; e.g., diffuse large B-cell lymphoma (DLBCL; e.g., Richter transformed), follicular lymphoma (FL; e.g., grade 1 FL, grade 2 FL, grade 3 FL (e.g., grade 3a FL, grade 3b FL) or transformed FL), mantle cell lymphoma (MCL), or marginal zone lymphoma (MZL)), or chronic lymphocytic leukemia (CLL), e.g., relapsed or refractory NHL (e.g., relapsed or refractory DLBCL, relapsed or refractory FL, relapsed or refractory MCL or marginal zone lymphoma (MZL)), or relapsed or refractory CLL). Examples of chemotherapeutic agents include EGFR inhibitors (including small molecule inhibitors (e.g., erlotinib (TARCEVA®, Genentech / OSI Pharm.); PD 183805 (CI 1033, 2-propenamide, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(4-morpholinyl)propoxy]-6-quinazolinyl]-, dihydrochloride, Pfizer Inc.); ZD1839, gefitinib (IRESSA®) 4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline, AstraZeneca); ZM 105180 ((6-amino-4-(3-methylphenyl-amino)-quinazoline, Zeneca); BIBX-1382 (N8-(3-chloro-4-fluoro-phenyl)-N2-(1-methyl-piperidin-4-yl)-pyrimido[5,4-d]pyrimidine-2,8-diamine, Boehringer Ingelheim); PKI-166 ((R)-4-[4-[(1-phenylethyl)amino]-1H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenol); (R)-6-(4-hydroxyphenyl)-4-[(1-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine); CL-387785 (N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-2-butynamide);EKB-569 (N-[4-[(3-chloro-4-fluorophenyl)amino]-3-cyano-7-ethoxy-6-quinolinyl]-4-(dimethylamino)-2-butenamide) (Wyeth); AG1478 (Pfizer); AG1571 (SU 5271; Pfizer); and dual EGFR / HER2 tyrosine kinase inhibitors, such as lapatinib (TYKERB®, GSK572016 or N-[3-chloro-4-[(3fluorophenyl)methoxy]phenyl]-6[5[[[2methylsulfonyl)ethyl]amino]methyl]-2-furanyl]-4-quinazolinamine)); tyrosine kinase inhibitors (e.g., EGFR inhibitors; small molecule HER2 tyrosine kinase inhibitors, such as TAK165 (Takeda); ErbB2 receptor tyrosine kinase inhibitors, such as CP-724,714 (Pfizer and OSI), an oral selective inhibitor of EGFR kinase; dual HER inhibitors, e.g., EKB-569 (available from Wyeth), which preferentially binds EGFR but inhibits both HER2-overexpressing and EGFR-overexpressing cells; PKI-166 (Novartis); pan-HER inhibitors, e.g., canertinib (CI-1033; Pharmacia); Raf-1 inhibitors, e.g., ISIS-5132 (ISIS), an antisense agent that inhibits Raf-1 signaling. Pharmaceuticals; non-HER-targeted tyrosine kinase inhibitors, such as imatinib mesylate (GLEEVEC®, GlaxoSmithkline); multi-targeted tyrosine kinase inhibitors, such as sunitinib (SUTENT®, Pfizer); VEGF receptor tyrosine kinase inhibitors, such as vatalanib (PTK787 / ZK222584, Novartis / Schering AG); MAPK extracellular regulated kinase I inhibitor CI-1040 (Pharmacia); quinazolines, such as PD 153035, 4-(3-chloroanilino)quinazoline; pyridopyrimidines; pyrimidopyrimidines; pyrrolopyrimidines, such as CGP 59326, CGP 60261 and CGP 62706;Pyrazolopyrimidine, 4-(phenylamino)-7H-pyrrolo[2,3-d]pyrimidine;Curcumin (diferuloylmethane, 4,5-bis(4-fluoroanilino)phthalimide);Tyrphostins containing a nitrothiophene moiety; PD-0183805 (Warner-Lambert); antisense molecules (e.g., those that bind to nucleic acids encoding HERs); quinoxalines (U.S. Patent No. 5,804,396); tyrphostins (U.S. Patent No. 5,804,396); ZD6474 (AstraZeneca); PTK-787 (Novartis / Schering); pan-HER inhibitors, such as CI-1033 (Pfizer); Affinitac (ISIS 3521; Isis / Lilly); PKI 166 (Novartis); GW2016 (GlaxoSmithKline); CI-1033 (Pfizer); EKB-569 (Wyeth); semaxinib (Pfizer); ZD6474 (AstraZeneca); PTK-787 (Novartis / Schering AG); INC-1C11 (Imclone); and rapamycin (sirolimus, RAPAMUNE®); proteasome inhibitors such as bortezomib (VELCADE®, Millennium Pharm.); disulfiram; epigallocatechin gallate; salinosporamide A; carfilzomib; 17-AAG (geldanamycin); radicicol; lactate dehydrogenase A (LDH-A); fulvestrant (FASLODEX®, AstraZeneca); letrozole (FEMARA®, Novartis), finasunate (VATALANIB®, Novartis); oxaliplatin (ELOXATIN®, Sanofi); 5-FU (5-fluorouracil); leucovorin; lonafarnib (SCH 66336); sorafenib (NEXAVAR®, Bayer Labs); AG1478, alkylating agents such as thiotepa and CYTOXAN® cyclophosphamide; alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa;Ethylenimines and methylamelamines, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylmelamine; acetogenins (especially bullatacin and bullatacinone); camptothecins (including topotecan and irinotecan); bryostatin; kallistatin; CC-1065 (including its synthetic analogs adozelesin, carzelesin, and bizelesin); cryptophycins (especially cryptophycin 1 and cryptophycin 8); corticosteroids (including prednisone and prednisolone); cyproterone acetate; 5α-reductase inhibitors, including finasteride and dutasteride; vorinostat, romidepsin, panobinostat, valproic acid, mocetinostat; dolastatins; aldesleukin, talc, duocarmycin (talc) duocarmycin) (including synthetic analogs KW-2189 and CB1-TM1); eluetherobin; pancratistatin; sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlomaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine; antibiotics such as enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gamma 1 and calicheamicin omega 1); dynemicins, including dynemicin A; bisphosphonates such as clodronate; esperamicin;and neocarzinostatin chromophores and related chromoprotein enediyne antibiotic chromophores), aclacinomycin, actinomycin, anthramycin, azaserine, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycin, dactinomycin, detorubicin, 6-diazo-5-oxo-L-norleucine, morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, Streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogues such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calsterone, dromostanolone propionate, epithiostanol, mepitiostane, testolactone; antiadrenergics such as aminoglutethimide, mitotane, trilostane; folic acid supplements such as florinic acid acid); aceglatone; aldophosphamide glycosides; aminolevulinic acid; eniluracil; amsacrine; bestravcil; bisantrene; edatrexate; defofamine; demecolcine; diaziquone; elfomithine; elliptinium acetate; epothilone; etoglucide; gallium nitrate; hydroxyurea; lentinan; lonidamine; maytansinoids, such as maytansine and ansamitocin; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin;Fenamet; pirarubicin; losoxantrone; podophyllic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products); razoxane; rhizoxin; schizophyllan; spirogermanium; tenuazonic acid; triazicon; 2,2',2"-trichlorotriethylamine; trichothecenes (especially T-2 toxin, veracrine A, roridin A, and anguidine); urethane; vindesine; dacarbazine; Mannomustine; Mitobronitol; Mitolactol; Pipobroman; Gacytosine; Arabinoside ("Ara-C"); Thiotepa; Chlorambucil; GEMZAR® (Gemcitabine); 6-Thioguanine; Mercaptopurine; Methotrexate; Etoposide (VP-16); Ifosfamide; Mitoxantrone; Novantrone; Teniposide; Edatrexate; Daunomycin; Aminopterin; Capecitabine (XELODA®); ibandronate; CPT-11; the topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids, such as retinoic acid; and pharmaceutically acceptable salts, acids, prodrugs and derivatives of any of the above.

[0169] Chemotherapeutic agents also include (i) antihormonal agents that act to regulate or inhibit hormone action on tumors, such as antiestrogens and selective estrogen receptor modulators (SERMs), including tamoxifen (including Nolvadex®; tamoxifen citrate), raloxifene, droloxifene, iodoxyfene, 4-hydroxytamoxifen, trioxifene, ketoxifene, LY117018, onapristone, and Fairston® (cetamine). (ii) aromatase inhibitors, which inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as 4(5)-imidazole, aminoglutethimide, Megase® (megestrol acetate), Aromasin® (exemestane; Pfizer), formestany, fadrozole, RIVISOR® (vorozole), Femara® (letrozole; Novartis), and Arimidex® ( (trademark) (anastrozole; AltraZeneca); (iii) antiandrogens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; buserelin, tripterelin, medroxyprogesterone acetate, diethylstilbestrol, premarin, fluoxymesterone, all-trans retinoic acid, fenretinide, and troxacitabine (a 1,3-dioxolane nucleoside cytosine analog); (iv) protein kinase inhibitors; (v) lipid kinase inhibitors; (vi) antisense oligonucleotides, particularly those that inhibit the expression of genes in signal transduction pathways involved in abnormal cell proliferation, e.g., PKC-alpha, Ralf, and H-Ras; (vii) ribozymes such as VEGF expression inhibitors (e.g., Angiozyme®) and HER2 expression inhibitors; (viii) gene therapy vaccines, e.g., ALLOVECTIN®, Leuvectin®, and VAXID®;(ix) growth inhibitors, including vincas (e.g., vincristine and vinblastine), Navelbine® (vinorelbine), taxanes (e.g., paclitaxel, nab-paclitaxel, and docetaxel), topoisomerase II inhibitors (e.g., doxorubicin, epirubicin, daunorubicin, etoposide, and bleomycin), and DNA alkylating agents (e.g., tamoxigen, dacarbazine, mechlorethamine, cisplatin, methotrexate, 5-fluorouracil, and ara-C); and (x) pharmaceutically acceptable salts, acids, prodrugs, and derivatives of any of the above.

[0170] The term "chemoimmunotherapy" refers to a combination therapy that includes both a chemotherapeutic agent and an immunotherapeutic agent. In some embodiments, chemoimmunotherapy is used to treat cancer, such as a CD20-positive cancer, such as NHL, such as FL. In some embodiments, the immunotherapeutic agent includes an antibody, such as an anti-CD20 antibody (e.g., an anti-CD20 monoclonal antibody). In some embodiments, the anti-CD20 antibody or anti-CD20 monoclonal antibody is rituximab or obinutuzumab. In some embodiments, the chemoimmunotherapy includes R-CHOP.

[0171] As used herein, the term "cytotoxic agent" refers to any agent that is detrimental to cells (e.g., causes cell death, inhibits growth, or otherwise interferes with cellular function). Cytotoxic agents include radioisotopes (e.g., At 211 , I 131 , I 125 , Y 90 ,Re 186 ,Re 188 , Sm 153 , Bi 212 , P 32 , Pb 212, and radioactive isotopes of Lu); chemotherapeutic agents; enzymes such as nucleases and fragments thereof; and toxins such as small molecule or enzymatically active toxins of bacterial, fungal, plant, or animal origin, including fragments and / or variants thereof. Exemplary cytotoxic agents may be selected from anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormone analogs, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents, proapoptotic agents, inhibitors of LDH-A, inhibitors of fatty acid biosynthesis, cell cycle signaling inhibitors, HDAC inhibitors, proteasome inhibitors, and inhibitors of cancer metabolism. In one example, the cytotoxic agent is a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin). In one example, the cytotoxic agent is an EGFR antagonist, such as N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (e.g., erlotinib). In one example, the cytotoxic agent is a RAF inhibitor, such as a BRAF and / or CRAF inhibitor. In one example, the RAF inhibitor is vemurafenib. In one example, the cytotoxic agent is a PI3K inhibitor. In one example, the PI3K inhibitor inhibits the delta isoform of PI3K (i.e., P110δ). In some cases, the PI3K inhibitor is 5-fluoro-3-phenyl-2-[(1S)-1-(7H-purin-6-ylamino)propyl]-4(3H)-quinazolinone and salts thereof. In some cases, the PI3K inhibitor is taselisib (CAS number: 870281-82-6). In one example, the PI3K inhibitor inhibits the alpha and delta isoforms of PI3K. In some cases, the PI3K inhibitor is 2-{3-[2-(1-isopropyl-3-methyl-1H-1,2-4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl]-1H-pyrazol-1-yl}-2-methylpropanamide and salts thereof. In some cases, the PI3K inhibitor is taselisib (CAS number: 1282512-48-4).In some cases, the PI3K inhibitor is 2-amino-N-[2,3-dihydro-7-methoxy-8-[3-(4-morpholinyl)propoxy]imidazo[1,2-c]quinazolin-5-yl]-5-pyrimidinecarboxamide and salts thereof. In some cases, the PI3K inhibitor is copanlisib (CAS number: 1032568-63-0). In some cases, the PI3K inhibitor is 8-chloro-2-phenyl-3-[(1S)-1-(9H-purin-6-ylamino)ethyl]-1(2H)-isoquinolinone and salts thereof. In some cases, the PI3K inhibitor is duvelisib (CAS number: 1201438-56-3). In some cases, the PI3K inhibitor is (2S)-N. 1 -[4-methyl-5-[2-(2,2,2-trifluoro-1,1-dimethylethyl)-4-pyridinyl]-2-thiazolyl]-1,2-pyrrolidinedicarboxamide and salts thereof. In some cases, the PI3K inhibitor is alpelisib (CAS number: 1217486-61-7). In some cases, the PI3K inhibitor is 2-[(1S)-1-[4-amino-3-[3-fluoro-4-(1-methylethoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl]-6-fluoro-3-(3-fluorophenyl)-4H-1-benzopyran-4-one and salts thereof. In some cases, the PI3K inhibitor is ambralisib (CAS number: 1532533-67-7).

[0172] The term "package insert" is used to refer to instructions typically included in commercial packaging of therapeutic products that contain information about the indications, usage, dosage, administration, concomitant therapy, contraindications and / or warnings for use of such therapeutic products.

[0173] III. Treatment method Provided are methods of treating a subject having a CD20-positive cell proliferative disorder (e.g., a B-cell proliferative disorder, e.g., NHL (e.g., DLBCL or FL) or CLL) by subcutaneously administering mosunetuzumab to the subject in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein the treatment comprising subcutaneous administration of mosunetuzumab as monotherapy or in combination with lenalidomide exhibits non-inferior or improved outcomes compared to intravenous administration of mosunetuzumab as monotherapy or in combination with lenalidomide, respectively, as measured using pharmacokinetics (PK), efficacy, safety, or a combination thereof.

[0174] A. Treatment Methods for the Administration of Mosunetuzumab in Combination with Lenalidomide In one aspect, the invention features a method for treating follicular lymphoma (FL) in a subject in need thereof, the method comprising administering to the subject a combination treatment comprising subcutaneously administered mosunetuzumab and orally administered lenalidomide, wherein administering the combination treatment to the plurality of subjects results in a non-inferior or improved efficacy response in the plurality of subjects compared to a reference efficacy response, where the reference efficacy response is the efficacy response of the plurality of subjects who received a control treatment comprising intravenously administered mosunetuzumab and orally administered lenalidomide, and the efficacy response is complete response rate (CRR), objective response rate (ORR), duration of response (DOR), duration of complete response (DOCR), overall survival (OS), or progression-free survival (PFS).

[0175] In some embodiments, the efficacy response is a CRR, and the CRR or reference CRR is the proportion of subjects receiving the corresponding treatment whose best overall response is a complete response (CR).

[0176] In some embodiments, the improved response in CRR is an increase in CRR compared to a reference CRR of 1% to 25% (e.g., 5% to 25%, 10% to 25%, 15% to 25%, 20% to 25%, 5% to 10%, 5% to 15%, 5% to 20%, 10% to 20%, 10% to 15%, or 15% to 20%; e.g., about 1%, 5%, 10%, 15%, 20%, or 25%). In some embodiments, the efficacy response in CRR is non-inferior to the reference CRR.

[0177] In some embodiments, the efficacy response is ORR, where the ORR or reference ORR is the proportion of subjects receiving the corresponding treatment whose best overall response is CR or partial response (PR). In some embodiments, an improvement in response in ORR is an increase in ORR compared to the reference ORR of 1% to 24% (e.g., 5% to 24%, 10% to 24%, 15% to 24%, 20% to 24%, 5% to 10%, 5% to 15%, 5% to 20%, 10% to 20%, 10% to 15%, or 15% to 20%; e.g., about 1%, 5%, 10%, 15%, 20%, or 24%). In some embodiments, the efficacy response in ORR is non-inferior to the reference ORR.

[0178] In some embodiments, the efficacy response is DOR, and the DOR or reference DOR is measured starting from the first occurrence of documented CR or PR until disease progression or recurrence or death from any cause, whichever occurs first. In some embodiments, the DOR or reference DOR is the median DOR of multiple human patients receiving the corresponding treatment. In some embodiments, the improvement in median DOR is an increase in DOR compared to the reference DOR at 1 to 22 months (e.g., 1 to 5 months, 5 to 22 months, 10 to 22 months, 15 to 22 months, 5 to 10 months, 5 to 15 months, 10 to 22 months, 10 to 15 months, or 15 to 22 months; e.g., about 1 month, 5 months, 10 months, 15 months, 20 months, or 22 months). In some embodiments, the efficacy response in DOR is non-inferior to the reference DOR.

[0179] In some embodiments, the efficacy response is DOCR, and the DOCR or reference DOCR is measured starting from the first occurrence of a documented CR until disease progression or recurrence or death from any cause, whichever occurs first. In some embodiments, the DOCR or reference DOCR is the median DOCR of multiple human patients receiving the corresponding treatment. In some embodiments, the improvement in median DOCR is an increase in DOCR compared to the reference DOCR at 1 to 22 months (e.g., 1 to 5 months, 5 to 22 months, 10 to 22 months, 15 to 22 months, 5 to 10 months, 5 to 15 months, 10 to 22 months, 10 to 15 months, or 15 to 22 months; e.g., about 1 month, 5 months, 10 months, 15 months, 20 months, or 22 months). In some embodiments, the efficacy response in DOCR is non-inferior to the reference DOCR.

[0180] In some embodiments, CR or PR is determined by PET / CT. In some embodiments, CR or PR is determined based on the Lugano response criteria for malignant lymphoma (Cheson et al., 2014).

[0181] In some embodiments, the efficacy response is OS, and the OS or reference OS is measured starting from the first treatment (e.g., the first dose of mosunetuzumab or the first dose of lenalidomide; e.g., day 1 of dosing cycle 1) until death from any cause. In some embodiments, the OS or reference OS is the median OS of multiple human patients receiving the corresponding treatment. In some embodiments, the improvement in median OS is an increase in OS compared to a reference OS of 1 to 28 months (e.g., 1 to 5 months, 5 to 28 months, 10 to 28 months, 15 to 28 months, 20 to 28 months, 25 to 28 months, 5 to 10 months, 5 to 15 months, 5 to 20 months, 5 to 25 months, 10 to 20 months, 10 to 25 months, 10 to 15 months, 15 to 25 months, or 20 to 28 months; e.g., about 1 month, 5 months, 10 months, 15 months, 20 months, 25 months, or 28 months). In some embodiments, the efficacy response in OS is non-inferior to the reference OS.

[0182] In some embodiments, the efficacy response is PFS, and the PFS or reference PFS is measured from the first treatment (e.g., the first dose of mosunetuzumab or the first dose of lenalidomide; e.g., day 1 of dosing cycle 1) to the first occurrence of disease progression or death from any cause. In some embodiments, the PFS or reference PFS is the median PFS of multiple human patients receiving the corresponding treatment. In some embodiments, the improvement in median PFS is an increase in PFS compared to a reference PFS of 1 to 26 months (e.g., 1 to 5 months, 5 to 26 months, 10 to 26 months, 15 to 26 months, 5 to 10 months, 5 to 15 months, 10 to 26 months, 10 to 15 months, 15 to 20 months, or 20 to 26 months; e.g., about 1 month, 5 months, 10 months, 15 months, 20 months, or 26 months). In some embodiments, the efficacy response in PFS is non-inferior compared to the reference PFS.

[0183] In another aspect, the invention features a method for treating follicular lymphoma (FL) in a subject in need thereof, the method comprising administering to the subject a combination treatment comprising subcutaneously administered mosunetuzumab and orally administered lenalidomide, wherein administering the combination treatment to the plurality of subjects results in a non-inferior or improved safety response in the plurality of subjects compared to a reference safety response, where the reference safety response is the safety response of the plurality of subjects who received a control treatment comprising intravenously administered mosunetuzumab and orally administered lenalidomide, and the safety response is an incidence of adverse events (AEs), an incidence of cytokine release syndrome (CRS), or an incidence of serious AEs (SAEs).

[0184] In some embodiments, the safety response is the incidence of an AE, and the prior incidence of an AE or the reference incidence of an AE is the incidence of the AE in multiple subjects receiving the corresponding treatment. In some embodiments, the safety response in the incidence of an AE is non-inferior to the reference AE.

[0185] In some embodiments, the safety response is the incidence of CRS, and the incidence of CRS or reference incidence of CRS is the incidence of CRS in multiple subjects receiving a corresponding treatment. In some embodiments, the improved incidence of CRS is a reduction in the incidence of CRS compared to a reference incidence of CRS of 7% to 17% (e.g., 7% to 12%, 12% to 17%, or 10% to 14%; e.g., about 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, or 17%). In some embodiments, the improved incidence of CRS is a reduction in the incidence of CRS compared to a reference incidence of CRS of about 12%. In some embodiments, the incidence of CRS is the incidence of Grade 1 or 2 CRS in multiple patients receiving a corresponding treatment. In some embodiments, the incidence of Grade 3+ CRS is non-inferior to the reference incidence of Grade 3+ CRS. In some embodiments, CRS is graded based on the American Society of Transplantation and Cellular Therapy (ASTCT) consensus grading for cytokine release syndrome (Lee et al., 2019).

[0186] In some embodiments, the safety response is the incidence of SAE, and the incidence of SAE or the reference incidence of SAE is the incidence of SAE in multiple subjects receiving the corresponding treatment. In some embodiments, the safety response in the incidence of SAE is non-inferior to the reference SAE.

[0187] In another aspect, the present invention provides a method for treating follicular lymphoma (FL) in a subject in need thereof, comprising administering to the subject a combination treatment comprising subcutaneously administered mosunetuzumab and orally administered lenalidomide according to a dosing regimen comprising an initial 21-day dosing cycle and three 28-day dosing cycles, wherein administering the combination treatment to the plurality of subjects results in a non-inferiority pharmacokinetic (PK) endpoint for the plurality of subjects compared to a reference PK endpoint, wherein the PK endpoint is an observed dosing cycle 2 serum trough concentration (scConc). トラフCYC2-OBS ) or cumulative area under the concentration-time curve (scAUC) over 0 to 77 days 0~77) and the reference PK endpoint is a PK endpoint in subjects receiving a control treatment comprising intravenously administered mosunetuzumab and orally administered lenalidomide according to a dosing regimen comprising an initial 21-day dosing cycle and three 28-day dosing cycles, and the reference PK endpoint is the observed dosing cycle 2 serum trough concentration (ivConc トラフCYC2-OBS ) or cumulative area under the concentration-time curve (ivAUC 0~77 ) is a method.

[0188] In some embodiments, the scAUC 0~77 and ivAUC 0~77 One or both of the above are determined using population PK (popPK) model-predicted individual empirical Bayes estimates (EBE).

[0189] In some embodiments, the combination treatment comprises subcutaneous administration of mosunetuzumab and oral administration of lenalidomide according to a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein the first dosing cycle is a 21-day dosing cycle and the second dosing cycle is a 28-day dosing cycle, and (a) the first dosing cycle comprises a first subcutaneous administration (scC1D1), a second subcutaneous administration (scC1D2), and a third subcutaneous administration (scC1D3) of mosunetuzumab administered on days 1, 8, and 15, respectively, of the first dosing cycle, wherein scC1D1 is about 5 mg (e.g., 5 mg ± 10%; 5 mg ± 0.5 mg) and scC1D2 is about (b) a second dosing cycle comprising: (i) a first subcutaneous administration (scC2D1) of mosunetuzumab administered on day 1 of the second dosing cycle, wherein the scC2D1 is about 45 mg (e.g., 45 mg ± 10%; 45 mg ± 4.5 mg); and (ii) 21 oral doses of lenalidomide administered on days 1-21 of the second dosing cycle, wherein each oral dose of lenalidomide is about 20 mg (e.g., 20 mg ± 10%; 20 mg ± 2 mg).In certain embodiments, the combination treatment comprises subcutaneous administration of mosunetuzumab and oral administration of lenalidomide according to a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein the first dosing cycle is a 21-day dosing cycle and the second dosing cycle is a 28-day dosing cycle, and wherein (a) the first dosing cycle comprises a first subcutaneous administration (scC1D1), a second subcutaneous administration (scC1D2), and a third subcutaneous administration (scC1D3), administered on days 1, 8, and 15, respectively, of the first dosing cycle. (b) a second dosing cycle comprising (i) a first subcutaneous administration (scC2D1) of mosunetuzumab administered on day 1 of the second dosing cycle, where scC2D1 is 45 mg; and (ii) 21 oral doses of lenalidomide administered on days 1-21 of the second dosing cycle, where each oral dose of lenalidomide is 20 mg.

[0190] In some embodiments, the combination treatment dosing regimen further comprises one or more additional 28-day dosing cycles, hi some embodiments, the combination treatment dosing regimen comprises ten additional 28-day dosing cycles.

[0191] In some embodiments, each additional dosing cycle comprises: (a) a subcutaneous dose of mosunetuzumab administered on day 1 of the additional dosing cycle, wherein the subcutaneous dose of mosunetuzumab is about 45 mg (e.g., 45 mg ± 10%; 45 mg ± 4.5 mg); and (b) 21 oral doses of lenalidomide administered on days 1-21 of the additional dosing cycle, wherein each oral dose of lenalidomide is about 20 mg (e.g., 20 mg ± 10%; 20 mg ± 2 mg). In certain embodiments, each additional dosing cycle comprises: (i) mosunetuzumab administered subcutaneously on day 1 of the additional dosing cycle, wherein each subcutaneous dose of mosunetuzumab is 45 mg; and (b) 21 oral doses of lenalidomide administered on days 1-21 of the additional dosing cycle, wherein each oral dose of lenalidomide is 20 mg.

