Methods of treating cancer with anti-PD-1 antibodies

Abstract

The present disclosure provides a method of treating cancer in a patient by administering certain PD-1 antagonists. The present disclosure also provides treatment regimens for patients previously treated with one or more chemotherapeutic agents or radiation therapy.

Description

Technical Field

[0001] The present disclosure generally relates to methods of treating cancer in a patient by administering certain PD-1 antagonists. The present disclosure also discloses treatment regimens for patients previously treated with one or more chemotherapeutic agents or radiation therapy. Background Art

[0002] Cancer is a serious public health problem. According to the American Cancer Society's Cancer Facts & Figures 2022 (www.cancer.org / content / dam / cancer-org / research / cancer-facts-and-statistics / annual-cancer-facts-and-figures / 2022 / 2022-cancer-facts-and-figures.pdf), approximately 609,360 people are expected to die from cancer in the United States in 2022 alone. Therefore, there remains a need for effective therapies to treat cancer patients. Summary of the Invention

[0003] In one aspect, the present disclosure provides a method of treating cancer in a human patient, comprising administering to the human patient a therapeutically effective amount of a combination comprising 500 mg to 1000 mg of dotarizumab or a biosimilar thereof, a platinum-based chemotherapy, and paclitaxel, e.g., wherein the platinum-based chemotherapy is cisplatin or carboplatin. In one embodiment, the platinum-based chemotherapy is carboplatin.

[0004] In one embodiment, the administration comprises a first dose of 500 mg of dotalizumab or its biosimilar once every 3 weeks (Q3W) for 4 to 6 cycles, followed by a second dose of 1000 mg of dotalizumab or its biosimilar once every 6 weeks (Q6W). In one embodiment, the second dose of dotalizumab or its biosimilar is Q6W for up to 3 years. In one embodiment, the first dose and / or the second dose of dotalizumab or its biosimilar is administered by intravenous infusion, for example, by intravenous infusion over 30 minutes. In one embodiment, the administration comprises a dose of carboplatin with an area under the concentration time curve of 5 mg / ml / min once every 3 weeks (Q3W) for 4 to 6 cycles. In one embodiment, the administration comprises 175 mg per square meter (mg / m 2 ) of paclitaxel once every 3 weeks (Q3W) for 4 to 6 cycles.

[0005] In one embodiment, the administration comprises: a first dose of 500 mg of dotalimumab or its biosimilar once every 3 weeks (Q3W) for 6 cycles, a dose of carboplatin with an area under the concentration-time curve of 5 mg / mL / min once every 3 weeks (Q3W) for 6 cycles, and 175 mg / m 2 ) paclitaxel dose every 3 weeks (Q3W) for 6 cycles, followed by a second dose of 1000 mg of dotalizumab or its biosimilar once every 6 weeks (Q6W). In one embodiment, the first dose of dotalizumab or its biosimilar, the carboplatin dose, and the paclitaxel dose are administered on day 1 of a 21-day cycle. In one embodiment, the second dose of dotalizumab or its biosimilar is administered on day 1 of a 42-day cycle.

[0006] In one embodiment, the patient has not previously received treatment for the cancer. In one embodiment, the patient has not previously received immunotherapy treatment for the cancer.

[0007] In one embodiment, the cancer is a gynecological cancer. In one embodiment, the gynecological cancer is selected from endometrial cancer, ovarian cancer, fallopian tube cancer, cervical cancer, vaginal cancer, vulvar cancer, uterine cancer, uterine papillary serous carcinoma, primary peritoneal cancer, adnexal tumors, gestational trophoblastic tumors or breast cancer. In one embodiment, the gynecological cancer is endometrial cancer. In one embodiment, the cancer is mismatch repair defective (dMMR) endometrial cancer. In one embodiment, the cancer is microsatellite high instability (MSI-H) endometrial cancer. In one embodiment, the cancer is recurrent or advanced endometrial cancer. In one embodiment, the cancer is primary advanced endometrial cancer. In one embodiment, the cancer is phase III or IV endometrial cancer.

[0008] In one embodiment, the administration results in improved progression-free survival (PFS) relative to administration of the platinum-based chemotherapy and paclitaxel in the absence of dotalitamab or its biosimilar. In one embodiment, the administration results in improved overall survival (OS) relative to administration of the platinum-based chemotherapy and paclitaxel in the absence of dotalitamab or its biosimilar. In one embodiment, the administration results in improved duration of response (DoR) relative to administration of the platinum-based chemotherapy and paclitaxel in the absence of dotalitamab or its biosimilar.