[0192] In some embodiments, the combination treatment dosing regimen further comprises 1 to 9 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9) subcutaneous maintenance administrations of mosunetuzumab.

[0193] In another aspect, a method for treating follicular lymphoma (FL) in a subject in need thereof comprises administering to the subject a combination treatment comprising subcutaneously administered mosunetuzumab and orally administered lenalidomide, wherein the combination treatment comprises administering mosunetuzumab subcutaneously and administering lenalidomide orally according to a dosing regimen comprising a first dosing cycle and a second dosing cycle, wherein the first dosing cycle is a 21-day dosing cycle and the second dosing cycle is a 28-day dosing cycle; and ten additional 28-day dosing cycles. and 1 to 9 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9) subcutaneous maintenance administrations of mosunetuzumab, wherein (a) a first dosing cycle comprises a first subcutaneous administration (scC1D1), a second subcutaneous administration (scC1D2), and a third subcutaneous administration (scC1D3) of mosunetuzumab administered on days 1, 8, and 15, respectively, of the first dosing cycle, wherein scC1D1 is about 5 mg (e.g., 5 mg ± 10%; 5 mg ± 0.5 mg) and scC1D2 is about 45 mg (e.g., 45 mg ± 10%; 45 mg ± 4.5 mg), and scC1 (b) a second dosing cycle comprising: (i) a first subcutaneous administration (scC2D1) of mosunetuzumab administered on day 1 of the second dosing cycle, wherein scC2D1 is about 45 mg (e.g., 45 mg ± 10%; 45 mg ± 4.5 mg); and (ii) 21 oral doses of lenalidomide administered on days 1-21 of the second dosing cycle, wherein each oral dose of lenalidomide is about 20 mg (e.g., 20 mg ± 10%; 20 mg ± 2 mg). and (c) 10 additional dosing cycles each comprising: (i) a first subcutaneous dose (scC3D1-scC12D1) of mosunetuzumab administered on day 1 of each additional dosing cycle, where scC3D1 to scC12D1 is about 45 mg (e.g., 45 mg ± 10%; 45 mg ± 4.5 mg); and (ii) 21 oral doses of lenalidomide administered on days 1-21 of each additional dosing cycle, where each oral dose of lenalidomide is about 20 mg (e.g., 20 mg ± 10%; 20 mg ± 2 mg).

[0194] In some embodiments, the combination treatment dosing regimen further comprises nine subcutaneous maintenance doses of mosunetuzumab.

[0195] In some embodiments, one to nine (e.g., one, two, three, four, five, six, seven, eight, or nine) subcutaneous maintenance doses of mosunetuzumab are administered every eight weeks, starting eight weeks after day 1 of a tenth additional 28-day dosing cycle. In some embodiments, each maintenance dose is about 45 mg (e.g., 45 mg ± 10%; 45 mg ± 4.5 mg). In certain embodiments, each maintenance dose is 45 mg.

[0196] In some embodiments, the control treatment comprises intravenously administering mosunetuzumab and orally administering lenalidomide according to a dosing regimen comprising at least a first 21-day dosing cycle and a second 28-day dosing cycle, wherein (a) the first dosing cycle comprises a first intravenous administration (ivC1D1), a second intravenous administration (ivC1D2), and a third intravenous administration (ivC1D3) of mosunetuzumab administered on days 1, 8, and 15, respectively, of the first dosing cycle, wherein ivC1D1 is about 1 mg (e.g., 1 mg ± 10%) and ivC1D2 is about 2 mg. g (e.g., 2 mg ± 10%) and ivC1D3 is about 30 mg (e.g., 30 mg ± 10%); (b) a second dosing cycle comprising: (i) a first intravenous administration (ivC2D1) of mosunetuzumab administered on day 1 of the second dosing cycle, wherein ivC2D1 is about 30 mg (e.g., 30 mg ± 10%); and (ii) 21 oral doses of lenalidomide administered on days 1-21 of the second dosing cycle, wherein each oral dose of lenalidomide is about 20 mg (e.g., 20 mg ± 10%; 20 mg ± 2 mg). In certain embodiments, the control treatment comprises intravenously administering mosunetuzumab and orally administering lenalidomide according to a dosing regimen comprising at least a first 21-day dosing cycle and a second 28-day dosing cycle, wherein (a) the first dosing cycle comprises a first intravenous administration (ivC1D1), a second intravenous administration (ivC1D2), and a third intravenous administration (ivC1D3) of mosunetuzumab administered on days 1, 8, and 15, respectively, of the first dosing cycle. (b) a second dosing cycle comprising: (i) a first intravenous administration (ivC2D1) of mosunetuzumab administered on day 1 of the second dosing cycle, wherein ivC2D1 is 1 mg, ivC1D2 is 2 mg, and ivC1D3 is 30 mg; and (ii) 21 oral doses of lenalidomide administered on days 1-21 of the second dosing cycle, wherein each oral dose of lenalidomide is 20 mg. In some embodiments, the control treatment dosing regimen further comprises one or more additional 28-day dosing cycles.In some embodiments, the control treatment dosing regimen includes 10 additional 28-day dosing cycles, in which each additional dosing cycle includes: (a) intravenous mosunetuzumab administered on day 1 of the additional dosing cycle, where the intravenous dose of mosunetuzumab is about 30 mg (e.g., 30 mg ± 10%); and (b) 21 oral doses of lenalidomide administered on days 1-21 of the additional dosing cycle, where each oral dose of lenalidomide is about 20 mg (e.g., 20 mg ± 10%; 20 mg ± 2 mg). In certain embodiments, each additional dosing cycle comprises: (i) intravenous mosunetuzumab administered on day 1 of the additional dosing cycle, wherein the intravenous dose of mosunetuzumab is 30 mg; and (b) 21 oral doses of lenalidomide administered on days 1-21 of the additional dosing cycle, wherein each oral dose of lenalidomide is 20 mg.

[0197] In one aspect, the invention provides a method for treating follicular lymphoma (FL) in a subject in need thereof, comprising administering to the subject a combination treatment comprising subcutaneously administered mosunetuzumab and orally administered lenalidomide, wherein administering the combination treatment to the plurality of subjects results in a non-inferior or improved efficacy response in the plurality of subjects compared to a reference efficacy response, wherein the reference efficacy response is the efficacy response of the plurality of subjects who received a control treatment comprising intravenously administered mosunetuzumab and orally administered lenalidomide, wherein the efficacy response is complete response rate (CRR), objective response rate (ORR), duration of response (DOR), duration of complete response (DOCR), overall survival (OS), or progression-free survival (PFS), wherein the combination treatment comprises subcutaneous administration of mosunetuzumab and lenalidomide according to a dosing regimen comprising at least a first dosing cycle and a second dosing cycle. the first dosing cycle is a 21-day dosing cycle and the second dosing cycle is a 28-day dosing cycle; (a) the first dosing cycle comprises a first subcutaneous administration (scC1D1), a second subcutaneous administration (scC1D2), and a third subcutaneous administration (scC1D3) of mosunetuzumab administered on days 1, 8, and 15, respectively, of the first dosing cycle; and wherein scC1D1 is about 5 mg (e.g., 5 mg ± 10%; 5 mg ± 10%). mg ± 0.5 mg), scC1D2 is about 45 mg (e.g., 45 mg ± 10%; 45 mg ± 4.5 mg), and scC1D3 is about 45 mg (e.g., 45 mg ± 10%; 45 mg ± 4.5 mg); (b) a second dosing cycle comprising: (i) a first subcutaneous dose (scC2D1) of mosunetuzumab administered on day 1 of the second dosing cycle, wherein scC2D1 is about 45 mg (e.g., 45 mg ± 10%; 45 mg ± 4.5 mg).and (ii) 21 oral doses of lenalidomide administered on days 1-21 of a second dosing cycle, wherein each oral dose of lenalidomide is about 20 mg (e.g., 20 mg ± 10%; 20 mg ± 2 mg); and / or the control treatment comprises intravenously administering mosunetuzumab and orally administering lenalidomide according to a dosing regimen comprising at least a first 21-day dosing cycle and a second 28-day dosing cycle, wherein (a) the first dosing cycle comprises a first intravenous dose (ivC1D1), a second intravenous dose (ivC1D2), and a third intravenous dose (ivC1D3), administered on days 1, 8, and 15, respectively, of the first dosing cycle. (b) a second dosing cycle comprising: (i) a first intravenous administration (ivC2D1) of mosunetuzumab administered on day 1 of the second dosing cycle, wherein ivC2D1 is about 30 mg (e.g., 30 mg ± 10%); and (ii) 21 oral doses of lenalidomide administered on days 1-21 of the second dosing cycle, wherein each oral dose of lenalidomide is about 20 mg (e.g., 20 mg ± 10%; 20 mg ± 2 mg).

[0198] In another aspect, the present invention provides a method for treating follicular lymphoma (FL) in a subject in need thereof, comprising administering to the subject a combination treatment comprising subcutaneously administered mosunetuzumab and orally administered lenalidomide, wherein administering the combination treatment to the plurality of subjects results in a non-inferior or improved safety response in the plurality of subjects compared to a reference safety response, wherein the reference safety response is a safety response in the plurality of subjects who received a control treatment comprising intravenously administered mosunetuzumab and orally administered lenalidomide, wherein the safety response is an incidence of adverse events (AEs), an incidence of cytokine release syndrome (CRS), or an incidence of serious AEs (SAEs), wherein the combination treatment comprises subcutaneous administration of mosunetuzumab and oral administration of lenalidomide according to a dosing regimen comprising at least a first dosing cycle and a second dosing cycle. wherein the first dosing cycle is a 21-day dosing cycle and the second dosing cycle is a 28-day dosing cycle, (a) the first dosing cycle comprises a first subcutaneous administration (scC1D1), a second subcutaneous administration (scC1D2), and a third subcutaneous administration (scC1D3) of mosunetuzumab administered on days 1, 8, and 15, respectively, of the first dosing cycle, wherein scC1D1 is about 5 mg (e.g., 5 mg ± 10%; 5 mg ± 0%). 0.5 mg), scC1D2 is about 45 mg (e.g., 45 mg ± 10%; 45 mg ± 4.5 mg), and scC1D3 is about 45 mg (e.g., 45 mg ± 10%; 45 mg ± 4.5 mg); (b) a second dosing cycle comprising: (i) a first subcutaneous dose (scC2D1) of mosunetuzumab administered on day 1 of the second dosing cycle, wherein scC2D1 is about 45 mg (e.g., 45 mg ± 10%; 45 mg ± 4.5 mg);and (ii) 21 oral doses of lenalidomide administered on days 1-21 of a second dosing cycle, wherein each oral dose of lenalidomide is about 20 mg (e.g., 20 mg ± 10%; 20 mg ± 2 mg); and / or the control treatment comprises intravenously administering mosunetuzumab and orally administering lenalidomide according to a dosing regimen comprising at least a first 21-day dosing cycle and a second 28-day dosing cycle, wherein (a) the first dosing cycle comprises a first intravenous dose (ivC1D1), a second intravenous dose (ivC1D2), and a third intravenous dose (ivC1D3), administered on days 1, 8, and 15, respectively, of the first dosing cycle. (b) the second dosing cycle comprises (i) a first intravenous administration (ivC2D1) of mosunetuzumab administered on day 1 of the second dosing cycle, where ivC2D1 is about 30 mg (e.g., 30 mg ± 10%); and (ii) 21 oral doses of lenalidomide administered on days 1-21 of the second dosing cycle, where each oral dose of lenalidomide is about 20 mg (e.g., 20 mg ± 10%; 20 mg ± 2 mg).

[0199] In another aspect, the present invention provides a method for treating follicular lymphoma (FL) in a subject in need thereof, comprising administering to the subject a combination treatment comprising subcutaneously administered mosunetuzumab and orally administered lenalidomide according to a dosing regimen comprising an initial 21-day dosing cycle and three 28-day dosing cycles, wherein administering the combination treatment to the plurality of subjects results in a non-inferiority pharmacokinetic (PK) endpoint for the plurality of subjects compared to a reference PK endpoint, wherein the PK endpoint is an observed dosing cycle 2 serum trough concentration (scConc). トラフCYC2-OBS ) or cumulative area under the concentration-time curve (scAUC) over 0 to 77 days 0~77); the reference PK endpoint is a PK endpoint in subjects receiving a control treatment comprising intravenously administered mosunetuzumab and orally administered lenalidomide according to a dosing regimen comprising an initial 21-day dosing cycle and three 28-day dosing cycles, and the reference PK endpoint is the observed dosing cycle 2 serum trough concentration (ivConc トラフCYC2-OBS ) or cumulative area under the concentration-time curve (ivAUC 0~77), wherein the combination treatment comprises subcutaneous administration of mosunetuzumab and oral administration of lenalidomide according to a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, the first dosing cycle being a 21-day dosing cycle and the second dosing cycle being a 28-day dosing cycle, and (a) the first dosing cycle comprising a first subcutaneous administration (scC1D1), a second subcutaneous administration (scC1D2), and a third subcutaneous administration (scC1D3) administered on days 1, 8, and 15, respectively, of the first dosing cycle. (b) a second dosing cycle comprising: (i) a first subcutaneous dose (scC2D1) of mosunetuzumab administered on day 1 of the second dosing cycle, wherein scC2D1 is about 5 mg (e.g., 5 mg ± 10%; 5 mg ± 0.5 mg), scC1D2 is about 45 mg (e.g., 45 mg ± 10%; 45 mg ± 4.5 mg), and scC1D3 is about 45 mg (e.g., 45 mg ± 10%; 45 mg ± 4.5 mg); and (b) a second dosing cycle comprising: (i) a first subcutaneous dose (scC2D1) of mosunetuzumab administered on day 1 of the second dosing cycle, wherein scC2D1 is about 45 mg (e.g., 45 mg ± 10%; 45 mg ± 4.5 mg).and (ii) 21 oral doses of lenalidomide administered on days 1-21 of a second dosing cycle, wherein each oral dose of lenalidomide is about 20 mg (e.g., 20 mg ± 10%; 20 mg ± 2 mg); and / or the control treatment comprises intravenously administering mosunetuzumab and orally administering lenalidomide according to a dosing regimen comprising at least a first 21-day dosing cycle and a second 28-day dosing cycle, wherein (a) the first dosing cycle comprises a first intravenous dose (ivC1D1), a second intravenous dose (ivC1D2), and a third intravenous dose (ivC1D3), administered on days 1, 8, and 15, respectively, of the first dosing cycle. (b) the second dosing cycle comprises (i) a first intravenous administration (ivC2D1) of mosunetuzumab administered on day 1 of the second dosing cycle, where ivC2D1 is about 30 mg (e.g., 30 mg ± 10%); and (ii) 21 oral doses of lenalidomide administered on days 1-21 of the second dosing cycle, where each oral dose of lenalidomide is about 20 mg (e.g., 20 mg ± 10%; 20 mg ± 2 mg).

[0200] In some embodiments, the combination treatment dosing regimen further comprises one or more additional 28-day dosing cycles, hi some embodiments, the combination treatment dosing regimen comprises ten additional 28-day dosing cycles.

[0201] In some embodiments, each additional dosing cycle comprises: (a) a subcutaneous dose of mosunetuzumab administered on day 1 of the additional dosing cycle, wherein the subcutaneous dose of mosunetuzumab is about 45 mg (e.g., 45 mg ± 10%; 45 mg ± 4.5 mg); and (b) 21 oral doses of lenalidomide administered on days 1-21 of the additional dosing cycle, wherein each oral dose of lenalidomide is about 20 mg (e.g., 20 mg ± 10%; 20 mg ± 2 mg).

[0202] In some embodiments, the combination treatment dosing regimen further comprises one to nine (e.g., one, two, three, four, five, six, seven, eight, or nine) subcutaneous maintenance doses of mosunetuzumab. In some embodiments, the one to nine (e.g., one, two, three, four, five, six, seven, eight, or nine) subcutaneous maintenance doses of mosunetuzumab are administered every eight weeks starting eight weeks after day 1 of a tenth additional 28-day dosing cycle. In some embodiments, each maintenance dose is about 45 mg (e.g., 45 mg ± 10%; 45 mg ± 4.5 mg).

[0203] In some embodiments, the control treatment dosing regimen further comprises one or more additional 28-day dosing cycles. In some embodiments, the control treatment dosing regimen comprises ten additional 28-day dosing cycles. In some embodiments, each additional dosing cycle comprises: (a) intravenous mosunetuzumab administered on day 1 of the additional dosing cycle, wherein the intravenous dose of mosunetuzumab is about 30 mg (e.g., 30 mg ± 10%); and (b) 21 oral doses of lenalidomide administered on days 1-21 of the additional dosing cycle, wherein each oral dose of lenalidomide is about 20 mg (e.g., 20 mg ± 10%; 20 mg ± 2 mg).

[0204] In some embodiments, the subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2. In some embodiments, the subject has not been previously treated for FL. In some embodiments, the subject has relapsed after or is refractory to one or more prior lines of systemic therapy. In some embodiments, the one or more prior lines of systemic therapy comprise immunotherapy or chemoimmunotherapy. In some embodiments, the one or more prior lines of systemic therapy comprise an anti-CD20 antibody. In some embodiments, the anti-CD20 antibody is rituximab.

[0205] In some embodiments, the FL is grade 1, 2, or 3a.

[0206] In some embodiments, the method comprises administering an additional therapeutic agent. In some embodiments, the additional therapeutic agent comprises a corticosteroid, an antihistamine, an antipyretic, or an IL-6R antagonist. In some embodiments, the additional therapeutic agent is a corticosteroid, and the corticosteroid comprises prednisone, methylprednisolone, or dexamethasone. In some embodiments, the additional therapeutic agent is an antihistamine, and the antihistamine comprises diphenhydramine hydrochloride or an equivalent. In some embodiments, the additional therapeutic agent is an antipyretic, and the antipyretic is acetaminophen. In some embodiments, the additional therapeutic agent is an IL-6R antagonist, and the IL-6R antagonist is tocilizumab. In some embodiments, the additional therapeutic agent is administered according to the methods described below in Part C (Dosing Strategies to Reduce Adverse Events (e.g., Cytokine Release Syndrome)).

[0207] In one aspect, the invention features use of mosunetuzumab to treat non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL) in a subject in need of such treatment, wherein mosunetuzumab is administered subcutaneously as a treatment, and the administration of the treatment to a plurality of subjects results in a non-inferior or improved efficacy response in the plurality of subjects compared to a reference efficacy response, where the reference efficacy response is the efficacy response of a plurality of subjects who received a control treatment comprising mosunetuzumab administered intravenously, and the efficacy response is complete response rate (CRR), objective response rate (ORR), duration of response (DOR), duration of complete response (DOCR), progression-free survival (PFS), or overall survival (OS).

[0208] In one aspect, the invention features the use of mosunetuzumab in the manufacture of a medicament for treating non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL) in a subject in need of such treatment, wherein mosunetuzumab is administered subcutaneously as a treatment, and the administration of the treatment to the plurality of subjects results in a non-inferior or improved efficacy response in the plurality of subjects compared to a reference efficacy response, where the reference efficacy response is the efficacy response of the plurality of subjects who received a control treatment comprising mosunetuzumab administered intravenously, and the efficacy response is complete response rate (CRR), objective response rate (ORR), duration of response (DOR), duration of complete response (DOCR), progression-free survival (PFS), or overall survival (OS).

[0209] In one aspect, the invention features mosunetuzumab for use in treating non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL) in a subject in need thereof, wherein the mosunetuzumab is administered subcutaneously as a treatment, and the administration of the treatment to a plurality of subjects results in a non-inferior or improved efficacy response in the plurality of subjects compared to a reference efficacy response, wherein the reference efficacy response is the efficacy response of a plurality of subjects who received a control treatment comprising mosunetuzumab administered intravenously, and the efficacy response is complete response rate (CRR), objective response rate (ORR), duration of response (DOR), duration of complete response (DOCR), progression-free survival (PFS), or overall survival (OS).

[0210] In one aspect, the invention features use of mosunetuzumab to treat non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL) in a subject in need of such treatment, wherein mosunetuzumab is administered subcutaneously as a treatment, and the administration of the treatment to a plurality of subjects results in a non-inferior or improved safety response in the plurality of subjects compared to a reference safety response, where the reference safety response is the safety response of a plurality of subjects who received a control treatment comprising mosunetuzumab administered intravenously, and the safety response is the incidence of adverse events (AEs), the incidence of cytokine release syndrome (CRS), or the incidence of serious AEs (SAEs).

[0211] In one aspect, the invention features use of mosunetuzumab in the manufacture of a medicament for treating non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL) in a subject in need of such treatment, wherein mosunetuzumab is administered subcutaneously as a treatment, and the administration of the treatment to the plurality of subjects results in a non-inferior or improved safety response in the plurality of subjects compared to a reference safety response, where the reference safety response is the safety response of the plurality of subjects who received a control treatment comprising mosunetuzumab administered intravenously, and the safety response is the incidence of adverse events (AEs), the incidence of cytokine release syndrome (CRS), or the incidence of serious AEs (SAEs).

[0212] In one aspect, the invention features mosunetuzumab for treating non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL) in a subject in need of such treatment, wherein the mosunetuzumab is administered subcutaneously as a treatment, and the administration of the treatment to the plurality of subjects results in a non-inferior or improved safety response in the plurality of subjects compared to a reference safety response, wherein the reference safety response is the safety response of the plurality of subjects who received a control treatment comprising mosunetuzumab administered intravenously, and the safety response is an incidence of adverse events (AEs), an incidence of cytokine release syndrome (CRS), or an incidence of serious AEs (SAEs).

[0213] In one aspect, the present invention provides a use of mosunetuzumab to treat non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL) in a subject in need thereof, wherein the treatment comprises mosunetuzumab administered subcutaneously according to a dosing regimen comprising four 21-day dosing cycles, and the administration of the combination treatment to the plurality of subjects results in non-inferiority or improved pharmacokinetic (PK) endpoints compared to a reference PK endpoint, wherein the PK endpoint is observed dosing cycle 3 serum trough concentration (scConc トラフCYC3-OBS) or cumulative area under the concentration-time curve (scAUC) over 0 to 84 days 0~84 ), where the reference PK endpoint is a PK endpoint in multiple subjects receiving a control treatment containing intravenously administered mosunetuzumab according to a dosing regimen comprising four 21-day dosing cycles, and the reference PK endpoint is the observed dosing cycle 3 serum trough concentration (ivConc トラフCYC3-OBS ) or cumulative area under the concentration-time curve (ivAUC 0~84 ) and is characterized by its use.

[0214] In one aspect, the invention provides a use of mosunetuzumab in the manufacture of a medicament for treating non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL) in a subject in need thereof, wherein the treatment comprises mosunetuzumab administered subcutaneously according to a dosing regimen comprising four 21-day dosing cycles, and the combination treatment is administered to the plurality of subjects, resulting in non-inferiority or improved pharmacokinetic (PK) endpoints compared to a reference PK endpoint, wherein the PK endpoint is observed dosing cycle 3 serum trough concentration (scConc). トラフCYC3-OBS ) or cumulative area under the concentration-time curve (scAUC) over 0 to 84 days 0~84 ), where the reference PK endpoint is a PK endpoint in multiple subjects receiving a control treatment containing intravenously administered mosunetuzumab according to a dosing regimen comprising four 21-day dosing cycles, and the reference PK endpoint is the observed dosing cycle 3 serum trough concentration (ivConc トラフCYC3-OBS ) or cumulative area under the concentration-time curve (ivAUC 0~84 ) and is characterized by its use.

[0215] In one aspect, the present invention provides mosunetuzumab for the treatment of non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL) in a subject in need thereof, wherein the treatment comprises mosunetuzumab administered subcutaneously according to a dosing regimen comprising four 21-day dosing cycles, and the combination treatment is administered to the plurality of subjects, resulting in a non-inferiority or improved pharmacokinetic (PK) endpoint compared to a reference PK endpoint in the plurality of subjects, wherein the PK endpoint is observed dosing cycle 3 serum trough concentration (scConc トラフCYC3-OBS ) or cumulative area under the concentration-time curve (scAUC) over 0 to 84 days 0~84 ), where the reference PK endpoint is a PK endpoint in multiple subjects receiving a control treatment containing intravenously administered mosunetuzumab according to a dosing regimen comprising four 21-day dosing cycles, and the reference PK endpoint is the observed dosing cycle 3 serum trough concentration (ivConc トラフCYC3-OBS ) or cumulative area under the concentration-time curve (ivAUC 0~84 ) and is characterized by mosunetuzumab.

[0216] In some embodiments, administering a combination treatment comprising subcutaneously administered mosunetuzumab and orally administered lenalidomide to subjects with FL results in an ORR of about 81% to about 99% (e.g., 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) in the subjects. In some embodiments, the ORR is about 90%. In some embodiments, administering the combination treatment to a plurality of subjects with FL results in a CRR of about 79% to about 97% (e.g., 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, or 97%) in the plurality of subjects. In some embodiments, the CRR is about 88%. In some embodiments, administering the combination treatment to a plurality of subjects with FL results in a 12-month event-free rate of DOR of about 86% to about 100% (e.g., 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) in the plurality of subjects. In some embodiments, the 12-month event-free rate of DOR is about 94%. In some embodiments, administering the combination treatment to subjects with FL results in a 12-month event-free rate of DOCR of about 86% to about 100% (e.g., 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) in the subjects. In some embodiments, the 12-month event-free rate of DOCR is about 94%. In some embodiments, administering the combination treatment to subjects with FL results in a 12-month event-free PFS rate of about 76% to about 98% (e.g., 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, or 98%) in the subjects. In some embodiments, the 12-month event-free PFS rate is about 87%.In some embodiments, administering the combination treatment to subjects with FL results in a 12-month event-free rate of OS of about 92% to about 100% (e.g., 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) in the subjects. In some embodiments, the 12-month event-free rate of OS is about 97%. In some embodiments, the FL is previously untreated (1L) FL.