[0009] In one aspect, the present disclosure provides a method of treating cancer in a human patient previously treated with one or more chemotherapeutic agents and / or radiation therapy, the method comprising administering to the human patient a therapeutically effective amount of dotarizumab or a biosimilar thereof.

[0010] In one embodiment, the chemotherapeutic agent is a platinum-based chemotherapy. In one embodiment, the platinum-based chemotherapy is cisplatin or carboplatin.

[0011] In one embodiment, the patient stops administering the radiation therapy prior to initiating administration of dotarimab or a biosimilar thereof. In one embodiment, the patient stops administering the one or more chemotherapeutic agents prior to initiating administration of dotarimab or a biosimilar thereof.

[0012] In one embodiment, a platinum-based chemotherapy and paclitaxel are co-administered to the patient with dotalizumab or a biosimilar thereof, for example, wherein the platinum-based chemotherapy is cisplatin or carboplatin. In one embodiment, the platinum-based chemotherapy is carboplatin.

[0013] In one embodiment, the administration comprises a first dose of 500 mg of dotalizumab or its biosimilar once every 3 weeks (Q3W) for 4 to 6 cycles, followed by a second dose of 1000 mg of dotalizumab or its biosimilar once every 6 weeks (Q6W). In one embodiment, the second dose of dotalizumab or its biosimilar is Q6W for up to 3 years. In one embodiment, the first dose and / or the second dose of dotalizumab or its biosimilar is administered by intravenous infusion, for example, by intravenous infusion over 30 minutes. In one embodiment, the administration comprises a dose of carboplatin with an area under the concentration time curve of 5 mg / ml / min once every 3 weeks (Q3W) for 4 to 6 cycles. In one embodiment, the administration comprises 175 mg per square meter (mg / m 2 ) of paclitaxel once every 3 weeks (Q3W) for 4 to 6 cycles.

[0014] In one embodiment, the administration comprises: a first dose of 500 mg of dotalimumab or its biosimilar once every 3 weeks (Q3W) for 6 cycles, a dose of carboplatin with an area under the concentration-time curve of 5 mg / mL / min once every 3 weeks (Q3W) for 6 cycles, and 175 mg / m 2 ) paclitaxel dose every 3 weeks (Q3W) for 6 cycles, followed by a second dose of 1000 mg of dotalizumab or its biosimilar once every 6 weeks (Q6W). In one embodiment, the first dose of dotalizumab or its biosimilar, the carboplatin dose, and the paclitaxel dose are all administered on day 1 of a 21-day cycle. In one embodiment, the second dose of dotalizumab or its biosimilar is administered on day 1 of a 42-day cycle.

[0015] In one embodiment, the cancer is a gynecological cancer. In one embodiment, the gynecological cancer is selected from endometrial cancer, ovarian cancer, fallopian tube cancer, cervical cancer, vaginal cancer, vulvar cancer, uterine cancer, uterine papillary serous carcinoma, primary peritoneal cancer, adnexal tumors, gestational trophoblastic tumors or breast cancer. In one embodiment, the gynecological cancer is endometrial cancer. In one embodiment, the cancer is mismatch repair defective (dMMR) endometrial cancer. In one embodiment, the cancer is microsatellite high instability (MSI-H) endometrial cancer. In one embodiment, the cancer is recurrent or advanced endometrial cancer. In one embodiment, the cancer is primary advanced endometrial cancer. In one embodiment, the cancer is phase III or IV endometrial cancer.

[0016] In one embodiment, the administration results in improved progression-free survival (PFS) relative to administration of the platinum-based chemotherapy and paclitaxel in the absence of dotalitamab or its biosimilar. In one embodiment, the administration results in improved overall survival (OS) relative to administration of the platinum-based chemotherapy and paclitaxel in the absence of dotalitamab or its biosimilar. In one embodiment, the administration results in improved duration of response (DoR) relative to administration of the platinum-based chemotherapy and paclitaxel in the absence of dotalitamab or its biosimilar.

[0017] In one aspect, the present disclosure provides a method of treating cancer in a human patient, comprising: (a) selecting a human patient previously treated with one or more chemotherapeutic agents and / or radiation therapy; and (b) administering to the patient a therapeutically effective amount of dotarizumab or a biosimilar thereof.

[0018] In one embodiment, the chemotherapeutic agent is a platinum-based chemotherapy. In one embodiment, the platinum-based chemotherapy is cisplatin or carboplatin.