[0217] B. Treatment Methods for Dosing Mosunetuzumab Monotherapy In one aspect, the invention features a method for treating non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL) in a subject in need thereof, the method including administering to the subject a treatment comprising subcutaneously administered mosunetuzumab, wherein administering the treatment to the plurality of subjects results in a non-inferior or improved efficacy response in the plurality of subjects compared to a reference efficacy response, where the reference efficacy response is the efficacy response of the plurality of subjects who received a control treatment comprising intravenously administered mosunetuzumab, and the efficacy response is complete response rate (CRR), objective response rate (ORR), duration of response (DOR), duration of complete response (DOCR), progression-free survival (PFS), or overall survival (OS).

[0218] In some embodiments, the efficacy response is a CRR, and the CRR or reference CRR is the proportion of subjects receiving the corresponding treatment whose best overall response is a complete response (CR). In some embodiments, an improved response in CRR is an increase in CRR compared to the reference CRR of 1% to 20% (e.g., 5% to 20%, 10% to 20%, 15% to 20%, 1% to 15%, 1% to 10%, 1% to 5%, 5% to 15%, or 10% to 20%; e.g., about 1%, about 5%, about 10%, about 15%, or about 20%). In some embodiments, the efficacy response in CRR is non-inferior to the reference CRR rate.

[0219] In some embodiments, the efficacy response is ORR, where ORR or reference ORR is the proportion of subjects receiving the corresponding treatment whose best overall response is CR or partial response (PR). In some embodiments, an improvement in response in ORR is an increase in ORR compared to a reference ORR of 1% to 13% (e.g., 1% to 5%, 5% to 13%, or 3% to 10%; e.g., about 1%, about 5%, about 10%, or 13%). In some embodiments, the efficacy response in ORR is non-inferior to the reference ORR.

[0220] In some embodiments, the efficacy response is DOR, and the DOR or reference DOR is measured starting from the first occurrence of documented CR or PR until disease progression or recurrence or death from any cause, whichever occurs first. In some embodiments, the DOR or reference DOR is the median DOR of multiple human patients receiving the corresponding treatment. In some embodiments, the median improvement in DOR is an increase in DOR compared to the reference DOR of 1 to 13 months (e.g., 1 to 5 months, 5 to 13 months, or 3 to 10 months; e.g., about 1 month, 5 months, 10 months, or 13 months). In some embodiments, the efficacy response in DOR is non-inferior to the reference DOR. In some embodiments, the improved DOR is an increase in the 12-month DOR rate compared to a 12-month reference DOR rate of 1% to 31% (e.g., 1% to 25%, 1% to 20%, 1% to 15%, 1% to 10%, 1% to 5%, 5% to 10%, 5% to 15%, 5% to 20%, 5% to 25%, 5% to 31%, 1% to 10%, 10% to 20%, 20% to 31%, 15% to 31%, 1% to 20%, or 10% to 31%; e.g., about 1%, 5%, 10%, 15%, 20%, 25%, or 31%). In some embodiments, the improved DOR is an increase in the 12-month DOR rate compared to a 12-month reference DOR rate of about 8%.

[0221] In some embodiments, the efficacy response is a DOCR, and the DOCR or reference DOCR is measured starting from the first occurrence of a documented CR until disease progression or recurrence or death from any cause, whichever occurs first. In some embodiments, the DOCR or reference DOCR is the median DOCR of multiple human patients receiving the corresponding treatment. In some embodiments, the improvement in DOCR is an increase in the 12-month DOCR rate compared to the 12-month reference DOCR rate of 1% to 27% (e.g., 1% to 25%, 1% to 20%, 1% to 15%, 1% to 10%, 1% to 5%, 5% to 10%, 5% to 15%, 5% to 20%, 5% to 25%, 5% to 27%, 1% to 10%, 10% to 20%, 20% to 27%, 15% to 27%, 1% to 20%, or 10% to 27%; e.g., about 1%, 5%, 10%, 15%, 20%, 25%, or 27%). In some embodiments, the efficacy response in DOCR is non-inferior to the reference DOCR.

[0222] In some embodiments, CR or PR is determined by PET / CT. In some embodiments, CR or PR is determined based on the revised response criteria for malignant lymphoma (Cheson et al., 2007).

[0223] In some embodiments, the efficacy response is PFS, and the PFS or reference PFS is measured from the first treatment (e.g., the first dose of mosunetuzumab or the first dose of lenalidomide; e.g., day 1 of dosing cycle 1) to the first occurrence of disease progression or death from any cause. In some embodiments, the PFS or reference PFS is the median PFS of multiple human patients receiving the corresponding treatment. In some embodiments, the improvement in median PFS is an increase in PFS compared to a reference PFS of 1 to 14 months (e.g., between 1 to 5 months, 5 to 14 months, or 3 to 10 months; e.g., about 1 month, 5 months, 10 months, or 14 months). In some embodiments, the efficacy response in PFS is non-inferior to the reference PFS. In some embodiments, an improvement in PFS is an increase in the rate of PFS compared to a 12-month reference PFS rate of 1% to 26% (e.g., 1% to 20%, 1% to 15%, 1% to 10%, 1% to 5%, 5% to 10%, 5% to 15%, 5% to 20%, 5% to 26%, 1% to 10%, 10% to 20%, 20% to 26%, 15% to 26%, 1% to 20%, or 10% to 26%; e.g., about 1%, 5%, 10%, 15%, 20% or 26%). In some embodiments, an improvement in PFS is an increase in the rate of PFS compared to a 12-month reference PFS rate of about 5%.

[0224] In some embodiments, the efficacy response is OS, where OS or reference OS is measured starting from the first treatment (e.g., the first dose of mosunetuzumab or the first dose of lenalidomide; e.g., day 1 of dosing cycle 1) until death from any cause. In some embodiments, an improvement in OS is an increase in the OS rate compared to a 12-month reference OS rate of 1% to 9% (e.g., about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, or 9%). In some embodiments, the efficacy response in OS is non-inferior to the reference OS.

[0225] In another aspect, the invention features a method for treating non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL) in a subject in need thereof, the method including administering to the subject a treatment comprising subcutaneously administered mosunetuzumab, wherein administering the treatment to the plurality of subjects results in a non-inferior or improved safety response in the plurality of subjects compared to a reference safety response, where the reference safety response is the safety response of the plurality of subjects who received a control treatment comprising intravenously administered mosunetuzumab, and the safety response is an incidence of adverse events (AEs), an incidence of cytokine release syndrome (CRS), or an incidence of serious AEs (SAEs).

[0226] In some embodiments, the safety response is the incidence of an AE, and the incidence of an AE or reference incidence of an AE is the incidence of an AE in multiple subjects receiving a corresponding treatment. In some embodiments, the safety response in incidence of an AE is non-inferior compared to the reference AE. In some embodiments, the improved incidence of an AE is a reduction in the incidence of Grade 3 or 4 AEs by 11% to 21% (e.g., 11% to 16%, 16% to 21%, or 13% to 19%; e.g., about 11%, about 16%, or about 21%) compared to the reference incidence of Grade 3 or 4 AEs. In some embodiments, the improved incidence of an AE is a reduction in the incidence of Grade 3 or 4 AEs by about 16% compared to the reference incidence of Grade 3 or 4 AEs. In some embodiments, the incidence of an AE is the incidence of Grade 5 AEs in multiple subjects receiving a corresponding treatment, and the incidence of an AE is non-inferior compared to the reference incidence of AEs. In some embodiments, the grade of the AE is determined based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), v4.0.

[0227] In some embodiments, the safety response is the incidence of SAEs, and the incidence of SAEs or reference incidence of SAEs is the incidence of SAEs in multiple subjects receiving the corresponding treatment. In some embodiments, the improved safety response in incidence of SAEs is a reduction in the incidence of SAEs of 9% to 19% (e.g., 9% to 14%, 14% to 19%, or 11% to 17%, e.g., about 9%, about 14%, or about 19%) compared to the reference incidence of SAEs. In some embodiments, the improved safety response in incidence of SAEs is a reduction in the incidence of SAEs of about 14% compared to the reference incidence of SAEs.

[0228] In some embodiments, the safety response is the incidence of CRS, and the incidence of CRS or reference incidence of CRS is the incidence of CRS in multiple subjects receiving the corresponding treatment. In some embodiments, the improved incidence of CRS is a reduction in the incidence of CRS of 9% to 19% (e.g., 9% to 14%, 14% to 19%, or 11% to 17%, e.g., about 9%, about 14%, or about 19%) compared to the reference incidence of CRS. In some embodiments, the improved incidence of CRS is a reduction in the incidence of CRS compared to a reference incidence of about 14%. In some embodiments, the improved incidence of CRS is a reduction in the incidence of Grade 2+ CRS of 3% to 13% (e.g., 3% to 8%, 8% to 13%, or 5% to 11%; e.g., about 3%, about 8%, or about 13%) compared to the reference incidence of Grade 2+ CRS. In some embodiments, the improved incidence of CRS is an approximately 8% reduction in the incidence of Grade 2+ CRS compared to a reference incidence of Grade 2+ CRS. In some embodiments, the grade of CRS is determined based on the Modified Cytokine Release Syndrome Grading System (Lee et al., 2014).

[0229] In another aspect, the present invention provides a method for treating non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL) in a subject in need thereof, comprising administering to the subject a treatment comprising subcutaneously administered mosunetuzumab according to a dosing regimen comprising four 21-day dosing cycles, wherein administering the combination treatment to the plurality of subjects results in a non-inferiority or improved pharmacokinetic (PK) endpoint for the plurality of subjects compared to a reference PK endpoint, wherein the PK endpoint is an observed dosing cycle 3 serum trough concentration (scConc). トラフCYC3-OBS ) or cumulative area under the concentration-time curve (scAUC) over 0 to 84 days 0~84 ), where the reference PK endpoint is a PK endpoint in multiple subjects receiving a control treatment containing intravenously administered mosunetuzumab according to a dosing regimen comprising four 21-day dosing cycles, and the reference PK endpoint is the observed dosing cycle 3 serum trough concentration (ivConc トラフCYC3-OBS ) or cumulative area under the concentration-time curve (ivAUC 0~84 ) is a method.

[0230] In some embodiments, the scAUC 0~84 and ivAUC 0~84 One or more of the following are determined using a population PK (popPK) model predictive individual empirical Bayes estimate (EBE).

[0231] In some embodiments, the treatment comprises subcutaneously administering mosunetuzumab according to a dosing regimen comprising at least a first 21-day dosing cycle and a second 21-day dosing cycle, wherein (a) the first dosing cycle comprises a first subcutaneous administration (scC1D1), a second subcutaneous administration (scC1D2), and a third subcutaneous administration (scC1D3) of mosunetuzumab administered on days 1, 8, and 15, respectively, of the first dosing cycle, wherein scC1D1 is about 5 mg (e.g., 5 mg ± 10%; 5 mg ± 0.5 mg); (b) a second dosing cycle comprises a first subcutaneous administration (scC2D1) of mosunetuzumab administered on day 1 of the second dosing cycle, wherein scC2D1 is about 45 mg (e.g., 45 mg ± 10%; 45 mg ± 4.5 mg). In certain embodiments, scC1D2 is about 45 mg (e.g., 45 mg ± 10%; 45 mg ± 4.5 mg). In certain embodiments, the treatment comprises subcutaneously administering mosunetuzumab according to a dosing regimen comprising at least a first 21-day dosing cycle and a second 21-day dosing cycle, wherein (a) the first dosing cycle comprises a first subcutaneous administration (scC1D1), a second subcutaneous administration (scC1D2), and a third subcutaneous administration (scC1D3) of mosunetuzumab administered on days 1, 8, and 15, respectively, of the first dosing cycle, where scC1D1 is 5 mg, scC1D2 is 15 mg or 45 mg, and scC1D3 is 45 mg; and (b) the second dosing cycle comprises a first subcutaneous administration (scC2D1) of mosunetuzumab administered on day 1 of the second dosing cycle, where scC2D1 is 45 mg. In certain embodiments, scC1D2 is 45 mg.

[0232] In some embodiments, the treatment dosing regimen further comprises one or more additional 21-day dosing cycles. In some embodiments, the treatment dosing regimen comprises 6, 15, or 23 additional 21-day dosing cycles. In some embodiments, each additional dosing cycle comprises subcutaneous mosunetuzumab administered on day 1 of the additional dosing cycle, wherein the subcutaneous mosunetuzumab is about 45 mg (e.g., 45 mg ± 10%; 45 mg ± 4.5 mg). In certain embodiments, each additional dosing cycle comprises subcutaneous mosunetuzumab administered on day 1 of the additional dosing cycle, wherein the subcutaneous mosunetuzumab is 45 mg.

[0233] In some embodiments, the control treatment comprises administering mosunetuzumab intravenously according to a dosing regimen comprising at least a first 21-day dosing cycle and a second 21-day dosing cycle, wherein (a) the first dosing cycle comprises a first intravenous administration (ivC1D1), a second intravenous administration (ivC1D2), and a third intravenous administration (ivC1D3) of mosunetuzumab administered on days 1, 8, and 15, respectively, of the first dosing cycle. (b) a second dosing cycle comprising a first intravenous dose (ivC2D1) of mosunetuzumab administered on day 1 of the second dosing cycle, wherein ivC2D1 is about 1 mg (e.g., 1 mg ± 10%), ivC1D2 is about 2 mg (e.g., 2 mg ± 10%), and ivC1D3 is about 60 mg (e.g., 60 mg ± 10%); (b) a second dosing cycle comprising a first intravenous dose (ivC2D1) of mosunetuzumab administered on day 1 of the second dosing cycle, wherein ivC2D1 is 60 mg (e.g., 60 mg ± 10%). In certain embodiments, the control treatment comprises administering mosunetuzumab intravenously according to a dosing regimen comprising at least a first 21-day dosing cycle and a second 21-day dosing cycle, wherein (a) the first dosing cycle comprises a first intravenous administration (ivC1D1), a second intravenous administration (ivC1D2), and a third intravenous administration (ivC1D3) of mosunetuzumab administered on days 1, 8, and 15, respectively, of the first dosing cycle, wherein ivC1D1 is 1 mg, ivC1D2 is 2 mg, and ivC1D3 is 60 mg; and (b) the second dosing cycle comprises a first intravenous administration (ivC2D1) of mosunetuzumab administered on day 1 of the second dosing cycle, wherein ivC2D1 is 60 mg. In some embodiments, the control treatment dosing regimen further comprises one or more additional 21-day dosing cycles. In some embodiments, the control treatment dosing regimen comprises 6, 15, or 23 additional 21-day dosing cycles. In some embodiments, each additional dosing cycle comprises intravenous mosunetuzumab administered on day 1 of the additional dosing cycle, wherein the intravenous mosunetuzumab is about 30 mg (e.g., 30 mg ± 10%). In certain embodiments, each additional dosing cycle comprises intravenous mosunetuzumab administered on day 1 of the additional dosing cycle, wherein the intravenous mosunetuzumab is about 30 mg.

[0234] In one aspect, the invention provides a method for treating non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL) in a subject in need thereof, comprising administering to the subject a treatment comprising subcutaneously administered mosunetuzumab, wherein administering the treatment to the plurality of subjects results in a non-inferior or improved efficacy response in the plurality of subjects compared to a reference efficacy response, wherein the reference efficacy response is the efficacy response of the plurality of subjects who received a control treatment comprising intravenously administered mosunetuzumab, wherein the efficacy response is complete response rate (CRR), objective response rate (ORR), duration of response (DOR), duration of complete response (DOCR), progression-free survival (PFS), or overall survival (OS), wherein the treatment is administered with a dosing regimen comprising at least a first 21-day dosing cycle and a second 21-day dosing cycle. Thus, the method includes administering mosunetuzumab subcutaneously, wherein (a) a first dosing cycle includes a first subcutaneous administration (scC1D1), a second subcutaneous administration (scC1D2), and a third subcutaneous administration (scC1D3) of mosunetuzumab administered on days 1, 8, and 15, respectively, of the first dosing cycle, wherein scC1D1 is about 5 mg (e.g., 5 mg ± 10%; 5 mg ± 0.5 mg) and scC1D2 is about 15 mg (e.g., 15 mg ± 0.5 mg). ±10%; 15 mg ±1.5 mg) or about 45 mg (e.g., 45 mg ±10%; 45 mg ±4.5 mg) and scC1D3 is about 45 mg (e.g., 45 mg ±10%; 45 mg ±4.5 mg); (b) the second dosing cycle is a first subcutaneous dose (scC2D1) of mosunetuzumab administered on day 1 of the second dosing cycle, and scC2D1 is about 45 mg (e.g., 45 mg ±10%; 45 mg ±4.5 mg).and the control treatment comprises intravenously administering mosunetuzumab according to a dosing regimen comprising at least a first 21-day dosing cycle and a second 21-day dosing cycle, wherein (a) the first dosing cycle comprises a first intravenous dose (ivC1D1), a second intravenous dose (ivC1D2), and a third intravenous dose (ivC1D3) of mosunetuzumab administered on days 1, 8, and 15, respectively, of the first dosing cycle. (b) the second dosing cycle comprises a first intravenous administration (ivC2D1) of mosunetuzumab administered on day 1 of the second dosing cycle, wherein ivC2D1 is about 1 mg (e.g., 1 mg ± 10%), ivC1D2 is about 2 mg (e.g., 2 mg ± 10%), and ivC1D3 is about 60 mg (e.g., 60 mg ± 10%). In certain embodiments, scC1D2 is about 45 mg (e.g., 45 mg ± 10%; 45 mg ± 4.5 mg).

[0235] In another aspect, the present invention provides a method for treating non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL) in a subject in need thereof, comprising administering to the subject a treatment comprising subcutaneously administered mosunetuzumab, wherein administering the treatment to the plurality of subjects results in a non-inferior or improved safety response in the plurality of subjects compared to a reference safety response, wherein the reference safety response is a safety response in the plurality of subjects who received a control treatment comprising intravenously administered mosunetuzumab, wherein the safety response is an incidence of adverse events (AEs), an incidence of cytokine release syndrome (CRS), or an incidence of serious AEs (SAEs), wherein the treatment comprises administering mosunetuzumab according to a dosing regimen comprising at least a first 21-day dosing cycle and a second 21-day dosing cycle. (a) a first dosing cycle comprising a first subcutaneous administration (scC1D1), a second subcutaneous administration (scC1D2), and a third subcutaneous administration (scC1D3) of mosunetuzumab administered on days 1, 8, and 15, respectively, of the first dosing cycle, wherein scC1D1 is about 5 mg (e.g., 5 mg ± 10%; 5 mg ± 0.5 mg) and scC1D2 is about 15 mg (e.g., 15 mg ± 10%; ;15mg±1.5mg) or about 45mg (e.g., 45mg±10%; 45mg±4.5mg) and scC1D3 is about 45mg (e.g., 45mg±10%; 45mg±4.5mg); (b) the second dosing cycle is a first subcutaneous dose (scC2D1) of mosunetuzumab administered on day 1 of the second dosing cycle, and scC2D1 is about 45mg (e.g., 45mg±10%; 45mg±4.5mg).and the control treatment comprises intravenously administering mosunetuzumab according to a dosing regimen comprising at least a first 21-day dosing cycle and a second 21-day dosing cycle, wherein (a) the first dosing cycle comprises a first intravenous dose (ivC1D1), a second intravenous dose (ivC1D2), and a third intravenous dose (ivC1D3) of mosunetuzumab administered on days 1, 8, and 15, respectively, of the first dosing cycle. (b) the second dosing cycle comprises a first intravenous administration (ivC2D1) of mosunetuzumab administered on day 1 of the second dosing cycle, wherein ivC2D1 is about 1 mg (e.g., 1 mg ± 10%), ivC1D2 is about 2 mg (e.g., 2 mg ± 10%), and ivC1D3 is about 60 mg (e.g., 60 mg ± 10%). In certain embodiments, scC1D2 is about 45 mg (e.g., 45 mg ± 10%; 45 mg ± 4.5 mg).

[0236] In another aspect, the present invention provides a method for treating non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL) in a subject in need thereof, comprising administering to the subject a treatment comprising subcutaneously administered mosunetuzumab according to a dosing regimen comprising four 21-day dosing cycles, wherein administering the combination treatment to the plurality of subjects results in a non-inferiority or improved pharmacokinetic (PK) endpoint for the plurality of subjects compared to a reference PK endpoint, wherein the PK endpoint is an observed dosing cycle 3 serum trough concentration (scConc). トラフCYC3-OBS ) or cumulative area under the concentration-time curve (scAUC) over 0 to 84 days 0~84 ), where the reference PK endpoint is a PK endpoint in multiple subjects receiving a control treatment containing intravenously administered mosunetuzumab according to a dosing regimen comprising four 21-day dosing cycles, and the reference PK endpoint is the observed dosing cycle 3 serum trough concentration (ivConc トラフCYC3-OBS ) or cumulative area under the concentration-time curve (ivAUC 0~84), wherein the treatment comprises subcutaneously administering mosunetuzumab according to a dosing regimen comprising at least a first 21-day dosing cycle and a second 21-day dosing cycle, (a) the first dosing cycle comprises a first subcutaneous administration (scC1D1), a second subcutaneous administration (scC1D2), and a third subcutaneous administration (scC1D3) of mosunetuzumab administered on days 1, 8, and 15, respectively, of the first dosing cycle, and wherein scC1D1 is about 5 mg (e.g., 5 mg ± 10%; (b) a second dosing cycle comprising a first subcutaneous administration (scC2D1) of mosunetuzumab administered on day 1 of the second dosing cycle, wherein the scC2D1 is about 45 mg (e.g., 45 mg ± 0.5 mg), the scC1D2 is about 15 mg (e.g., 15 mg ± 10%; 15 mg ± 1.5 mg) or about 45 mg (e.g., 45 mg ± 10%; 45 mg ± 4.5 mg), and the scC1D3 is about 45 mg (e.g., 45 mg ± 10%; 45 mg ± 4.5 mg); and the control treatment comprises intravenously administering mosunetuzumab according to a dosing regimen comprising at least a first 21-day dosing cycle and a second 21-day dosing cycle, wherein (a) the first dosing cycle comprises a first intravenous dose (ivC1D1), a second intravenous dose (ivC1D2), and a third intravenous dose (ivC1D3) administered on days 1, 8, and 15, respectively, of the first dosing cycle. (b) a second dosing cycle comprising mosunetuzumab, wherein ivC1D1 is about 1 mg (e.g., 1 mg ± 10%), ivC1D2 is about 2 mg (e.g., 2 mg ± 10%), and ivC1D3 is about 60 mg (e.g., 60 mg ± 10%); (b) the second dosing cycle comprises a first intravenous administration (ivC2D1) of mosunetuzumab administered on day 1 of the second dosing cycle, wherein ivC2D1 is 60 mg (e.g., 60 mg ± 10%). In certain embodiments, scC1D2 is about 45 mg (e.g., 45 mg ± 10%; 45 mg ± 4.5 mg).

[0237] In some embodiments, the treatment dosing regimen further comprises one or more additional 21-day dosing cycles. In some embodiments, the treatment dosing regimen comprises 6, 15, or 23 additional 21-day dosing cycles. In some embodiments, each additional dosing cycle comprises subcutaneous mosunetuzumab administered on day 1 of the additional dosing cycle, and the subcutaneous mosunetuzumab is about 45 mg (e.g., 45 mg ± 10%; 45 mg ± 4.5 mg).

[0238] In some embodiments, the control treatment dosing regimen further comprises one or more additional 21-day dosing cycles. In some embodiments, the control treatment dosing regimen comprises 6, 15, or 23 additional 21-day dosing cycles. In some embodiments, each additional dosing cycle comprises intravenous mosunetuzumab administered on day 1 of the additional dosing cycle, and the intravenous mosunetuzumab is about 30 mg (e.g., 30 mg ± 10%).

[0239] In some embodiments, the subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. In some embodiments, the subject has relapsed after or is refractory to one or more prior lines of systemic therapy. In some embodiments, the subject has relapsed after or is refractory to two or more prior lines of systemic therapy. In some embodiments, the one or more prior lines of systemic therapy comprise an anti-CD20 antibody, an alkylating agent, a Bruton's tyrosine kinase (BTK) inhibitor, an anthracycline, or a combination thereof.

[0240] In some embodiments, the NHL is follicular lymphoma (FL), marginal zone lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), transformed FL (trFL), high-grade B-cell lymphoma (HGBL), primary mediastinal B-cell lymphoma (PMLBCL), transformed indolent NHL, mantle cell lymphoma (MCL), Richter's transformed, or small lymphocytic lymphoma (SLL). In some embodiments, the NHL is FL, and the FL is grade 1-3b FL or transformed FL. In some embodiments, the FL is grade 1-3a FL, and the subject has relapsed after or is refractory to two or more prior lines of systemic therapy, including an anti-CD20 antibody and an alkylating agent. In some embodiments, the NHL is DLBCL or trFL. In some embodiments, the NHL is DLBCL or trFL, and the subject has relapsed after or is refractory to two or more prior lines of systemic therapy including an anthracycline and an anti-CD20 antibody. In some embodiments, the NHL is Richter transformed. In some embodiments, the NHL is Richter transformed, and the subject has relapsed after or is refractory to one or more prior lines of systemic therapy including an anthracycline and an anti-CD20 antibody. In some embodiments, the anti-CD20 antibody is rituximab. In some embodiments, the NHL is MCL. In some embodiments, the NHL is MCL, and the subject has relapsed after or is refractory to one or more prior lines of systemic therapy including a BTK inhibitor.

[0241] In some embodiments, the alkylating agent is cyclophosphamide (CAS No.: 50-18-0) or bendamustine (CAS No.: 3543-75-7). In some embodiments, the anthracycline is daunomycin (CAS No.: 20830-81-3) or doxorubicin (CAS No.: 23214-92-8). In some embodiments, the BTK inhibitor is 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one and salts thereof, ibrutinib (CAS No.: 936563-96-1), acalabrutinib (CAS No.: 1420477-60-6), or zanubrutinib (CAS No.: 1691249-45-2).

[0242] In some embodiments, the method comprises administering an additional therapeutic agent. In some embodiments, the additional therapeutic agent comprises a corticosteroid, an antihistamine, an antipyretic, or an IL-6R antagonist. In some embodiments, the additional therapeutic agent is a corticosteroid, and the corticosteroid comprises prednisone, methylprednisolone, or dexamethasone. In some embodiments, the additional therapeutic agent is an antihistamine, and the antihistamine comprises diphenhydramine hydrochloride or an equivalent. In some embodiments, the additional therapeutic agent is an antipyretic, and the antipyretic is acetaminophen. In some embodiments, the additional therapeutic agent is an IL-6R antagonist, and the IL-6R antagonist is tocilizumab. In some embodiments, the additional therapeutic agent is administered according to the methods described below in Part C (Dosing Strategies to Reduce Adverse Events (e.g., Cytokine Release Syndrome)).

[0243] In one aspect, the invention features use of mosunetuzumab to treat non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL) in a subject in need of such treatment, wherein mosunetuzumab is administered subcutaneously as a treatment, and the administration of the treatment to a plurality of subjects results in a non-inferior or improved efficacy response in the plurality of subjects compared to a reference efficacy response, where the reference efficacy response is the efficacy response of a plurality of subjects who received a control treatment comprising mosunetuzumab administered intravenously, and the efficacy response is complete response rate (CRR), objective response rate (ORR), duration of response (DOR), duration of complete response (DOCR), progression-free survival (PFS), or overall survival (OS).

[0244] In one aspect, the invention features the use of mosunetuzumab in the manufacture of a medicament for treating non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL) in a subject in need of such treatment, wherein mosunetuzumab is administered subcutaneously as a treatment, and the administration of the treatment to the plurality of subjects results in a non-inferior or improved efficacy response in the plurality of subjects compared to a reference efficacy response, where the reference efficacy response is the efficacy response of the plurality of subjects who received a control treatment comprising mosunetuzumab administered intravenously, and the efficacy response is complete response rate (CRR), objective response rate (ORR), duration of response (DOR), duration of complete response (DOCR), progression-free survival (PFS), or overall survival (OS).

[0245] In one aspect, the invention features mosunetuzumab for use in treating non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL) in a subject in need thereof, wherein the mosunetuzumab is administered subcutaneously as a treatment, and the administration of the treatment to a plurality of subjects results in a non-inferior or improved efficacy response in the plurality of subjects compared to a reference efficacy response, wherein the reference efficacy response is the efficacy response of a plurality of subjects who received a control treatment comprising mosunetuzumab administered intravenously, and the efficacy response is complete response rate (CRR), objective response rate (ORR), duration of response (DOR), duration of complete response (DOCR), progression-free survival (PFS), or overall survival (OS).

[0246] In one aspect, the invention features use of mosunetuzumab to treat non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL) in a subject in need of such treatment, wherein mosunetuzumab is administered subcutaneously as a treatment, and the administration of the treatment to a plurality of subjects results in a non-inferior or improved safety response in the plurality of subjects compared to a reference safety response, where the reference safety response is the safety response of a plurality of subjects who received a control treatment comprising mosunetuzumab administered intravenously, and the safety response is the incidence of adverse events (AEs), the incidence of cytokine release syndrome (CRS), or the incidence of serious AEs (SAEs).

[0247] In one aspect, the invention features use of mosunetuzumab in the manufacture of a medicament for treating non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL) in a subject in need of such treatment, wherein mosunetuzumab is administered subcutaneously as a treatment, and the administration of the treatment to the plurality of subjects results in a non-inferior or improved safety response in the plurality of subjects compared to a reference safety response, where the reference safety response is the safety response of the plurality of subjects who received a control treatment comprising mosunetuzumab administered intravenously, and the safety response is the incidence of adverse events (AEs), the incidence of cytokine release syndrome (CRS), or the incidence of serious AEs (SAEs).

[0248] In one aspect, the invention features mosunetuzumab for treating non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL) in a subject in need of such treatment, wherein the mosunetuzumab is administered subcutaneously as a treatment, and the administration of the treatment to the plurality of subjects results in a non-inferior or improved safety response in the plurality of subjects compared to a reference safety response, wherein the reference safety response is the safety response of the plurality of subjects who received a control treatment comprising mosunetuzumab administered intravenously, and the safety response is an incidence of adverse events (AEs), an incidence of cytokine release syndrome (CRS), or an incidence of serious AEs (SAEs).

[0249] In one aspect, the present invention provides a use of mosunetuzumab to treat non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL) in a subject in need thereof, wherein the treatment comprises mosunetuzumab administered subcutaneously according to a dosing regimen comprising four 21-day dosing cycles, and the administration of the combination treatment to the plurality of subjects results in non-inferiority or improved pharmacokinetic (PK) endpoints compared to a reference PK endpoint, wherein the PK endpoint is observed dosing cycle 3 serum trough concentration (scConc トラフCYC3-OBS) or cumulative area under the concentration-time curve (scAUC) over 0 to 84 days 0~84 ), where the reference PK endpoint is a PK endpoint in multiple subjects receiving a control treatment containing intravenously administered mosunetuzumab according to a dosing regimen comprising four 21-day dosing cycles, and the reference PK endpoint is the observed dosing cycle 3 serum trough concentration (ivConc トラフCYC3-OBS ) or cumulative area under the concentration-time curve (ivAUC 0~84 ) and is characterized by its use.

[0250] In one aspect, the present invention provides the use of mosunetuzumab in the manufacture of a medicament for treating non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL) in a subject in need thereof, wherein mosunetuzumab is administered subcutaneously as a treatment according to a dosing regimen comprising four 21-day dosing cycles, and the combination treatment is administered to the plurality of subjects to demonstrate non-inferiority or superiority compared to a reference pharmacokinetic (PK) endpoint in the plurality of subjects. improved PK endpoints were obtained, where the PK endpoint was the observed dosing cycle 3 serum trough concentration (scConcTroughCYC3-OBS) or the cumulative area under the concentration-time curve over days 0 to 84 (scAUC0-84), and the reference PK endpoint was a PK endpoint in multiple subjects receiving a control treatment containing intravenously administered mosunetuzumab according to a dosing regimen including four 21-day dosing cycles, where the reference PK endpoint was the observed dosing cycle 3 serum trough concentration (ivConcTroughCYC3-OBS). トラフCYC3-OBS ) or cumulative area under the concentration-time curve (ivAUC 0~84 ) and is characterized by its use.

[0251] In one aspect, the present invention provides mosunetuzumab for the treatment of non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL) in a subject in need thereof, wherein the treatment comprises administering mosunetuzumab subcutaneously according to a dosing regimen comprising four 21-day dosing cycles, and administering the combination treatment to the plurality of subjects results in non-inferiority or improved efficacy compared to a reference pharmacokinetic (PK) endpoint in the plurality of subjects. PK endpoints were obtained, where the PK endpoint was the observed dosing cycle 3 serum trough concentration (scConcTroughCYC3-OBS) or the cumulative area under the concentration-time curve over days 0 to 84 (scAUC0-84), and the reference PK endpoint was a PK endpoint in multiple subjects receiving a control treatment containing intravenously administered mosunetuzumab according to a dosing regimen including four 21-day dosing cycles, where the reference PK endpoint was the observed dosing cycle 3 serum trough concentration (ivConcTroughCYC3-OBS). トラフCYC3-OBS ) or cumulative area under the concentration-time curve (ivAUC 0~84 ) and is characterized by mosunetuzumab.

[0252] In some embodiments, administering a treatment comprising subcutaneous mosunetuzumab to subjects with R / R FL results in an ORR of about 66% to about 85% (e.g., 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, or 85%). In some embodiments, the ORR is about 77%. In some embodiments, administering treatment to subjects with R / R FL results in a CRR of about 51% to about 72% (e.g., 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, or 72%) in the subjects. In some embodiments, the CRR is about 62%. In some embodiments, administering the treatment to a plurality of subjects with R / R FL results in an 18-month event-free rate of DOCR of about 57% to about 83% (e.g., 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, or 83%) in the plurality of subjects. In some embodiments, the 18-month event-free rate of DOCR is about 70%. In some embodiments, administering the treatment to a plurality of subjects with R / R FL results in a median DOCR of at least about 20 months (e.g., 20, 24, 28, 32, 36, 40, 44, 48, 60, 72 months or longer) in the plurality of subjects. In some embodiments, the median DOCR is about 35 months. In some embodiments, administering treatment to subjects with R / R FL results in an 18-month event-free PFS rate of about 46% to about 68% (e.g., 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, or 68%) in the subjects. In some embodiments, the 18-month event-free PFS rate is about 57%.In some embodiments, administering treatment to multiple subjects with R / R FL results in a median PFS of at least 14 months (e.g., 14, 18, 22, 24, 28, 30, 34, 38, 42 months or longer) in the multiple subjects. In some embodiments, the median PFS is about 24 months.

[0253] In some embodiments, administration of a treatment comprising subcutaneous mosunetuzumab to multiple subjects with 1L FL results in an ORR of about 76% to about 96% (e.g., 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95% or 96%). In some embodiments, administering a treatment comprising subcutaneous mosunetuzumab to multiple subjects with 1L FL results in an ORR of about 72% to about 96% (e.g., 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, or 96%). In some embodiments, the ORR is about 87%. In some embodiments, administering a treatment to multiple subjects with 1L FL results in a CRR of about 55% to about 67% (e.g., 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, or 67%) in the multiple subjects. In some embodiments, treatment results in a CRR of at least about 44% to about 77% (e.g., 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, or 77%) of the subject population. In some embodiments, the CRR is about 61%. In some embodiments, administering the treatment to a plurality of subjects with 1L FL results in a 12-month event-free rate of PFS of about 73% to about 90% (e.g., 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, or 90%) in the plurality of subjects. In some embodiments, the 12-month event-free rate of PFS is about 83%. In some embodiments, administering the treatment to a plurality of subjects with 1L FL results in a median time to response (TTR) of about 1 month to about 6 months (e.g., about 1, 2, 3, 4, 5, or 6 months) in the plurality of subjects who respond.In some embodiments, the median TTR is about 3 months. In some embodiments, a plurality of subjects have high tumor burden according to the Groupe d'Etude des Lymphomes Folliculaires (GELF) criteria. In some embodiments, a plurality of subjects with 1L FL and exhibiting above-mentioned ORR or CRR are 65 years of age or older. In some embodiments, a plurality of subjects with 1L FL and exhibiting above-mentioned ORR or CRR are under 65 years of age. In some embodiments, a plurality of subjects with 1L FL and exhibiting above-mentioned ORR or CRR have a FLIPI score of 0 or 1. In some embodiments, a plurality of subjects with 1L FL and exhibiting above-mentioned ORR or CRR have a FLIPI score of 2. In some embodiments, a plurality of subjects with 1L FL and exhibiting above-mentioned ORR or CRR have a FLIPI score of 3-5. In some embodiments, a plurality of subjects with 1L FL and exhibiting above-mentioned ORR or CRR have elevated lactate dehydrogenase (LDH) levels (i.e., ≥ upper limit of normal (ULN) (e.g., >280 units / L)). In some embodiments, a plurality of subjects with 1L FL and exhibiting above-mentioned ORR or CRR do not have elevated LDH. In some embodiments, a plurality of subjects with 1L FL and exhibiting above-mentioned ORR or CRR have B symptoms (e.g., fever, night sweats, and weight loss). In some embodiments, a plurality of subjects with 1L FL and exhibiting above-mentioned ORR or CRR do not have B symptoms. In some embodiments, a plurality of subjects with 1L FL and exhibiting above-mentioned ORR or CRR have bulky disease (i.e., defined in the context of TLS as any lesion ≥ 10 cm on a screening CT scan). In some embodiments, a plurality of subjects with 1L FL and exhibiting above-mentioned ORR or CRR do not have bulky disease. In some embodiments, a plurality of subjects with 1L FL and exhibiting above-mentioned ORR or CRR have Grade 1 or 2 FL. In some embodiments, a plurality of subjects with 1L FL and exhibiting ORR or CRR above have grade 3a FL.

[0254] In some embodiments, administering a treatment comprising subcutaneous mosunetuzumab to subjects with 1L MZL results in an ORR of about 58% to about 88% (e.g., 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, or 88%). In some embodiments, the ORR is about 75%. In some embodiments, administering the treatment to a plurality of subjects with 1L MZL results in a CRR of about 44% to about 77% (e.g., 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, or 77%) in the plurality of subjects. In some embodiments, the CRR is about 61%. In some embodiments, administering the treatment to a plurality of subjects with 1L MZL results in a median TTR of about 2 months to about 6 months (e.g., about 2, 3, 4, 5, or 6 months) in the plurality of responding subjects. In some embodiments, the median TTR is about 3 months.

[0255] C. Medication strategies for mitigation of adverse events (e.g., cytokine release syndrome) In some embodiments, administration of mosunetuzumab and / or lenalidomide to a subject according to the methods herein may result in an adverse event in the subject. Described herein are methods for administering one or more additional therapeutic agents to alleviate (e.g., reduce the severity or duration of) and / or prevent the adverse event in a subject.

[0256] In some embodiments, the first dosing cycle further comprises administration of a corticosteroid. In some embodiments, the second dosing cycle further comprises administration of a corticosteroid. In some embodiments, any of one or more additional dosing cycles comprises administration of a corticosteroid. In some embodiments, a single dose of a corticosteroid is administered to the subject prior to administration of any dose of mosunetuzumab. In some embodiments, the corticosteroid comprises dexamethasone or methylprednisolone. In some embodiments, the corticosteroid is administered intravenously or orally. In some embodiments, the corticosteroid comprises dexamethasone and is administered at a dose of about 20 mg (e.g., 20 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 3 mg, or ± 4 mg; e.g., 20 mg). In some embodiments, the corticosteroid comprises methylprednisolone and is administered at a dose of about 80 mg (e.g., 80 mg ± 0.01 mg, ± 0.025 mg, ± 0.05 mg, ± 0.075 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 3 mg, ± 4 mg, ± 5 mg, ± 6 mg, ± 7 mg, ± 8 mg, ± 10 mg, ± 12 mg, ± 14 mg, or ± 16 mg; e.g., 80 mg).

[0257] In some embodiments, the first dosing cycle further comprises administration of an antihistamine. In some embodiments, the second dosing cycle further comprises administration of an antihistamine. In some embodiments, any of one or more additional dosing cycles comprises administration of an antihistamine. In some embodiments, a single dose of the antihistamine is administered to the subject prior to administration of any dose of mosunetuzumab (e.g., 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 60 minutes, 70 minutes, 80 minutes, 90 minutes, 120 minutes, 150 minutes, 180 minutes, or more). In some embodiments, the antihistamine is administered to the subject at least 30 minutes (e.g., 30, 35, 40, 45, 50, 60, 70, 80, 90, 120, 150, 180 minutes, or more) prior to administration of any dose of mosunetuzumab. In some embodiments, the antihistamine is administered orally or intravenously. In some embodiments, the antihistamine comprises diphenhydramine hydrochloride and is administered at a dose of about 50-100 mg (e.g., 50-90 mg, 50-80 mg, 50-70 mg, 50-60 mg, 60-100 mg, 70-100 mg, 80-100 mg, 90-100 mg, 70-80 mg, 60-90 mg, 60-80 mg, 70-90 mg, or 65-85 mg; e.g., about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 mg).

[0258] In some embodiments, the first dosing cycle further comprises administration of an antipyretic agent. In some embodiments, the second dosing cycle further comprises administration of an antipyretic agent. In some embodiments, any of one or more additional dosing cycles comprises administration of an antipyretic agent. In some embodiments, a single dose of the antipyretic agent is administered to the subject prior to administration of any dose of mosunetuzumab. In some embodiments, the antipyretic agent is administered to the subject at least 30 minutes (e.g., 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 60 minutes, 70 minutes, 80 minutes, 90 minutes, 120 minutes, 150 minutes, 180 minutes, or more) prior to administration of any dose of mosunetuzumab. In some embodiments, the antipyretic agent is administered orally. In some embodiments, the antipyretic comprises acetaminophen and is administered at a dose of about 500-1000 mg (e.g., 500-900 mg, 500-800 mg, 500-700 mg, 500-600 mg, 600-1000 mg, 700-1000 mg, 800-1000 mg, 900-1000 mg, 700-800 mg, 600-900 mg, 600-800 mg, 700-900 mg, or 650-850 mg; e.g., about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, or about 1000 mg).

[0259] In some embodiments, the first dosing cycle further comprises administration of an initial dose of a prophylactic agent against tumor lysis syndrome (TLS). In some embodiments, the second dosing cycle further comprises administration of an initial dose of a prophylactic agent against TLS. In some embodiments, any of one or more additional dosing cycles comprises administration of an initial dose of a prophylactic agent against TLS. In some embodiments, the initial dose of a prophylactic agent against TLS is administered to the subject prior to administration of any dose of mosunetuzumab. In some embodiments, the prophylactic agent against TLS comprises allopurinol. In some embodiments, the initial dose of allopurinol is administered about 72 hours (e.g., 72 hours ± 0.5 hours, ± 1 hour, ± 2 hours, ± 3 hours, ± 4 hours, ± 8 hours, ± 12 hours, or ± 16 hours; e.g., 72 hours) before administration of any dose of mosunetuzumab. In some embodiments, an additional single dose of allopurinol is administered daily for 6 to 10 days (± 1 day) after administration of the initial dose. In some embodiments, the initial dose of allopurinol is about 300 mg (e.g., 300 mg ± 5 mg, ± 10 mg, ± 15 mg, ± 20 mg, ± 25 mg, ± 30 mg, ± 45 mg, or ± 60 mg; e.g., 300 mg). In some embodiments, each additional single dose of allopurinol is about 300 mg (e.g., 300 mg ± 5 mg, ± 10 mg, ± 15 mg, ± 20 mg, ± 25 mg, ± 30 mg, ± 45 mg, or ± 60 mg; e.g., 300 mg). In some embodiments, allopurinol is administered orally. In some embodiments, the prophylactic agent against TLS comprises rasburicase. In some embodiments, the first dose of rasburicase is administered about 30 minutes (e.g., 30±0.5 minutes, 1 minute, ±2 minutes, ±3 minutes, ±4 minutes, ±5 minutes, or ±6 minutes; e.g., 30 minutes) before the administration of any dose of mosunetuzumab. In some embodiments, an additional single dose of rasburicase is administered daily for 1 to 5 days (±1 day) after administration of the first dose. In some embodiments, the first dose of rasburicase is about 0.2 mg / kg (e.g., 0.2±0.005 mg / kg, ±0.01 mg / kg, ±0.02 mg / kg, ±0.03 mg / kg, or ±0.04 mg / kg; e.g., 0.2 mg / kg).In some embodiments, each additional single dose of rasburicase is about 0.2 mg / kg (e.g., 0.2±0.005 mg / kg, ±0.01 mg / kg, ±0.02 mg / kg, ±0.03 mg / kg, or ±0.04 mg / kg; e.g., 0.2 mg / kg). In some embodiments, rasburicase is administered intravenously.

[0260] In some embodiments, an IL-6R antagonist may be administered to a subject treated with the methods of the present invention, for example, after administration of any dose of mosunetuzumab, for example, if the subject exhibits CRS. In some embodiments, the IL-6R antagonist is tocilizumab. In some embodiments, tocilizumab is administered to a subject as a single dose of about 8 mg / kg (e.g., 8 mg / kg ± 0.01 mg / kg, ± 0.025 mg / kg, ± 0.05 mg / kg, ± 0.075 mg / kg, ± 0.1 mg / kg, ± 0.2 mg / kg, ± 0.3 mg / kg, ± 0.4 mg / kg, ± 0.5 mg / kg, ± 0.75 mg / kg, ± 1 mg / kg, ± 1.5 mg / kg, or ± 2 mg / kg; e.g., 8 mg / kg), where the single dose does not exceed 800 mg. In some embodiments, tocilizumab is administered to a subject as a single dose of about 12 mg / kg (e.g., 12 mg / kg ± 0.01 mg / kg, ± 0.025 mg / kg, ± 0.05 mg / kg, ± 0.075 mg / kg, ± 0.1 mg / kg, ± 0.2 mg / kg, ± 0.3 mg / kg, ± 0.4 mg / kg, ± 0.5 mg / kg, ± 0.75 mg / kg, ± 1 mg / kg, ± 1.5 mg / kg, or ± 2 mg / kg; e.g., 12 mg / kg), wherein the single dose does not exceed 800 mg. In some embodiments, tocilizumab is administered intravenously.

[0261] The methods described herein may result in an acceptable safety profile for subjects with a CD20-positive cell proliferative disorder (e.g., a B-cell proliferative disorder; e.g., NHL or CLL) being treated with mosunetuzumab monotherapy or mosunetuzumab in combination with lenalidomide. In some cases, treatment using the methods described herein, including administration of mosunetuzumab and / or oral administration of lenalidomide, results in a reduction (e.g., by 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more) of undesirable adverse events, such as cytokine-driven toxicity (e.g., cytokine release syndrome (CRS)), infusion reaction (IRR), macrophage activation syndrome (MAS), neurotoxicity, tumor lysis syndrome (TLS), neutropenia, thrombocytopenia, elevated liver enzymes, and / or hepatotoxicity. or more, 96% or more, 97% or more, 98% or more, or 99% or more; for example, 20% to 100%, 20% to 90%, 20% to 80%, 20% to 70%, 20% to 60%, 20% to 50%, 20% to 40%, 20% to 30%, 40% to 100%, 60% to 100%, 80% to 100%, 30% to 70%, 40% to 60%, 30% to 50 %, 50% to 80%, or 90% to 100%; e.g., about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 97%, about 99%, or about 100%) or complete inhibition (a 100% reduction).

[0262] In some cases, subcutaneous administration of mosunetuzumab as monotherapy or in combination with lenalidomide in accordance with the methods described herein results in a reduction (e.g., by 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, 50% or more, 55% or more, 60% or more, 65% or more) in undesirable adverse events such as cytokine-driven toxicity (e.g., cytokine release syndrome (CRS)), infusion reaction (IRR), macrophage activation syndrome (MAS), neurotoxicity, tumor lysis syndrome (TLS), neutropenia, thrombocytopenia, liver enzyme elevation, and / or hepatotoxicity, when compared to intravenous administration of mosunetuzumab as monotherapy or in combination with lenalidomide in accordance with the methods described herein. 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 96% or more, 97% or more, 98% or more, or 99% or more; for example, 20% to 100%, 20% to 90%, 20% to 80%, 20% to 70%, 20% to 60%, 20% to 50%, 20% to 40%, 20% to 30%, 40% to 100%, 60% to 100%, 80% to 100%, 30% to 7 0%, 40% to 60%, 30% to 50%, 50% to 80%, or 90% to 100%; e.g., about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 97%, about 99%, or about 100%) or complete inhibition (100% reduction).

[0263] IV. Therapeutic Agents A. Mosunetuzumab The present invention provides mosunetuzumab, a bispecific antibody that binds CD20 and CD3, useful for treating a CD20-positive cell proliferative disorder, such as a B-cell proliferative disorder (e.g., non-Hodgkin's lymphoma (NHL) (e.g., previously untreated (1L) NHL, diffuse large B-cell lymphoma (DLBCL) (e.g., 1L DLBCL, relapsed and / or refractory DLBCL, or Richter's transformation), follicular lymphoma (FL) (e.g., 1L FL, relapsed and / or refractory FL, or transformed FL), mantle cell lymphoma (MCL), high-grade B-cell lymphoma, or primary mediastinal (thymic) large B-cell lymphoma (PMLBCL)) or chronic lymphocytic leukemia (CLL).

[0264] Mosunetuzumab has an anti-CD20 arm with a first binding domain comprising the following six hypervariable regions (HVRs): (a) HVR-H1 comprising the amino acid sequence of GYTFTSYNMH (SEQ ID NO: 1); (b) HVR-H2 comprising the amino acid sequence of AIYPGNGDTSYNQKFKG (SEQ ID NO: 2); (c) HVR-H3 comprising the amino acid sequence of VVYYSNSYWYFDV (SEQ ID NO: 3); (d) HVR-L1 comprising the amino acid sequence of RASSSVSYMH (SEQ ID NO: 4); (e) HVR-L2 comprising the amino acid sequence of APSNLAS (SEQ ID NO: 5); and (f) HVR-L3 comprising the amino acid sequence of QQWSFNPPT (SEQ ID NO: 6). Mosunetuzumab comprises an anti-CD20 arm comprising a first binding domain comprising heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequences of SEQ ID NOs: 17 to 20, respectively, and light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequences of SEQ ID NOs: 21 to 24, respectively. Mosunetuzumab comprises an anti-CD20 arm comprising a first binding domain comprising (a) a heavy chain variable (VH) domain comprising the amino acid sequence of SEQ ID NO: 7 and (b) a light chain variable (VL) domain comprising the amino acid sequence of SEQ ID NO: 8.

[0265] Mosunetuzumab has an anti-CD3 arm with a second binding domain comprising the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of NYYIH (SEQ ID NO: 9); (b) HVR-H2 comprising the amino acid sequence of WIYPGDGNTKYNEKFKG (SEQ ID NO: 10); (c) HVR-H3 comprising the amino acid sequence of DSYSNYYFDY (SEQ ID NO: 11); (d) HVR-L1 comprising the amino acid sequence of KSSQSLLNSRTRKNYLA (SEQ ID NO: 12); (e) HVR-L2 comprising the amino acid sequence of WASTRES (SEQ ID NO: 13); and (f) HVR-L3 comprising the amino acid sequence of TQSFILRT (SEQ ID NO: 14). Mosunetuzumab comprises an anti-CD3 arm comprising a second binding domain comprising heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequences of SEQ ID NOs: 25 to 28, respectively, and light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequences of SEQ ID NOs: 29 to 32, respectively. Mosunetuzumab comprises an anti-CD3 arm comprising a second binding domain comprising (a) a VH domain comprising an amino acid sequence having the amino acid sequence of SEQ ID NO: 15 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 16.

[0266] Mosunetuzumab has International Nonproprietary Name (INN) List 117 (WHO Drug Information, Vol. 31, No. 2, 2017, pp. 304-305), or CAS Registry Number 1905409-39-3, and has (1) an anti-CD20 arm comprising the heavy chain and light chain sequences of SEQ ID NOs: 33 and 34, respectively, and (2) an anti-CD3 arm comprising the heavy chain and light chain sequences of SEQ ID NOs: 35 and 36, respectively. Mosunetuzumab comprises (1) an anti-CD20 arm comprising a first binding domain comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 33 and a light chain comprising the amino acid sequence of SEQ ID NO: 34, and (2) an anti-CD3 arm comprising a second binding domain comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 35 and a light chain comprising the amino acid sequence of SEQ ID NO: 36.

[0267] The amino acid sequence of mosunetuzumab is summarized in Table 1 below. [Table 1]

[0268] Mosunetuzumab can be produced using recombinant methods and compositions, for example, as described in US Pat. No. 4,816,567.

[0269] B. Lenalidomide Lenalidomide is an immunomodulatory imide (IMiD) drug that binds to the E3 ubiquitin ligase protein cereblon (Gribben et al. J. Clin. Oncol. 33(25):2803-2811, 2015). Although lenalidomide's immunomodulatory activity is not fully understood, it has been shown to enhance CD4+ and CD8+ T cell costimulation, induce T cell proliferation, and enhance IL-2 and IFN-γ (Haslett et al. J. Exp. Med. 187(11):1885-1892, 1998; Davies et al. Blood 98(1):210-216, 2001).

[0270] Lenalidomide has the CAS Registry Number 191732-72-6 and the IUPAC name (3RS)-3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione. Lenalidomide is also known by trade names including REVLIMID®, linamide, and lenalid. Lenalidomide has DrugBank Accession Number DB00480, PubChem CID 216326, and the chemical formula C 13 H 13 It has N3O3.

[0271] C. Additional Therapeutic Agents In some cases, the methods described herein include administering mosunetuzumab and lenalidomide in combination with one or more additional therapeutic agents.

[0272] In some cases, one or more additional therapeutic agents may prevent, reduce the incidence of, or reduce the severity of cytokine release syndrome (CRS) and / or symptoms associated with CRS. In certain cases, additional therapeutic agents used to reduce the rate or severity of CRS or prevent symptoms associated with CRS include corticosteroids (e.g., dexamethasone (CAS#: 50-02-2), prednisone (CAS#: 53-03-2), prednisolone (CAS#: 50-42-8), or methylprednisolone (CAS#: 83-43-2)), antihistamines (e.g., diphenhydramine (CAS#: 58-73-1), and their pharmaceutical equivalents). and a pharmaceutically acceptable salt thereof, e.g., diphenhydramine hydrochloride (CAS No.: 147-24-0) or an interleukin-6 receptor (IL-6R) antagonist (e.g., tocilizumab (CAS No.: 375823-41-9), sarilumab (CAS No.: 1189541-98-7), bovalilizumab (ALX-0061; CAS No.: 1628814-88-9), satralizumab (SA-237; CAS No.: 1535963-91-7), and alternatives thereof). In some cases, the additional therapeutic agent is a corticosteroid. In particular examples, the corticosteroid is dexamethasone or methylprednisolone. In particular examples, the antihistamine is diphenhydramine hydrochloride. In particular examples, the antipyretic is acetaminophen (i.e., paracetamol) or a pharmaceutically acceptable salt thereof. In a particular example, the IL-6R antagonist is tocilizumab.

[0273] In some cases, one or more additional therapeutic agents may be used in the treatment of neutropenia. In some cases, the additional therapeutic agent may prevent symptoms associated with neutropenia. In some cases, the additional therapeutic agent may reduce the incidence or severity of neutropenia. In certain examples, the additional therapeutic agent is granulocyte colony-stimulating factor (G-CSF or GCSF) or colony-stimulating factor 3 (CSF3). Human G-CSF / CSF3 mRNA sequences include, for example, NCBI reference sequence numbers NM_000759, NM_001178147, NM_172219, and NM_172220, and human G-CSF / CSF3 protein amino acid sequences include, for example, NCBI reference sequence numbers NP_000750, NP_001171618, NP_757373, and NP_757374.

[0274] In some cases, the one or more additional therapeutic agents are prophylactic agents, for example, for preventing, reducing the incidence of, or reducing the severity of tumor lysis syndrome (TLS). In some cases, the prophylactic agent for TLS is allopurinol (CAS No.: 315-30-0), rasburicase (Elitek™; CAS No.: 134774-45-1), or a suitable substitute and / or pharmaceutically acceptable salt thereof. In some cases, the prophylactic agent for TLS reduces serum uric acid (e.g., reduces elevated uric acid levels, e.g., compared to baseline or reference values).

[0275] In some cases, additional therapeutic agents useful in the present invention include therapeutic antibodies such as alemtuzumab (CAMPATH®), bevacizumab (AVASTIN®, Genentech), cetuximab (ERBITUX®, Imclone), panitumumab (VECTIBIX®, Amgen), rituximab (RITUXAN®, Genentech / Biogen Idec), pertuzumab (OMNITARG®, 2C4, Genentech), trastuzumab (HERCEPTIN®, Genentech), tositumomab (BEXXAR®, Corixia), and the antibody-drug conjugate gemtuzumab ozogamicin (MYLOTARG®, Wyeth). Additional humanized monoclonal antibodies with therapeutic potential as agents in combination with the compounds of the invention include apolizumab, aselizumab, atlizumab, bapineuzumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, certolizumab pegol, cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, felvizumab, fontolizumab, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, motavizumab, natalizumab, nimotuzumab, and the like. Examples of such agents include tacatuzumab, norobizumab, numavizumab, ocrelizumab, omalizumab, palivizumab, pascolizumab, pecfusituzumab, pectuzumab, pexelizumab, ralivizumab, ranibizumab, reslivizumab, reslizumab, resivizumab, rovelizumab, ruplizumab, sibrotuzumab, siplizumab, sontuzumab, tacatuzumab tetraxetan, tadocizumab, tafasitamab, talizumab, tefibazumab, tocilizumab, toralizumab, tucotuzumab celmoleukin, tuxituzumab, umavizumab, urtoxazumab, ustekinumab, visilizumab, and briakinumab.

[0276] V. Pharmaceutical Compositions and Formulations Mosunetuzumab, lenalidomide and other therapeutic agents described herein can be used in pharmaceutical compositions and formulations. Pharmaceutical compositions and formulations of mosunetuzumab, lenalidomide, and / or other agents (e.g., corticosteroids, antihistamines, antipyretics, prophylactic agents against TLS and / or IL-6R antagonists) described herein can be prepared by mixing one, two, three or more of the agents with the desired purity in the form of a lyophilized formulation or aqueous solution with one or more optional pharmaceutically acceptable carriers (Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)). Corticosteroids, antihistamines, antipyretics, prophylactic agents against TLS, and / or IL-6R antagonists can also be formulated according to standard formulation and / or manufacturing practices.Pharmaceutically acceptable carriers are typically nontoxic to recipients at the dosages and concentrations employed and include, but are not limited to, buffers, such as phosphate, citrate, and other organic acids; antioxidants, including ascorbic acid and methionine; preservatives (e.g., octadecyldimethylbenzylammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butyl, or benzyl alcohol; alkyl parabens, such as methyl paraben or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) soluble polymers. ) polypeptides; proteins such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions such as sodium; metal complexes (e.g., Zn-protein complexes); and / or non-ionic surfactants such as polyethylene glycol (PEG). Exemplary pharmaceutically acceptable carriers herein further include interstitial drug dispersing agents, such as soluble neutral active hyaluronidase glycoproteins (sHASEGPs), for example, human soluble PH-20 hyaluronidase glycoproteins, such as rHuPH20 (HYLENEX®, Baxter International, Inc.). Certain exemplary sHASEGPs and methods of use, including rHuPH20, are described in U.S. Patent Publication Nos. 2005 / 0260186 and 2006 / 0104968. In one embodiment, the sHASEGP is combined with one or more additional glycosaminoglycanases (e.g., chondroitinases).

[0277] Exemplary lyophilized antibody formulations are described in U.S. Patent No. 6,267,958. Aqueous antibody formulations include those described in U.S. Patent No. 6,171,586 and WO 2006 / 044908, the latter formulations containing a histidine acetate buffer.

[0278] The preparation herein may also contain two or more active ingredients if necessary for the specific indication to be treated, and preferably contain two or more active ingredients with complementary activities that do not adversely affect each other.For example, it may be desirable to further provide additional therapeutic agent (for example, chemotherapeutic agent, cytotoxic agent, growth inhibitor, and / or antihormonal agent, for example, as mentioned herein above).Such active ingredient is suitably present in combination in the amount that is effective for the intended purpose.

[0279] The active ingredient can be encapsulated in microcapsules, for example, prepared by coacervation techniques or by interfacial polymerization, such as hydroxymethylcellulose or gelatin microcapsules and poly(methyl methacrylate) microcapsules, respectively, in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules) or in macroemulsions. Such techniques are disclosed in Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980).

[0280] Sustained-release preparations may be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the antibody, which matrices are in the form of shaped articles, e.g., films, or microcapsules.

[0281] Formulations to be used for in vivo administration are generally sterile. Sterility may be readily accomplished, for example, by filtration through sterile filtration membranes.

[0282] In some embodiments, mosunetuzumab is formulated for subcutaneous administration. In some embodiments, mosunetuzumab is formulated for intravenous administration. In some embodiments, lenalidomide is formulated for oral administration. In some embodiments, dexamethasone is formulated for oral or intravenous administration. In some embodiments, methylprednisolone is formulated for oral or intravenous administration. In some embodiments, allopurinol is formulated for oral administration. In some embodiments, rasburicase is formulated for intravenous administration. In some embodiments, tocilizumab is formulated for intravenous administration.

[0283] VI. Kits and Manufactured Articles In another aspect of the present invention, a kit or article of manufacture containing materials useful for the treatment, prevention, and / or diagnosis of the aforementioned disorders is provided. The kit or article of manufacture comprises a container and a label or package insert on or associated with the container. Suitable containers include, for example, bottles, vials, syringes, IV infusion bags, etc. The container can be formed from a variety of materials, such as glass or plastic. The container can hold a composition alone or in combination with another composition effective for treating, preventing, and / or diagnosing a condition, and can have a sterile access port (e.g., the container can be a vial with a stopper pierceable by a hypodermic needle). At least one active agent in the composition is mosunetuzumab and / or lenalidomide, as described herein. The label or package insert may indicate that the composition is for use in treating a selected condition (e.g., a CD20-positive cell proliferative disorder, e.g., a B-cell proliferative disorder (e.g., non-Hodgkin's lymphoma (NHL) (e.g., previously untreated (1L) NHL), diffuse large B-cell lymphoma (DLBCL) (e.g., 1L DLBCL, relapsed and / or refractory DLBCL, or Richter's transformation), follicular lymphoma (FL) (e.g., 1L The kit or article of manufacture may further include information regarding at least one of the dosing regimens described herein for use in treating FL, relapsed and / or refractory FL, or transformed FL), mantle cell lymphoma (MCL), high-grade B-cell lymphoma, or primary mediastinal (thymic) large B-cell lymphoma (PMLBCL), or chronic lymphocytic leukemia (CLL). The kit or article of manufacture may further include (a) a first container having a composition contained therein, the composition comprising mosunetuzumab and / or lenalidomide as described herein, and (b) a second container having a composition contained therein, the composition comprising an additional cytotoxic or other therapeutic agent. Alternatively or additionally, the kit or article of manufacture may further include a second (or third) container containing a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution, and dextrose solution.The kit or article of manufacture may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.

[0284] VII. Embodiments Some embodiments of the technology described herein may be defined according to any of the following numbered embodiments.

[0285] 1. A method for treating follicular lymphoma (FL) in a subject in need thereof, comprising administering to the subject a combination treatment comprising subcutaneously administered mosunetuzumab and orally administered lenalidomide, wherein administering the combination treatment to the plurality of subjects results in a non-inferior or improved efficacy response in the plurality of subjects compared to a reference efficacy response, wherein the reference efficacy response is the efficacy response of the plurality of subjects who received a control treatment comprising intravenously administered mosunetuzumab and orally administered lenalidomide, and the efficacy response is complete response rate (CRR), objective response rate (ORR), duration of response (DOR), duration of complete response (DOCR), overall survival (OS), or progression-free survival (PFS).

[0286] 2. Use of mosunetuzumab in combination with lenalidomide to treat follicular lymphoma (FL) in a subject in need thereof, wherein the combination treatment comprises mosunetuzumab administered subcutaneously and lenalidomide administered orally, and administering the combination treatment to the plurality of subjects results in a non-inferior or improved efficacy response in the plurality of subjects compared to a reference efficacy response, wherein the reference efficacy response is the efficacy response of the plurality of subjects who received a control treatment comprising mosunetuzumab administered intravenously and lenalidomide administered orally, and the efficacy response is complete response rate (CRR), objective response rate (ORR), duration of response (DOR), duration of complete response (DOCR), overall survival (OS), or progression-free survival (PFS).

[0287] 3. Use of lenalidomide in combination with mosunetuzumab to treat follicular lymphoma (FL) in a subject in need thereof, wherein the combination treatment comprises mosunetuzumab administered subcutaneously and lenalidomide administered orally, and administering the combination treatment to the plurality of subjects results in a non-inferior or improved efficacy response in the plurality of subjects compared to a reference efficacy response, wherein the reference efficacy response is the efficacy response of the plurality of subjects who received a control treatment comprising mosunetuzumab administered intravenously and lenalidomide administered orally, and the efficacy response is complete response rate (CRR), objective response rate (ORR), duration of response (DOR), duration of complete response (DOCR), overall survival (OS), or progression-free survival (PFS).

[0288] 4. Use of mosunetuzumab and lenalidomide to treat follicular lymphoma (FL) in a subject in need thereof, wherein mosunetuzumab is administered subcutaneously and lenalidomide is administered orally as a combination treatment, and administering the combination treatment to the plurality of subjects results in a non-inferior or improved efficacy response in the plurality of subjects compared to a reference efficacy response, wherein the reference efficacy response is the efficacy response of the plurality of subjects who received a control treatment comprising mosunetuzumab administered intravenously and lenalidomide administered orally, and the efficacy response is complete response rate (CRR), objective response rate (ORR), duration of response (DOR), duration of complete response (DOCR), overall survival (OS), or progression-free survival (PFS).

[0289] 5. Use of mosunetuzumab in the manufacture of a medicament for use in combination with lenalidomide for treating follicular lymphoma (FL) in a subject in need thereof, wherein mosunetuzumab is administered subcutaneously and lenalidomide is administered orally as a combination treatment, and administering the combination treatment to the plurality of subjects results in a non-inferior or improved efficacy response in the plurality of subjects compared to a reference efficacy response, wherein the reference efficacy response is the efficacy response of the plurality of subjects who received a control treatment comprising mosunetuzumab administered intravenously and lenalidomide administered orally, and the efficacy response is complete response rate (CRR), objective response rate (ORR), duration of response (DOR), duration of complete response (DOCR), overall survival (OS), or progression-free survival (PFS).

[0290] 6. Use of lenalidomide in the manufacture of a medicament for use in combination with mosunetuzumab to treat follicular lymphoma (FL) in a subject in need thereof, wherein mosunetuzumab is administered subcutaneously and lenalidomide is administered orally as the combination treatment, and the administration of the combination treatment to the plurality of subjects results in a non-inferior or improved efficacy response in the plurality of subjects compared to a reference efficacy response, wherein the reference efficacy response is the efficacy response of the plurality of subjects who received a control treatment comprising mosunetuzumab administered intravenously and lenalidomide administered orally, and the efficacy response is complete response rate (CRR), objective response rate (ORR), duration of response (DOR), duration of complete response (DOCR), overall survival (OS), or progression-free survival (PFS).

[0291] 7. Use of mosunetuzumab and lenalidomide in the manufacture of a medicament for treating follicular lymphoma (FL) in a subject in need thereof, wherein mosunetuzumab is administered subcutaneously and lenalidomide is administered orally as a combination treatment, and administering the combination treatment to the plurality of subjects results in a non-inferior or improved efficacy response in the plurality of subjects compared to a reference efficacy response, wherein the reference efficacy response is the efficacy response of the plurality of subjects who received a control treatment comprising mosunetuzumab administered intravenously and lenalidomide administered orally, and the efficacy response is complete response rate (CRR), objective response rate (ORR), duration of response (DOR), duration of complete response (DOCR), overall survival (OS), or progression-free survival (PFS).

[0292] 8. Mosunetuzumab for use in combination with lenalidomide for treating follicular lymphoma (FL) in a subject in need thereof, wherein the combination treatment comprises mosunetuzumab administered subcutaneously and lenalidomide administered orally, and wherein administering the combination treatment to the plurality of subjects results in a non-inferior or improved efficacy response in the plurality of subjects compared to a reference efficacy response, wherein the reference efficacy response is the efficacy response of the plurality of subjects who received a control treatment comprising mosunetuzumab administered intravenously and lenalidomide administered orally, and the efficacy response is complete response rate (CRR), objective response rate (ORR), duration of response (DOR), duration of complete response (DOCR), overall survival (OS), or progression-free survival (PFS).

[0293] 9. Lenalidomide for use in combination with mosunetuzumab for treating follicular lymphoma (FL) in a subject in need thereof, wherein the combination treatment comprises mosunetuzumab administered subcutaneously and lenalidomide administered orally, and wherein administering the combination treatment to the plurality of subjects results in a non-inferior or improved efficacy response in the plurality of subjects compared to a reference efficacy response, wherein the reference efficacy response is the efficacy response of the plurality of subjects who received a control treatment comprising mosunetuzumab administered intravenously and lenalidomide administered orally, and the efficacy response is complete response rate (CRR), objective response rate (ORR), duration of response (DOR), duration of complete response (DOCR), overall survival (OS), or progression-free survival (PFS).

[0294] 10. Mosunetuzumab and lenalidomide for use in treating follicular lymphoma (FL) in a subject in need thereof, wherein the combination treatment comprises mosunetuzumab administered subcutaneously and lenalidomide administered orally, and wherein administering the combination treatment to the plurality of subjects results in a non-inferior or improved efficacy response in the plurality of subjects compared to a reference efficacy response, wherein the reference efficacy response is the efficacy response of the plurality of subjects who received a control treatment comprising mosunetuzumab administered intravenously and lenalidomide administered orally, and the efficacy response is complete response rate (CRR), objective response rate (ORR), duration of response (DOR), duration of complete response (DOCR), overall survival (OS), or progression-free survival (PFS).

[0295] 11. The method, use, mosunetuzumab for use, lenalidomide for use or mosunetuzumab and lenalidomide for use according to any one of embodiments 1 to 10, wherein the efficacy response is a CRR and the CRR or reference CRR is the proportion of subjects receiving the corresponding treatment whose best overall response is a complete response (CR).

[0296] 12. The method, use, mosunetuzumab for use, lenalidomide for use or mosunetuzumab and lenalidomide for use according to embodiment 11, wherein the improved response in CRR is an increase in CRR of between 1% and 25% compared to the reference CRR.

[0297] 13. The method, use, mosunetuzumab for use, lenalidomide for use or mosunetuzumab and lenalidomide for use according to embodiment 11, wherein the efficacy response in the CRR is non-inferior compared to the reference CRR.

[0298] 14. The method, use, mosunetuzumab for use, lenalidomide for use or mosunetuzumab and lenalidomide for use according to any one of embodiments 1 to 10, wherein the efficacy response is ORR and the ORR or reference ORR is a best overall response of CR or partial response (PR) among said subjects receiving a corresponding treatment.

[0299] 15. The method, use, mosunetuzumab for use, lenalidomide for use or mosunetuzumab and lenalidomide for use according to embodiment 14, wherein the improvement in response in ORR is an increase in ORR of between 1% and 24% compared to the reference ORR.

[0300] 16. The method, use, mosunetuzumab for use, lenalidomide for use or mosunetuzumab and lenalidomide for use according to embodiment 14, wherein the efficacy response in ORR is non-inferior compared to the reference ORR.

[0301] 17. The method, use, mosunetuzumab for use, lenalidomide for use or mosunetuzumab and lenalidomide for use of any one of embodiments 1-10, wherein the efficacy response is DOR and the DOR or reference DOR is measured starting from the time of the first occurrence of documented CR or PR until disease progression or recurrence, or death from any cause, whichever occurs first.

[0302] 18. The method, use, mosunetuzumab for use, lenalidomide for use or mosunetuzumab and lenalidomide for use according to embodiment 17, wherein the DOR or reference DOR is the median DOR of multiple subjects receiving a corresponding treatment.

[0303] 19. The method, use, mosunetuzumab for use, lenalidomide for use or mosunetuzumab and lenalidomide for use according to embodiment 17 or 18, wherein the improvement in median DOR is an increase in DOR between 1 and 22 months compared to the reference DOR.

[0304] 20. The method, use, mosunetuzumab for use, lenalidomide for use or mosunetuzumab and lenalidomide for use according to embodiment 17, wherein the efficacy response in the DOR is non-inferior to the reference DOR.

[0305] 21. The method, use, mosunetuzumab for use, lenalidomide for use or mosunetuzumab and lenalidomide for use of any one of embodiments 1-10, wherein the efficacy response is DOCR and the DOCR or reference DOCR is measured starting from the time of the first occurrence of a documented CR until disease progression or relapse or death from any cause, whichever occurs first.

[0306] 22. The method, use, mosunetuzumab for use, lenalidomide for use or mosunetuzumab and lenalidomide for use according to embodiment 21, wherein the DOCR or reference DOCR is the median of the DOCR of multiple subjects receiving the corresponding treatment.

[0307] 23. The method, use, mosunetuzumab for use, lenalidomide for use or mosunetuzumab and lenalidomide for use according to embodiment 21 or 22, wherein the improvement in median DOCR is an increase in DOCR between 1 and 22 months compared to the reference DOCR.

[0308] 24. The method, use, mosunetuzumab for use, lenalidomide for use or mosunetuzumab and lenalidomide for use according to embodiment 21, wherein the efficacy response in the DOCR is non-inferior to the reference DOCR.

[0309] 25. The method, use, mosunetuzumab for use, lenalidomide for use or mosunetuzumab and lenalidomide for use according to any one of embodiments 11-24, wherein CR or PR is determined by PET / computed tomography (CT).

[0310] 26. The method, use, mosunetuzumab for use, lenalidomide for use, or mosunetuzumab and lenalidomide for use according to embodiment 25, wherein CR or PR is determined based on the Lugano response criteria for malignant lymphoma (Cheson et al., 2014).

[0311] 27. The method, use, mosunetuzumab for use, lenalidomide for use or mosunetuzumab and lenalidomide for use according to any one of embodiments 1 to 10, wherein the efficacy response is OS, and wherein OS or reference OS is measured starting from the time of first treatment until death from any cause.

[0312] 28. The method, use, mosunetuzumab for use, lenalidomide for use or mosunetuzumab and lenalidomide for use according to embodiment 27, wherein the OS or reference OS is the median OS of multiple subjects receiving a corresponding treatment.

[0313] 29. The method, use, mosunetuzumab for use, lenalidomide for use or mosunetuzumab and lenalidomide for use according to embodiment 27 or 28, wherein the improvement in median OS is an increase in OS of between 1 and 28 months compared to the reference OS.

[0314] 30. The method, use, mosunetuzumab for use, lenalidomide for use or mosunetuzumab and lenalidomide for use according to embodiment 27, wherein the efficacy response in OS is non-inferior compared to reference OS.

[0315] 31. The method, use, mosunetuzumab for use, lenalidomide for use or mosunetuzumab and lenalidomide for use according to any one of embodiments 1 to 10, wherein the efficacy response is PFS, and wherein the PFS or reference PFS is measured starting from the time of first treatment to the first occurrence of disease progression or death from any cause.

[0316] 32. The method, use, mosunetuzumab for use, lenalidomide for use or mosunetuzumab and lenalidomide for use according to embodiment 31, wherein the PFS or reference PFS is the median PFS of multiple subjects receiving the corresponding treatment.

[0317] 33. The method, use, mosunetuzumab for use, lenalidomide for use or mosunetuzumab and lenalidomide for use according to embodiment 31 or 32, wherein the improvement in median PFS is an increase in PFS of between 1 and 26 months compared to the reference PFS.

[0318] 34. The method, use, mosunetuzumab for use, lenalidomide for use or mosunetuzumab and lenalidomide for use according to embodiment 31, wherein the efficacy response in PFS is non-inferior compared to the reference PFS.

[0319] 35. A method for treating follicular lymphoma (FL) in a subject in need thereof, comprising administering to the subject a combination treatment comprising subcutaneously administered mosunetuzumab and orally administered lenalidomide, wherein administering the combination treatment to the plurality of subjects results in a non-inferior or improved safety response in the plurality of subjects compared to a reference safety response, wherein the reference safety response is the safety response of the plurality of subjects who received a control treatment comprising intravenously administered mosunetuzumab and orally administered lenalidomide, and the safety response is an incidence of adverse events (AEs), an incidence of cytokine release syndrome (CRS), or an incidence of serious AEs (SAEs).

[0320] 36. Use of mosunetuzumab in combination with lenalidomide to treat follicular lymphoma (FL) in a subject in need thereof, wherein the combination treatment comprises mosunetuzumab administered subcutaneously and lenalidomide administered orally, and administering the combination treatment to the plurality of subjects results in a non-inferior or improved safety response in the plurality of subjects compared to a reference safety response, wherein the reference safety response is the safety response of the plurality of subjects receiving a control treatment comprising mosunetuzumab administered intravenously and lenalidomide administered orally, and the safety response is the incidence of adverse events (AEs), the incidence of cytokine release syndrome (CRS), or the incidence of serious AEs (SAEs).

[0321] 37. Use of lenalidomide in combination with mosunetuzumab to treat follicular lymphoma (FL) in a subject in need thereof, wherein the combination treatment comprises mosunetuzumab administered subcutaneously and lenalidomide administered orally, and administering the combination treatment to the plurality of subjects results in a non-inferior or improved safety response in the plurality of subjects compared to a reference safety response, wherein the reference safety response is the safety response of the plurality of subjects receiving a control treatment comprising mosunetuzumab administered intravenously and lenalidomide administered orally, and the safety response is the incidence of adverse events (AEs), the incidence of cytokine release syndrome (CRS), or the incidence of serious AEs (SAEs).

[0322] 38. Use of mosunetuzumab and lenalidomide for treating follicular lymphoma (FL) in a subject in need thereof, wherein mosunetuzumab is administered subcutaneously and lenalidomide is administered orally as a combination treatment, and administering the combination treatment to the plurality of subjects results in a non-inferior or improved safety response in the plurality of subjects compared to a reference safety response, wherein the reference safety response is the safety response of the plurality of subjects who received a control treatment comprising mosunetuzumab administered intravenously and lenalidomide administered orally, and the safety response is the incidence of adverse events (AEs), the incidence of cytokine release syndrome (CRS), or the incidence of serious AEs (SAEs).

[0323] 39. Use of mosunetuzumab in the manufacture of a medicament for use in combination with lenalidomide for treating follicular lymphoma (FL) in a subject in need thereof, wherein mosunetuzumab is administered subcutaneously and lenalidomide is administered orally as a combination treatment, and administering the combination treatment to the plurality of subjects results in a non-inferior or improved safety response in the plurality of subjects compared to a reference safety response, wherein the reference safety response is the safety response of the plurality of subjects who received a control treatment comprising mosunetuzumab administered intravenously and lenalidomide administered orally, and the safety response is the incidence of adverse events (AEs), the incidence of cytokine release syndrome (CRS), or the incidence of serious AEs (SAEs).

[0324] 40. Use of lenalidomide in the manufacture of a medicament for use in combination with mosunetuzumab to treat follicular lymphoma (FL) in a subject in need thereof, wherein mosunetuzumab is administered subcutaneously and lenalidomide is administered orally as a combination treatment, and administering the combination treatment to the plurality of subjects results in a non-inferior or improved safety response in the plurality of subjects compared to a reference safety response, wherein the reference safety response is the safety response of the plurality of subjects who received a control treatment comprising mosunetuzumab administered intravenously and lenalidomide administered orally, and the safety response is the incidence of adverse events (AEs), the incidence of cytokine release syndrome (CRS), or the incidence of serious AEs (SAEs).

[0325] 41. Use of mosunetuzumab and lenalidomide in the manufacture of a medicament for treating follicular lymphoma (FL) in a subject in need thereof, wherein mosunetuzumab is administered subcutaneously and lenalidomide is administered orally as a combination treatment, and administering the combination treatment to the plurality of subjects results in a non-inferior or improved safety response in the plurality of subjects compared to a reference safety response, wherein the reference safety response is the safety response of the plurality of subjects who received a control treatment comprising mosunetuzumab administered intravenously and lenalidomide administered orally, and the safety response is the incidence of adverse events (AEs), the incidence of cytokine release syndrome (CRS), or the incidence of serious AEs (SAEs).

[0326] 42. Mosunetuzumab for use in combination with lenalidomide for treating follicular lymphoma (FL) in a subject in need thereof, wherein the combination treatment comprises mosunetuzumab administered subcutaneously and lenalidomide administered orally, and wherein administering the combination treatment to the plurality of subjects results in a non-inferior ...

Claims

1. 1. A method for treating follicular lymphoma (FL) in a subject in need thereof, comprising administering to the subject a combination treatment comprising subcutaneously administered mosunetuzumab and orally administered lenalidomide, wherein administering the combination treatment to the plurality of subjects results in a non-inferior or improved efficacy response in the plurality of subjects compared to a reference efficacy response, wherein the reference efficacy response is the efficacy response of the plurality of subjects who received a control treatment comprising intravenously administered mosunetuzumab and orally administered lenalidomide, and the efficacy response is complete response rate (CRR), objective response rate (ORR), duration of response (DOR), duration of complete response (DOCR), overall survival (OS), or progression-free survival (PFS).

2. 2. The method of claim 1, wherein the efficacy response is a CRR, and the CRR or reference CRR is the proportion of subjects receiving the corresponding treatment whose best overall response is a complete response (CR).

3. 3. The method of claim 2, wherein the improved response in CRR is an increase in CRR of between 1% and 25% compared to the reference CRR.

4. 3. The method of claim 2, wherein the efficacy response in the CRR is non-inferior compared to the reference CRR.

5. 2. The method of claim 1, wherein the efficacy response is an ORR, and the ORR or reference ORR is the proportion of subjects receiving the corresponding treatment whose best overall response is a CR or a partial response (PR).

6. 6. The method of claim 5, wherein the improved response in ORR is an increase in ORR of between 1% and 24% compared to the reference ORR.

7. 6. The method of claim 5, wherein the efficacy response in the ORR is non-inferior compared to the reference ORR.

8. 2. The method of claim 1, wherein the efficacy response is DOR, and the DOR or reference DOR is measured starting from the time of the first occurrence of a documented CR or PR until disease progression or recurrence, or death from any cause, whichever occurs first.

9. 9. The method of claim 8, wherein the DOR or reference DOR is the median DOR of multiple subjects receiving the corresponding treatment.

10. 10. The method of claim 8 or 9, wherein the median improvement in DOR is an increase in DOR between 1 and 22 months compared to the reference DOR.

11. 9. The method of claim 8, wherein the efficacy response in DOR is non-inferior compared to the reference DOR.

12. 2. The method of claim 1, wherein the efficacy response is DOCR, and the DOCR or reference DOCR is measured starting from the time of the first occurrence of a documented CR until disease progression or recurrence, or death from any cause, whichever occurs first.

13. 13. The method of claim 12, wherein the DOCR or reference DOCR is the median of the DOCRs of multiple subjects receiving the corresponding treatment.

14. 14. The method of claim 12 or 13, wherein the median improvement in DOCR is an increase in DOCR between 1 and 22 months compared to the reference DOCR.

15. 13. The method of claim 12, wherein the efficacy response in the DOCR is non-inferior compared to the reference DOCR.

16. The method of any one of claims 2 to 15, wherein CR or PR is determined by PET / computed tomography (CT).

17. The method of claim 16, wherein CR or PR is determined based on the Lugano response criteria for malignant lymphoma (Cheson et al., 2014).

18. 2. The method of claim 1, wherein the efficacy response is OS, and the OS or reference OS is measured starting from the time of first treatment until death from any cause.

19. 19. The method of claim 18, wherein the OS or reference OS is the median OS of multiple subjects receiving the corresponding treatment.

20. 20. The method of claim 18 or 19, wherein the median improvement in OS is an increase in OS of between 1 and 28 months compared to the reference OS.

21. 19. The method of claim 18, wherein the efficacy response in the OS is non-inferior compared to the reference OS.

22. 2. The method of claim 1, wherein the efficacy response is PFS, and the PFS or reference PFS is measured starting from the time of first treatment until the first occurrence of disease progression or death from any cause.

23. 23. The method of claim 22, wherein the PFS or reference PFS is the median PFS of multiple subjects receiving the corresponding treatment.

24. 24. The method of claim 22 or 23, wherein the median improvement in PFS is an increase in PFS of between 1 and 26 months compared to the reference PFS.

25. 23. The method of claim 22, wherein the efficacy response in PFS is non-inferior compared to the reference PFS.

26. 1. A method for treating follicular lymphoma (FL) in a subject in need thereof, comprising administering to the subject a combination treatment comprising subcutaneously administered mosunetuzumab and orally administered lenalidomide, wherein administering the combination treatment to the plurality of subjects results in a non-inferior or improved safety response in the plurality of subjects compared to a reference safety response, wherein the reference safety response is the safety response of the plurality of subjects who received a control treatment comprising intravenously administered mosunetuzumab and orally administered lenalidomide, and the safety response is an incidence of adverse events (AEs), an incidence of cytokine release syndrome (CRS), or an incidence of serious AEs (SAEs).

27. 27. The method of claim 26, wherein the safety response is the incidence of an AE, and the incidence of the AE or the reference incidence of the AE is the incidence of the AE in multiple subjects receiving the corresponding treatment.

28. 28. The method of claim 27, wherein the safety response in incidence of the AE is non-inferior compared to a reference incidence of the AE.

29. 27. The method of claim 26, wherein the safety response is the incidence of CRS, and the incidence of CRS or reference incidence of CRS is the incidence of CRS in multiple subjects receiving the corresponding treatment.

30. 30. The method of claim 29, wherein the improved incidence of CRS is a reduction in the incidence of CRS of between 7% and 17% compared to a reference incidence of CRS.

31. 31. The method of claim 30, wherein the improvement in the incidence of CRS is a reduction in the incidence of CRS of about 12% compared to a reference incidence of CRS.

32. 32. The method of claim 30 or 31, wherein the incidence of CRS is the incidence of grade 1 or 2 CRS in multiple patients receiving the corresponding treatment.

33. 30. The method of claim 29, wherein the incidence of Grade 3+ CRS is non-inferior compared to a reference incidence of Grade 3+ CRS.

34. 34. The method of claim 32 or 33, wherein the grade of CRS is determined based on the American Society of Transplantation and Cellular Therapy (ASTCT) Consensus Grading for Cytokine Release Syndrome (Lee et al., 2019).

35. 27. The method of claim 26, wherein the safety response is the incidence of an SAE, and the incidence of an SAE or the reference incidence of an SAE is the incidence of the SAE in multiple subjects receiving the corresponding treatment.

36. 36. The method of claim 35, wherein the safety response in incidence of SAEs is non-inferior compared to a reference incidence of SAEs.

37. 1. A method for treating follicular lymphoma (FL) in a subject in need thereof, comprising administering to the subject a combination treatment comprising subcutaneously administered mosunetuzumab and orally administered lenalidomide according to a dosing regimen comprising an initial 21-day dosing cycle and three 28-day dosing cycles, wherein administering the combination treatment to the plurality of subjects results in a non-inferiority pharmacokinetic (PK) endpoint for the plurality of subjects compared to a reference PK endpoint, wherein the PK endpoint is an observed dosing cycle 2 serum trough concentration (scConc). トラフＣＹＣ２－ＯＢＳ ) or cumulative area under the concentration-time curve (scAUC) over 0 to 77 days ０～７７ ) and The reference PK endpoint was a PK endpoint in subjects receiving a control treatment comprising intravenously administered mosunetuzumab and orally administered lenalidomide according to a dosing regimen comprising an initial 21-day dosing cycle and three 28-day dosing cycles, and the reference PK endpoint was the observed dosing cycle 2 serum trough concentration (ivConc トラフＣＹＣ２－ＯＢＳ ) or cumulative area under the concentration-time curve (ivAUC) over 0 to 77 days ０～７７ ) a method.

38. scAUC ０～７７ and ivAUC ０～７７ 38. The method of claim 37, wherein one or both of the following is determined using a population PK (popPK) model predictive individual empirical Bayes estimate (EBE).

39. the combination treatment comprises subcutaneous administration of mosunetuzumab and oral administration of lenalidomide according to a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein the first dosing cycle is a 21-day dosing cycle and the second dosing cycle is a 28-day dosing cycle; (a) the first dosing cycle comprises a first subcutaneous administration (scC1D1), a second subcutaneous administration (scC1D2), and a third subcutaneous administration (scC1D3) of mosunetuzumab on days 1, 8, and 15 of the first dosing cycle, respectively, wherein the dose of scC1D1 is about 5 mg, the dose of scC1D2 is about 45 mg, and the dose of scC1D3 is about 45 mg; (b) the second dosing cycle comprises: (i) a first subcutaneous administration of approximately 45 mg of mosunetuzumab (scC2D1) administered on day 1 of a second dosing cycle; and (ii) 21 oral doses of about 20 mg of lenalidomide administered on days 1 through 21 of a second dosing cycle.

39. The method of any one of claims 1 to 38, comprising:

40. 40. The method of claim 39, wherein the dosing regimen of the combination treatment further comprises one or more additional 28-day dosing cycles.

41. 41. The method of claim 40, wherein the dosing regimen of the combination treatment comprises 10 additional 28-day dosing cycles.

42. Each additional dosing cycle: (a) about 45 mg of mosunetuzumab administered subcutaneously on day 1 of an additional dosing cycle; and (b) 21 oral doses of about 20 mg of lenalidomide administered on days 1 through 21 of an additional dosing cycle.

42. The method of claim 40 or 41, comprising:

43. 43. The method of claim 42, wherein the combination treatment dosing regimen further comprises 1 to 9 subcutaneous maintenance administrations of mosunetuzumab.

44. 1. A method for treating follicular lymphoma (FL) in a subject in need thereof, comprising administering to the subject a combination treatment comprising subcutaneously administered mosunetuzumab and orally administered lenalidomide, wherein the combination treatment comprises subcutaneous administration of mosunetuzumab and oral administration of lenalidomide according to a dosing regimen comprising a first dosing cycle that is a 21-day dosing cycle and a second dosing cycle that is a 28-day dosing cycle, 10 additional 28-day dosing cycles, and 1 to 9 subcutaneous maintenance doses of mosunetuzumab; (a) the first dosing cycle comprises a first subcutaneous administration (scC1D1), a second subcutaneous administration (scC1D2), and a third subcutaneous administration (scC1D3) of mosunetuzumab on days 1, 8, and 15 of the first dosing cycle, respectively, wherein the dose of scC1D1 is about 5 mg, the dose of scC1D2 is about 45 mg, and the dose of scC1D3 is about 45 mg; (b) the second dosing cycle comprises: (i) a first subcutaneous administration of approximately 45 mg of mosunetuzumab (scC2D1) administered on day 1 of a second dosing cycle; and (ii) 21 oral doses of about 20 mg of lenalidomide administered on days 1 through 21 of a second dosing cycle. Including, (c) 10 additional dosing cycles, each of (i) a first subcutaneous administration of about 45 mg each of mosunetuzumab (scC3D1 to scC12D1) on Day 1 of each additional dosing cycle; and (ii) 21 oral doses of about 20 mg of lenalidomide administered on days 1 through 21 of each additional dosing cycle. A method comprising:

45. 45. The method of claim 43 or 44, wherein the combination treatment dosing regimen further comprises nine subcutaneous maintenance doses of mosunetuzumab.

46. 46. ​​The method of any one of claims 43-45, wherein one to nine subcutaneous maintenance administrations of mosunetuzumab are administered every eight weeks, starting eight weeks after day 1 of a tenth additional 28-day dosing cycle.

47. 47. The method of any one of claims 43-46, wherein each maintenance dose of mosunetuzumab is about 45 mg.

48. the control treatment comprises intravenously administered mosunetuzumab and orally administered lenalidomide according to a dosing regimen comprising at least a first 21-day dosing cycle and a second 28-day dosing cycle; (a) the first dosing cycle comprises a first intravenous administration (ivC1D1), a second intravenous administration (ivC1D2), and a third intravenous administration (ivC1D3) of mosunetuzumab on days 1, 8, and 15, respectively, of the first dosing cycle, wherein the dose of ivC1D1 is about 1 mg, the dose of ivC1D2 is about 2 mg, and the dose of ivC1D3 is about 30 mg; (b) the second dosing cycle comprises: (i) a first intravenous administration of approximately 30 mg of mosunetuzumab administered on day 1 of a second dosing cycle (ivC2D1); and (ii) 21 oral doses of about 20 mg of lenalidomide administered on days 1 through 21 of a second dosing cycle.

47. The method of any one of claims 1 to 43 and 45 to 46, comprising:

49. 49. The method of claim 48, wherein the control treatment dosing regimen further comprises one or more additional 28-day dosing cycles.

50. 50. The method of claim 49, wherein the control treatment dosing regimen comprises 10 additional 28-day dosing cycles.

51. Each additional dosing cycle: (a) an intravenous administration of about 30 mg of mosunetuzumab on day 1 of an additional dosing cycle; and (b) 21 oral doses of about 20 mg of lenalidomide administered on days 1 through 21 of an additional dosing cycle.

51. The method of claim 49 or 50, comprising:

52. 52. The method of any one of claims 1-51, wherein the subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.

53. 53. The method of any one of claims 1 to 52, wherein the subject has not previously been treated for FL.

54. 53. The method of any one of claims 1-52, wherein the subject has relapsed after or is refractory to one or more prior lines of systemic therapy.

55. 55. The method of claim 54, wherein the one or more prior lines of systemic therapy comprise immunotherapy or chemoimmunotherapy.

56. 55. The method of claim 54, wherein one or more prior lines of systemic therapy comprise an anti-CD20 antibody.

57. 57. The method of claim 56, wherein the anti-CD20 antibody is rituximab.

58. 58. The method of any one of claims 1 to 57, wherein the FL is grade 1, 2 or 3a.

59. 1. A method for treating non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL) in a subject in need thereof, comprising administering to the subject a treatment comprising subcutaneously administered mosunetuzumab, wherein administering the treatment to the plurality of subjects results in a non-inferior or improved efficacy response in the plurality of subjects compared to a reference efficacy response, wherein the reference efficacy response is the efficacy response of the plurality of subjects who received a control treatment comprising intravenously administered mosunetuzumab, and the efficacy response is complete response rate (CRR), objective response rate (ORR), duration of response (DOR), duration of complete response (DOCR), progression-free survival (PFS), or overall survival (OS).

60. 60. The method of claim 59, wherein the efficacy response is a CRR, and the CRR or reference CRR is the proportion of subjects receiving a corresponding treatment whose best overall response is a complete response (CR).

61. 61. The method of claim 60, wherein the improved response in CRR is an increase in CRR of between 1% and 20% compared to the reference CRR.

62. 61. The method of claim 60, wherein the efficacy response in the CRR is non-inferior compared to the reference rate CRR.

63. 60. The method of claim 59, wherein the efficacy response is an ORR, and the ORR or reference ORR is the proportion of subjects receiving the corresponding treatment whose best overall response is a CR or a partial response (PR).

64. 64. The method of claim 63, wherein the improved response in ORR is an increase in ORR of between 1% and 13% compared to the reference ORR.

65. 64. The method of claim 63, wherein the efficacy response in the ORR is non-inferior compared to the reference ORR.

66. 60. The method of claim 59, wherein the efficacy response is DOR, and the DOR or reference DOR is measured starting from the first occurrence of documented CR or PR until the first occurrence of disease progression or relapse or death from any cause.

67. 67. The method of claim 66, wherein the DOR or reference DOR is the median of the DOR of multiple subjects receiving the corresponding treatment.

68. 68. The method of claim 66 or 67, wherein the median improvement in DOR is an increase in DOR of between 1 and 13 months compared to the reference DOR.

69. 67. The method of claim 66, wherein the efficacy response in DOR is non-inferior compared to the reference DOR.

70. 67. The method of claim 66, wherein the improvement in DOR is an increase in the rate of DOR at 12 months of between 1% and 31% compared to the reference rate of DOR at 12 months.

71. 71. The method of claim 70, wherein the improvement in DOR is an increase in the rate of DOR at 12 months of about 8% compared to the reference DOR rate at 12 months.

72. 60. The method of claim 59, wherein the efficacy response is DOCR, and wherein the DOCR or reference DOCR is measured starting from the first occurrence of documented CR until the first occurrence of disease progression or relapse or death from any cause.

73. 73. The method of claim 72, wherein the DOCR or reference DOCR is the median of the DOCRs of multiple subjects receiving the corresponding treatment.

74. 73. The method of claim 72, wherein the improvement in DOCR is an increase in DOCR rate at 12 months of between 1% and 27% compared to the reference DOCR rate at 12 months.

75. 73. The method of claim 72, wherein the efficacy response in the DOCR is non-inferior compared to the reference DOCR.

76. 76. The method of any one of claims 60 to 75, wherein CR or PR is determined by PET / computed tomography (CT).

77. 77. The method of claim 76, wherein CR or PR is determined based on the Revised Response Criteria for Malignant Lymphoma (Cheson et al., 2007).

78. 60. The method of claim 59, wherein the efficacy response is PFS, and the PFS or reference PFS is measured starting from the time of first treatment to the first occurrence of disease progression or death from any cause.

79. 79. The method of claim 78, wherein the PFS or reference PFS is the median PFS of multiple subjects receiving the corresponding treatment.

80. 80. The method of claim 78 or 79, wherein the median improvement in PFS is an increase in PFS of between 1 and 14 months compared to the reference PFS.

81. 80. The method of claim 79, wherein the efficacy response in PFS is non-inferior compared to the reference PFS.

82. 79. The method of claim 78, wherein the improvement in PFS is an increase in PFS rate of between 1% and 26% compared to the reference PFS rate at 12 months.

83. 83. The method of claim 82, wherein the improvement in PFS is an increase in PFS rate of about 5% compared to the reference PFS rate at 12 months.

84. 60. The method of claim 59, wherein the efficacy response is OS, and the OS or reference OS is measured starting from the first treatment until death from any cause.

85. 85. The method of claim 84, wherein the improvement in OS is an increase in OS rate of between 1% and 9% compared to the reference OS rate at 12 months.

86. 85. The method of claim 84, wherein the efficacy response in the OS is non-inferior compared to the reference OS.

87. 1. A method for treating non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL) in a subject in need thereof, comprising administering to the subject a treatment comprising subcutaneously administered mosunetuzumab, wherein administering the treatment to the plurality of subjects results in a non-inferior or improved safety response in the plurality of subjects compared to a reference safety response, wherein the reference safety response is the safety response of the plurality of subjects who received a control treatment comprising intravenously administered mosunetuzumab, and the safety response is an incidence of adverse events (AEs), an incidence of cytokine release syndrome (CRS), or an incidence of serious AEs (SAEs).

88. 88. The method of claim 87, wherein the safety response is the incidence of an AE, and the incidence of the AE or the reference incidence of the AE is the incidence of the AE in multiple subjects receiving the corresponding treatment.

89. 89. The method of claim 88, wherein the safety response in incidence of the AE is non-inferior compared to a reference incidence of the AE.

90. 88. The method of claim 87, wherein the improved incidence of AEs is a reduction in the incidence of grade 3 or 4 AEs of between 11% and 21% compared to a reference incidence of grade 3 or 4 AEs.

91. 91. The method of claim 90, wherein the improved incidence of AEs is a reduction in the incidence of grade 3 or 4 AEs by about 16% compared to a reference incidence of grade 3 or 4 AEs.

92. 89. The method of claim 88, wherein the incidence of the AE is the incidence of a Grade 5 AE in multiple subjects receiving a corresponding treatment, and the incidence of the AE is non-inferior compared to a reference incidence of the AE.

93. 93. The method of any one of claims 90-92, wherein the grade of the AE is determined based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), v4.

0.

94. 88. The method of claim 87, wherein the safety response is the incidence of an SAE, and the incidence of an SAE or the reference incidence of an SAE is the incidence of an SAE in multiple subjects receiving the corresponding treatment.

95. 95. The method of claim 94, wherein the improved safety response in incidence of an SAE is a reduction in the incidence of an SAE of between 9% and 19% compared to a reference incidence of the SAE.

96. 96. The method of claim 95, wherein the improved safety response in incidence of an SAE is a reduction in incidence of an SAE of about 14% compared to a reference incidence of the SAE.

97. 88. The method of claim 87, wherein the safety response is the incidence of CRS, and the incidence of CRS or reference incidence of CRS is the incidence of CRS in multiple subjects receiving the corresponding treatment.

98. 98. The method of claim 97, wherein the improved incidence of CRS is a reduction in the incidence of CRS of between 9% and 19% compared to a reference incidence of CRS.

99. 99. The method of claim 98, wherein the improvement in the incidence of CRS is a reduction in the incidence of CRS of about 14% compared to a reference incidence of CRS.

100. 98. The method of claim 97, wherein the improved incidence of CRS is a reduction in the incidence of Grade 2+ CRS of between 3% and 13% compared to a reference incidence of Grade 2+ CRS.

101. The method of claim 100, wherein the improved incidence of CRS is a reduction in the incidence of grade 2+ CRS of about 8% compared to a reference incidence of grade 2+ CRS.

102. 102. The method of claim 100 or 101, wherein the grade of CRS is determined based on the Modified Cytokine Release Syndrome Grading System (Lee et al., 2014).

103. 1. A method for treating non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL) in a subject in need thereof, comprising administering to the subject a treatment comprising subcutaneously administered mosunetuzumab according to a dosing regimen comprising four 21-day dosing cycles, wherein administering the combination treatment to the plurality of subjects results in a non-inferiority or improved pharmacokinetic (PK) endpoint for the plurality of subjects compared to a reference PK endpoint, wherein the PK endpoint is greater than or equal to the observed dosing cycle 3 serum trough concentration (scConc). トラフＣＹＣ３－ＯＢＳ ) or cumulative area under the concentration-time curve (scAUC) over 0 to 84 days ０～８４ ) and The reference PK endpoint was a PK endpoint in subjects receiving a control treatment containing intravenously administered mosunetuzumab according to a dosing regimen comprising four 21-day dosing cycles, and the reference PK endpoint was the observed dosing cycle 3 serum trough concentration (ivConc トラフＣＹＣ３－ＯＢＳ ) or cumulative area under the concentration-time curve (ivAUC) over 0 to 84 days ０～８４ ) a method.

104. scAUC ０～８４ and ivAUC ０～８４ 104. The method of claim 103, wherein one or more of: is determined using a population PK (popPK) model predictive individual empirical Bayes estimate (EBE).

105. the treatment comprises subcutaneously administering mosunetuzumab according to a dosing regimen comprising at least a first 21-day dosing cycle and a second 21-day dosing cycle; (a) the first dosing cycle comprises a first subcutaneous administration (scC1D1), a second subcutaneous administration (scC1D2), and a third subcutaneous administration (scC1D3) of mosunetuzumab on days 1, 8, and 15 of the first dosing cycle, respectively, wherein the dose of scC1D1 is about 5 mg, the dose of scC1D2 is about 15 mg or about 45 mg, and the dose of scC1D3 is about 45 mg; (b) the second dosing cycle comprises a first subcutaneous administration of about 45 mg of mosunetuzumab (scC2D1) administered on day 1 of the second dosing cycle.

106. 106. The method of claim 105, wherein the treatment dosing regimen further comprises one or more additional 21-day dosing cycles.

107. 107. The method of claim 106, wherein the treatment dosing regimen comprises 6, 15, or 23 additional 21-day dosing cycles.

108. 108. The method of claim 106 or 107, wherein each additional dosing cycle comprises a subcutaneous administration of about 45 mg of mosunetuzumab administered on day 1 of the additional dosing cycle.

109. the control treatment comprises intravenously administering mosunetuzumab according to a dosing regimen comprising at least a first 21-day dosing cycle and a second 21-day dosing cycle; (a) the first dosing cycle comprises a first intravenous administration (ivC1D1), a second intravenous administration (ivC1D2), and a third intravenous administration (ivC1D3) of mosunetuzumab on days 1, 8, and 15 of the first dosing cycle, respectively, wherein the dose of ivC1D1 is about 1 mg, the dose of ivC1D2 is about 2 mg, and the dose of ivC1D3 is about 60 mg; (b) the second dosing cycle comprises a first intravenous administration of about 60 mg of mosunetuzumab (ivC2D1) administered on day 1 of the second dosing cycle.

110. 110. The method of claim 109, wherein the control treatment dosing regimen further comprises one or more additional 21-day dosing cycles.

111. 111. The method of claim 110, wherein the control treatment dosing regimen comprises 6, 15, or 23 additional 21-day dosing cycles.

112. 112. The method of claim 110 or 111, wherein each additional dosing cycle comprises an intravenous administration of about 30 mg of mosunetuzumab administered on day 1 of the additional dosing cycle.

113. 113. The method of any one of claims 59-112, wherein the subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

114. 114. The method of any one of claims 59-113, wherein the subject has relapsed after or is refractory to one or more prior lines of systemic therapy.

115. 115. The method of claim 114, wherein the subject has relapsed after or is refractory to two or more prior lines of systemic therapy.

116. 116. The method of claim 114 or 115, wherein one or more prior lines of systemic therapy comprise an anti-CD20 antibody, an alkylating agent, a Bruton's tyrosine kinase (BTK) inhibitor, an anthracycline, or a combination thereof.

117. 117. The method of any one of claims 59 to 116, wherein the NHL is follicular lymphoma (FL), marginal zone lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), transformed FL (trFL), high-grade B-cell lymphoma (HGBL), primary mediastinal B-cell lymphoma (PMLBCL), transformed indolent NHL, mantle cell lymphoma (MCL), Richter's transformation, or small lymphocytic lymphoma (SLL).

118. The method of claim 117, wherein the NHL is FL, and the FL is grade 1-3b FL or transformed FL.

119. 119. The method of claim 118, wherein the FL is grade 1-3a FL and the subject has relapsed after or is refractory to two or more prior lines of systemic therapy comprising an anti-CD20 antibody and an alkylating agent.

120. 118. The method of claim 117, wherein the NHL is DLBCL or trFL.

121. 121. The method of claim 120, wherein the NHL is DLBCL or trFL and the subject has relapsed after or is refractory to two or more prior lines of systemic therapy including an anthracycline and an anti-CD20 antibody.

122. The method of claim 117, wherein the NHL is Richter's transformation.

123. 123. The method of claim 122, wherein the NHL is Richter transformed and the subject has relapsed after or is refractory to one or more prior lines of systemic therapy including an anthracycline and an anti-CD20 antibody.

124. The method of any one of claims 116 to 123, wherein the anti-CD20 antibody is rituximab.

125. 118. The method of claim 117, wherein the NHL is MCL.

126. 126. The method of claim 125, wherein the NHL is MCL and the subject has relapsed after or is refractory to one or more prior lines of systemic therapy including a BTK inhibitor.

127. 127. The method of any one of claims 1 to 126, comprising administering an additional therapeutic agent.

128. 128. The method of claim 127, wherein the additional therapeutic agent comprises a corticosteroid, an antihistamine, an antipyretic, or an IL-6R antagonist.

129. 129. The method of claim 128, wherein the additional therapeutic agent is a corticosteroid, and the corticosteroid comprises prednisone, methylprednisolone, or dexamethasone.

130. 129. The method of claim 128, wherein the additional therapeutic agent is an antihistamine, and the antihistamine comprises diphenhydramine hydrochloride or an equivalent.

131. 129. The method of claim 128, wherein the additional therapeutic agent is an antipyretic, and the antipyretic is acetaminophen.

132. 129. The method of claim 128, wherein the additional therapeutic agent is an IL-6R antagonist, and the IL-6R antagonist is tocilizumab.

133. 1. A method for treating follicular lymphoma (FL) in a subject in need thereof, comprising administering to the subject a combination treatment comprising subcutaneously administered mosunetuzumab and orally administered lenalidomide, wherein the combination treatment comprises subcutaneous administration of mosunetuzumab and oral administration of lenalidomide according to a dosing regimen comprising a first dosing cycle that is a 21-day dosing cycle and a second dosing cycle that is a 28-day dosing cycle, 10 additional 28-day dosing cycles, and 1 to 9 subcutaneous maintenance doses of mosunetuzumab; (a) the first dosing cycle comprises a first subcutaneous administration (scC1D1), a second subcutaneous administration (scC1D2), and a third subcutaneous administration (scC1D3) of mosunetuzumab on days 1, 8, and 15 of the first dosing cycle, respectively, wherein the dose of scC1D1 is 5 mg, the dose of scC1D2 is 45 mg, and the dose of scC1D3 is 45 mg; (b) the second dosing cycle comprises: (i) a first subcutaneous administration of approximately 45 mg of mosunetuzumab (scC2D1) administered on day 1 of a second dosing cycle; and (ii) 21 oral doses of 20 mg of lenalidomide administered on days 1 through 21 of a second dosing cycle. Includes (c) 10 additional dosing cycles, each of (i) a first subcutaneous administration of 45 mg of mosunetuzumab (scC3D1 to scC12D1) administered on Day 1 of each additional dosing cycle; and (ii) 21 oral doses of 20 mg of lenalidomide administered on days 1 through 21 of each additional dosing cycle. A method comprising:

134. 1. Use of mosunetuzumab in combination with lenalidomide to treat follicular lymphoma (FL) in a subject in need thereof, wherein the combination treatment comprises mosunetuzumab administered subcutaneously and lenalidomide administered orally, and the combination treatment is administered to the plurality of subjects, resulting in a non-inferior or improved efficacy response in the plurality of subjects compared to a reference efficacy response, wherein the reference efficacy response is the efficacy response of the plurality of subjects who received a control treatment comprising mosunetuzumab administered intravenously and lenalidomide administered orally, and the efficacy response is complete response rate (CRR), objective response rate (ORR), duration of response (DOR), duration of complete response (DOCR), overall survival (OS), or progression-free survival (PFS).

135. 1. Use of lenalidomide in combination with mosunetuzumab to treat follicular lymphoma (FL) in a subject in need thereof, wherein the combination treatment comprises mosunetuzumab administered subcutaneously and lenalidomide administered orally, and the combination treatment is administered to the plurality of subjects, resulting in a non-inferior or improved efficacy response in the plurality of subjects compared to a reference efficacy response, wherein the reference efficacy response is the efficacy response of the plurality of subjects who received a control treatment comprising mosunetuzumab administered intravenously and lenalidomide administered orally, and the efficacy response is complete response rate (CRR), objective response rate (ORR), duration of response (DOR), duration of complete response (DOCR), overall survival (OS), or progression-free survival (PFS).

136. 1. Use of mosunetuzumab and lenalidomide to treat follicular lymphoma (FL) in a subject in need thereof, wherein mosunetuzumab is administered subcutaneously and lenalidomide is administered orally as a combination treatment, and administering the combination treatment to the plurality of subjects results in a non-inferior or improved efficacy response in the plurality of subjects compared to a reference efficacy response, wherein the reference efficacy response is the efficacy response of the plurality of subjects who received a control treatment comprising mosunetuzumab administered intravenously and lenalidomide administered orally, and the efficacy response is complete response rate (CRR), objective response rate (ORR), duration of response (DOR), duration of complete response (DOCR), overall survival (OS), or progression-free survival (PFS).

137. 1. Use of mosunetuzumab in the manufacture of a medicament for use in combination with lenalidomide to treat follicular lymphoma (FL) in a subject in need thereof, wherein mosunetuzumab is administered subcutaneously and lenalidomide is administered orally as a combination treatment, and the combination treatment is administered to the plurality of subjects, resulting in a non-inferior or improved efficacy response in the plurality of subjects compared to a reference efficacy response, wherein the reference efficacy response is the efficacy response of the plurality of subjects who received a control treatment comprising mosunetuzumab administered intravenously and lenalidomide administered orally, and the efficacy response is complete response rate (CRR), objective response rate (ORR), duration of response (DOR), duration of complete response (DOCR), overall survival (OS), or progression-free survival (PFS).

138. 1. Use of lenalidomide in the manufacture of a medicament for use in combination with mosunetuzumab to treat follicular lymphoma (FL) in a subject in need thereof, wherein mosunetuzumab is administered subcutaneously and lenalidomide is administered orally as a combination treatment, and the combination treatment is administered to the plurality of subjects, resulting in a non-inferior or improved efficacy response in the plurality of subjects compared to a reference efficacy response, wherein the reference efficacy response is the efficacy response of the plurality of subjects who received a control treatment comprising mosunetuzumab administered intravenously and lenalidomide administered orally, and the efficacy response is complete response rate (CRR), objective response rate (ORR), duration of response (DOR), duration of complete response (DOCR), overall survival (OS), or progression-free survival (PFS).

139. 1. Use of mosunetuzumab and lenalidomide in the manufacture of a medicament for treating follicular lymphoma (FL) in a subject in need thereof, wherein mosunetuzumab is administered subcutaneously and lenalidomide is administered orally as a combination treatment, and administering the combination treatment to the plurality of subjects results in a non-inferior or improved efficacy response in the plurality of subjects compared to a reference efficacy response, wherein the reference efficacy response is the efficacy response of the plurality of subjects who received a control treatment comprising mosunetuzumab administered intravenously and lenalidomide administered orally, and the efficacy response is complete response rate (CRR), objective response rate (ORR), duration of response (DOR), duration of complete response (DOCR), overall survival (OS), or progression-free survival (PFS).

140. 1. Mosunetuzumab for use in combination with lenalidomide to treat follicular lymphoma (FL) in a subject in need thereof, wherein the combination treatment comprises mosunetuzumab administered subcutaneously and lenalidomide administered orally, and wherein administering the combination treatment to the plurality of subjects results in a non-inferior or improved efficacy response in the plurality of subjects compared to a reference efficacy response, wherein the reference efficacy response is the efficacy response of the plurality of subjects receiving a control treatment comprising mosunetuzumab administered intravenously and lenalidomide administered orally, and the efficacy response is complete response rate (CRR), objective response rate (ORR), duration of response (DOR), duration of complete response (DOCR), overall survival (OS), or progression-free survival (PFS).

141. 1. Lenalidomide for use in combination with mosunetuzumab to treat follicular lymphoma (FL) in a subject in need thereof, wherein the combination treatment comprises mosunetuzumab administered subcutaneously and lenalidomide administered orally, and wherein administering the combination treatment to the plurality of subjects results in a non-inferior or improved efficacy response in the plurality of subjects compared to a reference efficacy response, wherein the reference efficacy response is the efficacy response of the plurality of subjects receiving a control treatment comprising mosunetuzumab administered intravenously and lenalidomide administered orally, and the efficacy response is complete response rate (CRR), objective response rate (ORR), duration of response (DOR), duration of complete response (DOCR), overall survival (OS), or progression-free survival (PFS).

142. 1. The method of claim 1, wherein the combination treatment comprises administering mosunetuzumab subcutaneously and lenalidomide orally to a subject in need of treatment for follicular lymphoma (FL), wherein the combination treatment comprises administering mosunetuzumab subcutaneously and lenalidomide orally, and wherein the combination treatment is administered to a plurality of subjects and results in a non-inferior or improved efficacy response in the plurality of subjects compared to a reference efficacy response, wherein the reference efficacy response is the efficacy response of a plurality of subjects receiving a control treatment comprising mosunetuzumab administered intravenously and lenalidomide administered orally, and the efficacy response is a complete response rate (CRR), an objective response rate (ORR), a duration of response (DOR), a duration of complete response (DOCR), an overall survival (OS), or a progression-free survival (PFS).

143. 1. Use of mosunetuzumab in combination with lenalidomide to treat follicular lymphoma (FL) in a subject in need thereof, wherein the combination treatment comprises mosunetuzumab administered subcutaneously and lenalidomide administered orally, and the combination treatment is administered to the plurality of subjects, resulting in a non-inferior or improved safety response in the plurality of subjects compared to a reference safety response, wherein the reference safety response is the safety response of the plurality of subjects receiving a control treatment comprising mosunetuzumab administered intravenously and lenalidomide administered orally, and the safety response is the incidence of adverse events (AEs), the incidence of cytokine release syndrome (CRS), or the incidence of serious AEs (SAEs).

144. 1. Use of lenalidomide in combination with mosunetuzumab to treat follicular lymphoma (FL) in a subject in need thereof, wherein the combination treatment comprises mosunetuzumab administered subcutaneously and lenalidomide administered orally, and the combination treatment is administered to a plurality of subjects, resulting in a non-inferior or improved safety response in the plurality of subjects compared to a reference safety response, wherein the reference safety response is the safety response of a plurality of subjects receiving a control treatment comprising mosunetuzumab administered intravenously and lenalidomide administered orally, and the safety response is the incidence of adverse events (AEs), the incidence of cytokine release syndrome (CRS), or the incidence of serious AEs (SAEs).

145. 1. Use of mosunetuzumab and lenalidomide to treat follicular lymphoma (FL) in a subject in need thereof, wherein mosunetuzumab is administered subcutaneously and lenalidomide is administered orally as a combination treatment, and the combination treatment is administered to the plurality of subjects, resulting in a non-inferior or improved safety response in the plurality of subjects compared to a reference safety response, wherein the reference safety response is the safety response of the plurality of subjects receiving a control treatment comprising mosunetuzumab administered intravenously and lenalidomide administered orally, and the safety response is the incidence of adverse events (AEs), the incidence of cytokine release syndrome (CRS), or the incidence of serious AEs (SAEs).

146. 1. Use of mosunetuzumab in the manufacture of a medicament for use in combination with lenalidomide to treat follicular lymphoma (FL) in a subject in need thereof, wherein mosunetuzumab is administered subcutaneously and lenalidomide is administered orally as a combination treatment, and the combination treatment is administered to a plurality of subjects, resulting in a non-inferior or improved safety response in the plurality of subjects compared to a reference safety response, wherein the reference safety response is the safety response of a plurality of subjects receiving a control treatment comprising mosunetuzumab administered intravenously and lenalidomide administered orally, and the safety response is the incidence of adverse events (AEs), the incidence of cytokine release syndrome (CRS), or the incidence of serious AEs (SAEs).

147. 1. Use of lenalidomide in the manufacture of a medicament for use in combination with mosunetuzumab to treat follicular lymphoma (FL) in a subject in need thereof, wherein mosunetuzumab is administered subcutaneously and lenalidomide is administered orally as a combination treatment, and the combination treatment is administered to a plurality of subjects, resulting in a non-inferior or improved safety response in the plurality of subjects compared to a reference safety response, wherein the reference safety response is the safety response of a plurality of subjects receiving a control treatment comprising mosunetuzumab administered intravenously and lenalidomide administered orally, and the safety response is the incidence of adverse events (AEs), the incidence of cytokine release syndrome (CRS), or the incidence of serious AEs (SAEs).

148. 1. Use of mosunetuzumab and lenalidomide in the manufacture of a medicament for treating follicular lymphoma (FL) in a subject in need thereof, wherein mosunetuzumab is administered subcutaneously and lenalidomide is administered orally as a combination treatment, and administering the combination treatment to the plurality of subjects results in a non-inferior or improved safety response in the plurality of subjects compared to a reference safety response, wherein the reference safety response is the safety response of the plurality of subjects receiving a control treatment comprising mosunetuzumab administered intravenously and lenalidomide administered orally, and the safety response is the incidence of adverse events (AEs), the incidence of cytokine release syndrome (CRS), or the incidence of serious AEs (SAEs).

149. 1. Mosunetuzumab used in combination with lenalidomide to treat follicular lymphoma (FL) in a subject in need thereof, wherein the combination treatment comprises mosunetuzumab administered subcutaneously and lenalidomide administered orally, and wherein administering the combination treatment to the plurality of subjects results in a non-inferior or improved safety response in the plurality of subjects compared to a reference safety response, wherein the reference safety response is the safety response of the plurality of subjects receiving a control treatment comprising mosunetuzumab administered intravenously and lenalidomide administered orally, and the safety response is the incidence of adverse events (AEs), the incidence of cytokine release syndrome (CRS), or the incidence of serious AEs (SAEs).

150. 1. Lenalidomide used in combination with mosunetuzumab to treat follicular lymphoma (FL) in a subject in need thereof, wherein the combination treatment comprises mosunetuzumab administered subcutaneously and lenalidomide administered orally, and wherein administering the combination treatment to the plurality of subjects results in a non-inferior or improved safety response in the plurality of subjects compared to a reference safety response, the reference safety response being the safety response of the plurality of subjects receiving a control treatment comprising mosunetuzumab administered intravenously and lenalidomide administered orally, and the safety response being the incidence of adverse events (AEs), the incidence of cytokine release syndrome (CRS), or the incidence of serious AEs (SAEs).

151. 1. The method of claim 1, wherein the combination treatment comprises administering mosunetuzumab subcutaneously and lenalidomide orally to a subject in need of treatment for follicular lymphoma (FL), and wherein the combination treatment results in a non-inferior or improved safety response in the subjects compared to a reference safety response, the reference safety response being the safety response of the subjects receiving a control treatment comprising intravenously administered mosunetuzumab and orally administered lenalidomide, and the safety response is an incidence of adverse events (AEs), a incidence of cytokine release syndrome (CRS), or a incidence of serious AEs (SAEs).

152. 1. Use of mosunetuzumab in combination with lenalidomide to treat follicular lymphoma (FL) in a subject in need thereof, wherein the combination treatment comprises mosunetuzumab administered subcutaneously and lenalidomide administered orally, and the combination treatment is administered to a plurality of subjects, whereby a non-inferiority pharmacokinetic (PK) endpoint is achieved in a plurality of subjects compared to a reference PK endpoint, and the PK endpoint is observed dosing cycle 2 serum trough concentration (scConc). トラフＣＹＣ２－ＯＢＳ ) or cumulative area under the concentration-time curve (scAUC) over 0 to 77 days ０～７７ ) and The reference PK endpoint was a PK endpoint in subjects receiving a control treatment comprising intravenously administered mosunetuzumab and orally administered lenalidomide according to a dosing regimen comprising an initial 21-day dosing cycle and three 28-day dosing cycles, and the reference PK endpoint was the observed dosing cycle 2 serum trough concentration (ivConc トラフＣＹＣ２－ＯＢＳ ) or cumulative area under the concentration-time curve (ivAUC) over 0 to 77 days ０～７７ ) is used.

153. 1. Use of lenalidomide in combination with mosunetuzumab to treat follicular lymphoma (FL) in a subject in need thereof, wherein the combination treatment comprises mosunetuzumab administered subcutaneously and lenalidomide administered orally, and the combination treatment is administered to a plurality of subjects, whereby a non-inferiority pharmacokinetic (PK) endpoint is achieved in a plurality of subjects compared to a reference PK endpoint, and the PK endpoint is observed dosing cycle 2 serum trough concentration (scConc). トラフＣＹＣ２－ＯＢＳ ) or cumulative area under the concentration-time curve (scAUC) over 0 to 77 days ０～７７ ) and The reference PK endpoint was a PK endpoint in subjects receiving a control treatment comprising intravenously administered mosunetuzumab and orally administered lenalidomide according to a dosing regimen comprising a first 21-day dosing cycle and three 28-day dosing cycles, and the reference PK endpoint was observed dosing cycle 2 serum trough concentrations (ivConc トラフＣＹＣ２－ＯＢＳ ) or cumulative area under the concentration-time curve (ivAUC) over 0 to 77 days ０～７７ ) is used.

154. 1. Use of mosunetuzumab and lenalidomide to treat follicular lymphoma (FL) in subjects in need thereof, wherein the combination treatment comprises mosunetuzumab administered subcutaneously and lenalidomide administered orally, and wherein administering the combination treatment to the plurality of subjects results in a non-inferiority pharmacokinetic (PK) endpoint for the plurality of subjects compared to a reference PK endpoint, and the PK endpoint is observed dosing cycle 2 serum trough concentration (scConc). トラフＣＹＣ２－ＯＢＳ ) or cumulative area under the concentration-time curve (scAUC) over 0 to 77 days ０～７７ ) and The reference PK endpoint was a PK endpoint in subjects receiving a control treatment comprising intravenously administered mosunetuzumab and orally administered lenalidomide according to a dosing regimen comprising a first 21-day dosing cycle and three 28-day dosing cycles, and the reference PK endpoint was observed dosing cycle 2 serum trough concentrations (ivConc トラフＣＹＣ２－ＯＢＳ ) or cumulative area under the concentration-time curve (ivAUC) over 0 to 77 days ０～７７ ) is used.

155. 1. Use of mosunetuzumab in the manufacture of a medicament for use in combination with lenalidomide to treat follicular lymphoma (FL) in a subject in need thereof, wherein the combination treatment comprises mosunetuzumab administered subcutaneously and lenalidomide administered orally, and the combination treatment is administered to a plurality of subjects to achieve a non-inferiority pharmacokinetic (PK) endpoint compared to a reference PK endpoint, wherein the PK endpoint is observed dosing cycle 2 serum trough concentration (scConc). トラフＣＹＣ２－ＯＢＳ ) or cumulative area under the concentration-time curve (scAUC) over 0 to 77 days ０～７７ ) and The reference PK endpoint was a PK endpoint in subjects receiving a control treatment comprising intravenously administered mosunetuzumab and orally administered lenalidomide according to a dosing regimen comprising a first 21-day dosing cycle and three 28-day dosing cycles, and the reference PK endpoint was observed dosing cycle 2 serum trough concentrations (ivConc トラフＣＹＣ２－ＯＢＳ ) or cumulative area under the concentration-time curve (ivAUC) over 0 to 77 days ０～７７ ) is used.

156. 1. Use of lenalidomide in the manufacture of a medicament for use in combination with mosunetuzumab to treat follicular lymphoma (FL) in a subject in need thereof, wherein the combination treatment comprises mosunetuzumab administered subcutaneously and lenalidomide administered orally, and the combination treatment is administered to a plurality of subjects to achieve a non-inferiority pharmacokinetic (PK) endpoint compared to a reference PK endpoint, wherein the PK endpoint is observed dosing cycle 2 serum trough concentration (scConc). トラフＣＹＣ２－ＯＢＳ ) or cumulative area under the concentration-time curve (scAUC) over 0 to 77 days ０～７７ ) and The reference PK endpoint was a PK endpoint in subjects receiving a control treatment comprising intravenously administered mosunetuzumab and orally administered lenalidomide according to a dosing regimen comprising a first 21-day dosing cycle and three 28-day dosing cycles, and the reference PK endpoint was observed dosing cycle 2 serum trough concentrations (ivConc トラフＣＹＣ２－ＯＢＳ ) or cumulative area under the concentration-time curve (ivAUC) over 0 to 77 days ０～７７ ) is used.

157. 1. Use of mosunetuzumab and lenalidomide in the manufacture of a medicament for treating follicular lymphoma (FL) in a subject in need thereof, wherein the combination treatment comprises mosunetuzumab administered subcutaneously and lenalidomide administered orally, and wherein administering the combination treatment to the plurality of subjects results in a non-inferiority pharmacokinetic (PK) endpoint compared to a reference PK endpoint, and the PK endpoint is observed dosing cycle 2 serum trough concentration (scConc). トラフＣＹＣ２－ＯＢＳ ) or cumulative area under the concentration-time curve (scAUC) over 0 to 77 days ０～７７ ) and The reference PK endpoint was a PK endpoint in subjects receiving a control treatment comprising intravenously administered mosunetuzumab and orally administered lenalidomide according to a dosing regimen comprising a first 21-day dosing cycle and three 28-day dosing cycles, and the reference PK endpoint was observed dosing cycle 2 serum trough concentrations (ivConc トラフＣＹＣ２－ＯＢＳ ) or cumulative area under the concentration-time curve (ivAUC) over 0 to 77 days ０～７７ ) is used.

158. Mosunetuzumab used in combination with lenalidomide to treat follicular lymphoma (FL) in a subject in need thereof, wherein the combination treatment comprises mosunetuzumab administered subcutaneously and lenalidomide administered orally, and the combination treatment is administered to a plurality of subjects, whereby a non-inferiority pharmacokinetic (PK) endpoint is achieved in a plurality of subjects compared to a reference PK endpoint, and the PK endpoint is observed dosing cycle 2 serum trough concentration (scConc). トラフＣＹＣ２－ＯＢＳ ) or cumulative area under the concentration-time curve (scAUC) over 0 to 77 days ０～７７ ) and The reference PK endpoint was a PK endpoint in subjects receiving a control treatment comprising intravenously administered mosunetuzumab and orally administered lenalidomide according to a dosing regimen comprising a first 21-day dosing cycle and three 28-day dosing cycles, and the reference PK endpoint was observed dosing cycle 2 serum trough concentrations (ivConc トラフＣＹＣ２－ＯＢＳ ) or cumulative area under the concentration-time curve (ivAUC) over 0 to 77 days ０～７７ ) Mosunetuzumab.

159. 1. Lenalidomide used in combination with mosunetuzumab to treat follicular lymphoma (FL) in a subject in need thereof, wherein the combination treatment comprises mosunetuzumab administered subcutaneously and lenalidomide administered orally, and wherein administering the combination treatment to the plurality of subjects results in a non-inferiority pharmacokinetic (PK) endpoint compared to a reference PK endpoint, and the PK endpoint is observed dosing cycle 2 serum trough concentration (scConc). トラフＣＹＣ２－ＯＢＳ ) or cumulative area under the concentration-time curve (scAUC) over 0 to 77 days ０～７７ ) and The reference PK endpoint was a PK endpoint in subjects receiving a control treatment comprising intravenously administered mosunetuzumab and orally administered lenalidomide according to a dosing regimen comprising a first 21-day dosing cycle and three 28-day dosing cycles, and the reference PK endpoint was observed dosing cycle 2 serum trough concentrations (ivConc トラフＣＹＣ２－ＯＢＳ ) or cumulative area under the concentration-time curve (ivAUC) over 0 to 77 days ０～７７ ) lenalidomide.

160. Mosunetuzumab and lenalidomide are used to treat follicular lymphoma (FL) in subjects in need thereof, wherein the combination treatment comprises mosunetuzumab administered subcutaneously and lenalidomide administered orally, and the combination treatment is administered to the plurality of subjects to achieve a non-inferiority pharmacokinetic (PK) endpoint compared to a reference PK endpoint, and the PK endpoint is observed dosing cycle 2 serum trough concentration (scConc). トラフＣＹＣ２－ＯＢＳ ) or cumulative area under the concentration-time curve (scAUC) over 0 to 77 days ０～７７ ) and The reference PK endpoint was a PK endpoint in subjects receiving a control treatment comprising intravenously administered mosunetuzumab and orally administered lenalidomide according to a dosing regimen comprising a first 21-day dosing cycle and three 28-day dosing cycles, and the reference PK endpoint was observed dosing cycle 2 serum trough concentrations (ivConc トラフＣＹＣ２－ＯＢＳ ) or cumulative area under the concentration-time curve (ivAUC) over 0 to 77 days ０～７７ ), mosunetuzumab and lenalidomide.

161. 1. Use of mosunetuzumab in combination with lenalidomide to treat follicular lymphoma (FL) in a subject in need thereof, wherein mosunetuzumab is administered subcutaneously and lenalidomide is administered orally as combination treatment according to a dosing regimen comprising a first dosing cycle that is a 21-day dosing cycle and a second dosing cycle that is a 28-day dosing cycle, 10 additional 28-day dosing cycles, and 1 to 9 subcutaneous maintenance doses of mosunetuzumab; (a) the first dosing cycle comprises a first subcutaneous administration (scC1D1), a second subcutaneous administration (scC1D2), and a third subcutaneous administration (scC1D3) of mosunetuzumab on days 1, 8, and 15 of the first dosing cycle, respectively, wherein the dose of scC1D1 is about 5 mg, the dose of scC1D2 is about 45 mg, and the dose of scC1D3 is about 45 mg; (b) the second dosing cycle comprises: (i) a first subcutaneous administration of approximately 45 mg of mosunetuzumab (scC2D1) administered on day 1 of a second dosing cycle; and (ii) 21 oral doses of about 20 mg of lenalidomide administered on days 1-21 of a second dosing cycle. Includes (c) 10 additional dosing cycles, each of (i) a first subcutaneous administration of approximately 45 mg of mosunetuzumab (scC3D1-scC12D1) administered on Day 1 of each additional dosing cycle; and (ii) 21 oral doses of about 20 mg of lenalidomide administered on days 1 through 21 of each additional dosing cycle. Including, use.

162. 1. Use of lenalidomide in combination with mosunetuzumab to treat follicular lymphoma (FL) in a subject in need thereof, wherein mosunetuzumab is administered subcutaneously and lenalidomide is administered orally as combination treatment, according to a dosing regimen comprising a first dosing cycle that is a 21-day dosing cycle and a second dosing cycle that is a 28-day dosing cycle, 10 additional 28-day dosing cycles, and 1 to 9 subcutaneous maintenance doses of mosunetuzumab; (a) the first dosing cycle comprises a first subcutaneous administration (scC1D1), a second subcutaneous administration (scC1D2), and a third subcutaneous administration (scC1D3) of mosunetuzumab on days 1, 8, and 15 of the first dosing cycle, respectively, wherein the dose of scC1D1 is about 5 mg, the dose of scC1D2 is about 45 mg, and the dose of scC1D3 is about 45 mg; (b) the second dosing cycle comprises: (i) a first subcutaneous administration of approximately 45 mg of mosunetuzumab (scC2D1) administered on day 1 of a second dosing cycle; and (ii) 21 oral doses of about 20 mg of lenalidomide administered on days 1 through 21 of a second dosing cycle. Includes (c) 10 additional dosing cycles, each of (i) a first subcutaneous administration of approximately 45 mg of mosunetuzumab (scC3D1-scC12D1) administered on Day 1 of each additional dosing cycle; and (ii) 21 oral doses of about 20 mg of lenalidomide administered on days 1 through 21 of each additional dosing cycle. Including, use.

163. 1. Use of mosunetuzumab and lenalidomide to treat follicular lymphoma (FL) in a subject in need thereof, wherein mosunetuzumab is administered subcutaneously and lenalidomide is administered orally as combination treatment according to a dosing regimen comprising a first dosing cycle that is a 21-day dosing cycle and a second dosing cycle that is a 28-day dosing cycle, 10 additional 28-day dosing cycles, and 1 to 9 subcutaneous maintenance doses of mosunetuzumab; (a) the first dosing cycle comprises a first subcutaneous administration (scC1D1), a second subcutaneous dose (scC1D2), and a third subcutaneous dose (scC1D3) of mosunetuzumab on days 1, 8, and 15 of the first dosing cycle, respectively, wherein the dose of scC1D1 is about 5 mg, the dose of scC1D2 is about 45 mg, and the dose of scC1D3 is about 45 mg; (b) the second dosing cycle comprises: (i) a first subcutaneous dose of approximately 45 mg of mosunetuzumab administered on day 1 of the second dosing cycle (scC2D1); and (ii) 21 oral doses of about 20 mg of lenalidomide administered on days 1 through 21 of a second dosing cycle. Includes (c) 10 additional dosing cycles, each of (i) a first subcutaneous administration of approximately 45 mg of mosunetuzumab (scC3D1-scC12D1) administered on Day 1 of each additional dosing cycle; and (ii) 21 oral doses of about 20 mg of lenalidomide administered on days 1 through 21 of each additional dosing cycle. Including, use.

164. 1. Use of mosunetuzumab in the manufacture of a medicament for use in combination with lenalidomide to treat follicular lymphoma (FL) in a subject in need thereof, wherein the combination treatment comprises a first dosing cycle that is a 21-day dosing cycle and a second dosing cycle that is a 28-day dosing cycle, ten additional 28-day dosing cycles; and one to nine subcutaneous maintenance doses of mosunetuzumab, wherein the combination treatment comprises mosunetuzumab administered subcutaneously and lenalidomide administered orally, (a) the first dosing cycle comprises a first subcutaneous administration (scC1D1), a second subcutaneous administration (scC1D2), and a third subcutaneous administration (scC1D3) of mosunetuzumab on days 1, 8, and 15 of the first dosing cycle, respectively, wherein the dose of scC1D1 is about 5 mg, the dose of scC1D2 is about 45 mg, and the dose of scC1D3 is about 45 mg; (b) the second dosing cycle comprises: (i) a first subcutaneous administration of approximately 45 mg of mosunetuzumab (scC2D1) administered on day 1 of a second dosing cycle; and (ii) 21 oral doses of about 20 mg of lenalidomide administered on days 1 through 21 of a second dosing cycle. Includes (c) 10 additional dosing cycles, each of (i) a first subcutaneous administration of approximately 45 mg of mosunetuzumab (scC3D1-scC12D1) administered on Day 1 of each additional dosing cycle; and (ii) 21 oral doses of about 20 mg of lenalidomide administered on days 1 through 21 of each additional dosing cycle. Including, use.

165. 1. Use of lenalidomide in the manufacture of a medicament for use in combination with mosunetuzumab to treat follicular lymphoma (FL) in a subject in need thereof, wherein mosunetuzumab is administered subcutaneously and lenalidomide is administered orally as combination treatment according to a dosing regimen comprising 10 additional 28-day dosing cycles, where the first dosing cycle is a 21-day dosing cycle and the second dosing cycle is a 28-day dosing cycle, and 1 to 9 subcutaneous maintenance doses of mosunetuzumab; (a) the first dosing cycle comprises a first subcutaneous administration (scC1D1), a second subcutaneous administration (scC1D2), and a third subcutaneous administration (scC1D3) of mosunetuzumab on days 1, 8, and 15 of the first dosing cycle, respectively, wherein the dose of scC1D1 is about 5 mg, the dose of scC1D2 is about 45 mg, and the dose of scC1D3 is about 45 mg; (b) the second dosing cycle comprises: (i) a first subcutaneous administration of approximately 45 mg of mosunetuzumab (scC2D1) administered on day 1 of a second dosing cycle; and (ii) 21 oral doses of about 20 mg of lenalidomide administered on days 1 through 21 of a second dosing cycle. Includes (c) 10 additional dosing cycles, each of (i) a first subcutaneous administration of approximately 45 mg of mosunetuzumab (scC3D1-scC12D1) administered on Day 1 of each additional dosing cycle; and (ii) 21 oral doses of about 20 mg of lenalidomide administered on days 1 through 21 of each additional dosing cycle. Including, use.

166. 1. Use of mosunetuzumab and lenalidomide in the manufacture of a medicament for treating follicular lymphoma (FL) in a subject in need thereof, wherein mosunetuzumab is administered subcutaneously and lenalidomide is administered orally as combination treatment according to a dosing regimen comprising a first dosing cycle that is a 21-day dosing cycle and a second dosing cycle that is a 28-day dosing cycle, 10 additional 28-day dosing cycles, and 1 to 9 subcutaneous maintenance doses of mosunetuzumab; (a) the first dosing cycle comprises a first subcutaneous administration (scC1D1), a second subcutaneous administration (scC1D2), and a third subcutaneous administration (scC1D3) of mosunetuzumab on days 1, 8, and 15 of the first dosing cycle, respectively, wherein the dose of scC1D1 is about 5 mg, the dose of scC1D2 is about 45 mg, and the dose of scC1D3 is about 45 mg; (b) the second dosing cycle comprises: (i) a first subcutaneous administration of approximately 45 mg of mosunetuzumab (scC2D1) administered on day 1 of a second dosing cycle; and (ii) 21 oral doses of about 20 mg of lenalidomide administered on days 1 through 21 of a second dosing cycle. Includes (c) 10 additional dosing cycles, each of (i) a first subcutaneous administration of approximately 45 mg of mosunetuzumab (scC3D1-scC12D1) administered on Day 1 of each additional dosing cycle; and (ii) 21 oral doses of about 20 mg of lenalidomide administered on days 1 through 21 of each additional dosing cycle. Including, use.

167. 1. Mosunetuzumab used in combination with lenalidomide to treat follicular lymphoma (FL) in a subject in need thereof, wherein mosunetuzumab is administered subcutaneously and lenalidomide is administered orally according to a dosing regimen comprising a first dosing cycle that is a 21-day dosing cycle and a second dosing cycle that is a 28-day dosing cycle, 10 additional 28-day dosing cycles, and 1-9 subcutaneous maintenance doses of mosunetuzumab, wherein the combination treatment includes: (a) the first dosing cycle comprises a first subcutaneous administration (scC1D1), a second subcutaneous administration (scC1D2), and a third subcutaneous administration (scC1D3) of mosunetuzumab on days 1, 8, and 15 of the first dosing cycle, respectively, wherein the dose of scC1D1 is about 5 mg, the dose of scC1D2 is about 45 mg, and the dose of scC1D3 is about 45 mg; (b) the second dosing cycle comprises: (i) a first subcutaneous administration of approximately 45 mg of mosunetuzumab (scC2D1) administered on day 1 of a second dosing cycle; and (ii) 21 oral doses of about 20 mg of lenalidomide administered on days 1 through 21 of a second dosing cycle. Includes (c) 10 additional dosing cycles, each of (i) a first subcutaneous dose of about 45 mg each of mosunetuzumab (scC3D1-scC12D1) administered on Day 1 of each additional dosing cycle; and (ii) 21 oral doses of about 20 mg of lenalidomide administered on days 1 through 21 of each additional dosing cycle. including mosunetuzumab.

168. 1. Lenalidomide used in combination with mosunetuzumab to treat follicular lymphoma (FL) in a subject in need thereof, wherein mosunetuzumab is administered subcutaneously and lenalidomide is administered orally according to a dosing regimen comprising a first dosing cycle that is a 21-day dosing cycle and a second dosing cycle that is a 28-day dosing cycle, 10 additional 28-day dosing cycles, and 1 to 9 subcutaneous maintenance doses of mosunetuzumab, wherein the combination treatment includes: (a) the first dosing cycle comprises a first subcutaneous administration (scC1D1), a second subcutaneous administration (scC1D2), and a third subcutaneous administration (scC1D3) of mosunetuzumab on days 1, 8, and 15 of the first dosing cycle, respectively, wherein the dose of scC1D1 is about 5 mg, the dose of scC1D2 is about 45 mg, and the dose of scC1D3 is about 45 mg; (b) the second dosing cycle comprises: (i) a first subcutaneous dose of approximately 45 mg of mosunetuzumab (scC2D1) administered on day 1 of a second dosing cycle; and (ii) 21 oral doses of about 20 mg of lenalidomide administered on days 1 through 21 of a second dosing cycle. Includes (c) 10 additional dosing cycles, each of (i) a first subcutaneous administration of approximately 45 mg of mosunetuzumab (scC3D1-scC12D1) administered on Day 1 of each additional dosing cycle; and (ii) 21 oral doses of about 20 mg of lenalidomide administered on days 1 through 21 of each additional dosing cycle. including lenalidomide.

169. 1. Mosunetuzumab and lenalidomide used to treat follicular lymphoma (FL) in a subject in need thereof, wherein mosunetuzumab is administered subcutaneously and lenalidomide is administered orally as a combination treatment according to a dosing regimen comprising a first dosing cycle that is a 21-day dosing cycle and a second dosing cycle that is a 28-day dosing cycle, 10 additional 28-day dosing cycles, and 1 to 9 subcutaneous maintenance doses of mosunetuzumab; (a) the first dosing cycle comprises a first subcutaneous administration (scC1D1), a second subcutaneous administration (scC1D2), and a third subcutaneous administration (scC1D3) of mosunetuzumab on days 1, 8, and 15 of the first dosing cycle, respectively, wherein the dose of scC1D1 is about 5 mg, the dose of scC1D2 is about 45 mg, and the dose of scC1D3 is about 45 mg; (b) the second dosing cycle (i) a first subcutaneous administration of approximately 45 mg of mosunetuzumab (scC2D1) administered on day 1 of a second dosing cycle; and (ii) 21 oral doses of about 20 mg of lenalidomide administered on days 1 through 21 of a second dosing cycle. Includes (c) 10 additional dosing cycles, each of (i) a first subcutaneous administration of approximately 45 mg of mosunetuzumab (scC3D1-scC12D1) administered on Day 1 of each additional dosing cycle; and (ii) 21 oral doses of about 20 mg of lenalidomide administered on days 1 through 21 of each additional dosing cycle. including mosunetuzumab and lenalidomide.

170. 1. Use of mosunetuzumab to treat non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL) in a subject in need thereof, wherein the treatment comprises subcutaneous administration of mosunetuzumab, and wherein administering the treatment to a plurality of subjects results in a non-inferior or improved efficacy response in the plurality of subjects compared to a reference efficacy response, the reference efficacy response being the efficacy response of a plurality of subjects who received a control treatment comprising intravenously administered mosunetuzumab, and the efficacy response is complete response rate (CRR), objective response rate (ORR), duration of response (DOR), duration of complete response (DOCR), progression-free survival (PFS), or overall survival (OS).

171. 1. Use of mosunetuzumab in the manufacture of a medicament for treating non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL) in a subject in need thereof, wherein mosunetuzumab is administered subcutaneously as a treatment, and the administration of the treatment to the plurality of subjects results in a non-inferior or improved efficacy response in the plurality of subjects compared to a reference efficacy response, wherein the reference efficacy response is the efficacy response of the plurality of subjects who received a control treatment comprising mosunetuzumab administered intravenously, and the efficacy response is complete response rate (CRR), objective response rate (ORR), duration of response (DOR), duration of complete response (DOCR), progression-free survival (PFS), or overall survival (OS).

172. 1. The method of claim 1, wherein the administration of mosunetuzumab to a subject results in a non-inferior or improved efficacy response in a plurality of subjects compared to a reference efficacy response, the reference efficacy response being the efficacy response of a plurality of subjects who received a control treatment comprising intravenously administered mosunetuzumab, and the efficacy response is a complete response rate (CRR), an objective response rate (ORR), a duration of response (DOR), a duration of complete response (DOCR), a progression-free survival (PFS), or an overall survival (OS).

173. 1. Use of mosunetuzumab to treat non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL) in a subject in need thereof, wherein the treatment is administered subcutaneously, and the administration of the treatment to the plurality of subjects results in a non-inferior or improved safety response in the plurality of subjects compared to a reference safety response, the reference safety response being the safety response of the plurality of subjects receiving a control treatment comprising intravenously administered mosunetuzumab, and the safety response being the incidence of adverse events (AEs), the incidence of cytokine release syndrome (CRS), or the incidence of serious AEs (SAEs).

174. 1. Use of mosunetuzumab in the manufacture of a medicament for treating non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL) in a subject in need thereof, wherein mosunetuzumab is administered subcutaneously as a treatment, and the administration of the treatment to a plurality of subjects results in a non-inferior or improved safety response in the plurality of subjects compared to a reference safety response, the reference safety response being the safety response of a plurality of subjects who received a control treatment comprising mosunetuzumab administered intravenously, and the safety response being the incidence of adverse events (AEs), the incidence of cytokine release syndrome (CRS), or the incidence of serious AEs (SAEs).

175. 1. Mosunetuzumab for use in treating non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL) in a subject in need thereof, wherein the treatment comprises subcutaneous administration of mosunetuzumab, and wherein administering the treatment to a plurality of subjects results in a non-inferior or improved safety response in the plurality of subjects compared to a reference safety response, the reference safety response being the safety response of a plurality of subjects receiving a control treatment comprising intravenously administered mosunetuzumab, and the safety response being the incidence of adverse events (AEs), cytokine release syndrome (CRS), or serious AEs (SAEs).

176. 1. Use of mosunetuzumab to treat non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL) in subjects in need thereof, wherein the treatment comprises subcutaneous administration of mosunetuzumab according to a dosing regimen comprising four 21-day dosing cycles, and the combination treatment is administered to the plurality of subjects, resulting in non-inferiority or improved pharmacokinetic (PK) endpoints in the plurality of subjects compared to the reference PK endpoint, wherein the PK endpoint is observed dosing cycle 3 serum trough concentration (scConc). トラフＣＹＣ３－ＯＢＳ ) or cumulative area under the concentration-time curve (scAUC) over 0 to 84 days ０～８４ ) and The reference PK endpoint was a PK endpoint in subjects receiving a control treatment containing intravenously administered mosunetuzumab according to a dosing regimen comprising four 21-day dosing cycles, and the reference PK endpoint was the observed dosing cycle 3 serum trough concentration (ivConc トラフＣＹＣ３－ＯＢＳ ) or cumulative area under the concentration-time curve (ivAUC) over 0 to 84 days ０～８４ ) is used.

177. 1. Use of mosunetuzumab in the manufacture of a medicament for treating non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL) in subjects in need thereof, wherein the treatment comprises subcutaneous administration of mosunetuzumab according to a dosing regimen comprising four 21-day dosing cycles, and the combination treatment is administered to the plurality of subjects, resulting in non-inferiority or improved pharmacokinetic (PK) endpoints compared to a reference PK endpoint, wherein the PK endpoint is greater than or equal to the observed dosing cycle 3 serum trough concentration (scConc). トラフＣＹＣ３－ＯＢＳ ) or cumulative area under the concentration-time curve (scAUC) over 0 to 84 days ０～８４ ) and The reference PK endpoint was a PK endpoint in subjects receiving a control treatment containing intravenously administered mosunetuzumab according to a dosing regimen comprising four 21-day dosing cycles, and the reference PK endpoint was the observed dosing cycle 3 serum trough concentration (ivConc トラフＣＹＣ３－ＯＢＳ ) or cumulative area under the concentration-time curve (ivAUC) over 0 to 84 days ０～８４ ) is used.

178. Mosunetuzumab is used to treat non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL) in subjects in need thereof, wherein the treatment comprises subcutaneous administration of mosunetuzumab according to a dosing regimen comprising four 21-day dosing cycles, and the combination treatment is administered to a plurality of subjects, resulting in non-inferiority or improved pharmacokinetic (PK) endpoints compared to reference PK endpoints, wherein the PK endpoints are observed dosing cycle 3 serum trough concentrations (scConc). トラフＣＹＣ３－ＯＢＳ ) or cumulative area under the concentration-time curve (scAUC) over 0 to 84 days ０～８４ ) and The reference PK endpoint was a PK endpoint in subjects receiving a control treatment containing intravenously administered mosunetuzumab according to a dosing regimen comprising four 21-day dosing cycles, and the reference PK endpoint was the observed dosing cycle 3 serum trough concentration (ivConc トラフＣＹＣ３－ＯＢＳ ) or cumulative area under the concentration-time curve (ivAUC) over 0 to 84 days ０～８４ ) Mosunetuzumab.

179. 40. The method of claim 39, wherein the dose of scC1D1 is 5 mg, the dose of scC1D2 is 45 mg, the dose of scC1D3 is 45 mg; the dose of scC2D1 is 45 mg; and each oral dose of lenalidomide is 20 mg.

180. 43. The method of claim 42, wherein the subcutaneous dose of mosunetuzumab is 45 mg; and each oral dose of lenalidomide is 20 mg.

181. 48. The method of claim 47, wherein each maintenance dose of mosunetuzumab is 45 mg.

182. 49. The method of claim 48, wherein the dose of ivC1D1 is 1 mg, the dose of ivC1D2 is 2 mg, the dose of ivC1D3 is 30 mg; the dose of ivC2D1 is 30 mg; and each oral dose of lenalidomide is 20 mg.

183. 52. The method of claim 51, wherein the intravenous dose of mosunetuzumab is 30 mg and each oral dose of lenalidomide is 20 mg.

184. The method of claim 105, wherein the dose of scC1D1 is 5 mg, the dose of scC1D2 is 15 mg or 45 mg, the dose of scC1D3 is 45 mg; and the dose of scC2D1 is 45 mg.

185. 185. The method of claim 184, wherein the dose of scC1D2 is 45 mg.

186. 109. The method of claim 108, wherein the subcutaneous dose of mosunetuzumab is 45 mg.

187. The method of claim 109, wherein the dose of ivC1D1 is 1 mg, the dose of ivC1D2 is 2 mg, the dose of ivC1D3 is 60 mg; and the dose of ivC2D1 is 60 mg.

188. 113. The method of claim 112, wherein the intravenous dose of mosunetuzumab is 30 mg.

189. 134. The method of any one of claims 43-47 and 133, wherein administering the combination treatment to a plurality of subjects with FL results in an ORR in the plurality of subjects of between about 81% and about 99%.

190. 190. The method of claim 189, wherein the ORR is about 90%.

191. 134. The method of any one of claims 43-47 and 133, wherein administering the combination treatment to a plurality of subjects with FL results in a CRR in the plurality of subjects of between about 79% and about 97%.

192. 192. The method of claim 191, wherein the CRR is about 88%.

193. 134. The method of any one of claims 43-47 and 133, wherein administering the combination treatment to a plurality of subjects with FL results in a 12-month event-free rate of DOR of between about 86% and about 100% in the plurality of subjects.

194. The method of claim 193, wherein the 12-month event-free rate of DOR is about 94%.

195. 134. The method of any one of claims 43-47 and 133, wherein administering the combination treatment to a plurality of subjects with FL results in a 12-month event-free rate of DOCR of between about 86% and about 100% in the plurality of subjects.

196. The method of claim 195, wherein the 12-month event-free rate of DOCR is about 94%.

197. 134. The method of any one of claims 43-47 and 133, wherein administering the combination treatment to a plurality of subjects with FL results in a 12-month event-free rate of PFS of between about 76% and about 98% in the plurality of subjects.

198. The method of claim 197, wherein the 12-month event-free rate for PFS is about 87%.

199. 134. The method of any one of claims 43-47 and 133, wherein administering the combination treatment to a plurality of subjects with FL results in a 12-month event-free rate of OS of between about 92% and about 100% in the plurality of subjects.

200. 200. The method of claim 199, wherein the 12-month event-free rate of OS is about 97%.

201. 201. The method of any one of claims 189-200, wherein the FL is a previously untreated (1L) FL.

202. 109. The method of any one of claims 105-108, wherein administering the treatment to a plurality of subjects with R / R FL results in an ORR of between about 66% and about 85%.

203. 203. The method of claim 202, wherein the ORR is about 77%.

204. 109. The method of any one of claims 105-108, wherein administering treatment to a plurality of subjects with R / R FL results in a CRR in the plurality of subjects of between about 51% and about 72%.

205. The method of claim 204, wherein the CRR is about 62%.

206. 109. The method of any one of claims 105-108, wherein administering the treatment to a plurality of subjects with R / R FL results in an 18-month event-free rate of DOCR in the plurality of subjects of between about 57% and about 83%.

207. The method of claim 206, wherein the 18-month event-free rate of DOCR is about 70%.

208. 109. The method of any one of claims 105-108, wherein administering treatment to a plurality of subjects with R / R FL results in a median DOCR in the plurality of subjects of at least about 20 months.

209. 209. The method of claim 208, wherein the median DOCR is about 35 months.

210. 109. The method of any one of claims 105-108, wherein administering the treatment to a plurality of subjects with R / R FL results in an 18-month event-free rate of PFS in the plurality of subjects of between about 46% and about 68%.

211. The method of claim 210, wherein the 18-month event-free rate for PFS is about 57%.

212. 109. The method of any one of claims 105-108, wherein administering treatment to a plurality of subjects with R / R FL results in a median PFS of at least 14 months in the plurality of subjects.

213. The method of claim 212, wherein the median PFS is about 24 months.

214. 109. The method of any one of claims 105-108, wherein administering treatment to subjects with 1L FL results in an ORR of between about 76% and about 96%.

215. 215. The method of claim 214, wherein the ORR is about 87%.

216. 109. The method of any one of claims 105-108, wherein administering treatment to a plurality of subjects with 1L FL results in a CRR in the plurality of subjects of between about 55% and about 67%.

217. The method of claim 216, wherein the CRR is about 61%.

218. 109. The method of any one of claims 105-108, wherein administering the treatment to a plurality of subjects with 1L FL results in a 12-month event-free rate of PFS in the plurality of subjects of between about 73% and about 90%.

219. The method of claim 218, wherein the 12-month event-free rate for PFS is about 83%.

220. 109. The method of any one of claims 105-108, wherein administering treatment to a plurality of subjects having 1L FL results in a median time to response (TTR) of between about 1 month and about 6 months for a plurality of subjects who respond.

221. 221. The method of claim 220, wherein the median TTR is about 3 months.

222. 222. The method of any one of claims 214 to 221, wherein a plurality of subjects have high tumor burden according to the Follicular Lymphoma Study Group (Groupe d'Etude des Lymphomes Follicularaires, GELF) criteria.

223. 109. The method of any one of claims 105-108, wherein administering treatment to subjects with 1L MZL results in an ORR of between about 58% and about 88%.

224. 224. The method of claim 223, wherein the ORR is about 75%.

225. 109. The method of any one of claims 105-108, wherein administering treatment to a plurality of subjects with 1L MZL results in a CRR in the plurality of subjects of between about 44% and about 77%.

226. The method of claim 225, wherein the CRR is about 61%.

227. 109. The method of any one of claims 105-108, wherein administering treatment to a plurality of subjects with 1L MZL results in a median TTR of between about 2 months and about 6 months in a plurality of responding subjects.

228. The method of claim 227, wherein the median TTR is about 3 months.

Images