[0019] In one embodiment, the patient stops administering the radiation therapy prior to initiating administration of dotarimab or a biosimilar thereof. In one embodiment, the patient stops administering the one or more chemotherapeutic agents prior to initiating administration of dotarimab or a biosimilar thereof.

[0020] In one embodiment, a platinum-based chemotherapy and paclitaxel are co-administered to the patient with dotalizumab or a biosimilar thereof, for example, wherein the platinum-based chemotherapy is cisplatin or carboplatin. In one embodiment, the platinum-based chemotherapy is carboplatin.

[0021] In one embodiment, the administration comprises a first dose of 500 mg of dotalizumab or its biosimilar once every 3 weeks (Q3W) for 4 to 6 cycles, followed by a second dose of 1000 mg of dotalizumab or its biosimilar once every 6 weeks (Q6W). In one embodiment, the second dose of dotalizumab or its biosimilar is Q6W for up to 3 years. In one embodiment, the administration of the first dose and / or the second dose of dotalizumab or its biosimilar is by intravenous infusion, for example, by intravenous infusion over 30 minutes. In one embodiment, the administration comprises a dose of carboplatin with an area under the concentration time curve of 5 mg / ml / min once every 3 weeks (Q3W) for 4 to 6 cycles. In one embodiment, the administration comprises 175 mg per square meter (mg / m 2 ) of paclitaxel once every 3 weeks (Q3W) for 4 to 6 cycles.

[0022] In one embodiment, the administration comprises: a first dose of 500 mg of dotalimumab or its biosimilar once every 3 weeks (Q3W) for 6 cycles, a dose of carboplatin with an area under the concentration-time curve of 5 mg / mL / min once every 3 weeks (Q3W) for 6 cycles, and 175 mg / m 2 ) paclitaxel dose every 3 weeks (Q3W) for 6 cycles, followed by a second dose of 1000 mg of dotalizumab or its biosimilar once every 6 weeks (Q6W). In one embodiment, the first dose of dotalizumab or its biosimilar, the carboplatin dose, and the paclitaxel dose are administered on day 1 of a 21-day cycle. In one embodiment, the second dose of dotalizumab or its biosimilar is administered on day 1 of a 42-day cycle.

[0023] In one embodiment, the cancer is a gynecological cancer. In one embodiment, the gynecological cancer is selected from endometrial cancer, ovarian cancer, fallopian tube cancer, cervical cancer, vaginal cancer, vulvar cancer, uterine cancer, uterine papillary serous carcinoma, primary peritoneal cancer, adnexal tumors, gestational trophoblastic tumors or breast cancer. In one embodiment, the gynecological cancer is endometrial cancer. In one embodiment, the cancer is mismatch repair defective (dMMR) endometrial cancer. In one embodiment, the cancer is microsatellite high instability (MSI-H) endometrial cancer. In one embodiment, the cancer is recurrent or advanced endometrial cancer. In one embodiment, the cancer is primary advanced endometrial cancer. In one embodiment, the endometrial cancer is phase III or IV endometrial cancer.

[0024] In one embodiment, the administration results in improved progression-free survival (PFS) relative to administration of the platinum-based chemotherapy and paclitaxel in the absence of dotalitamab or its biosimilar. In one embodiment, the administration results in improved overall survival (OS) relative to administration of the platinum-based chemotherapy and paclitaxel in the absence of dotalitamab or its biosimilar. In one embodiment, the administration results in improved duration of response (DoR) relative to administration of the platinum-based chemotherapy and paclitaxel in the absence of dotalitamab or its biosimilar.

[0025] In one aspect, the present disclosure provides a method of treating a gynecological cancer in a human patient who has not received prior immunotherapy treatment, the method comprising administering to the patient a therapeutically effective amount of a combination comprising 500 mg to 1000 mg of dotarimab or a biosimilar thereof, a platinum-based chemotherapy, and paclitaxel. In one embodiment, the gynecological cancer is microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) gynecological cancer.

[0026] It should be understood that any and all embodiments of the present disclosure can be combined with any other (one or more) embodiments to describe additional more preferred embodiments. It should also be understood that each individual element of a preferred embodiment is its own independent preferred embodiment. In addition, any element of an embodiment is intended to be combined with any and all other elements from any embodiment to describe additional embodiments. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1A-1C For dMMR / MSI-H patients ( Figure 1A ), all participants (dMMR / MSI-H patients and MMRp / MSS patients) ( Figure 1B ) and MMRp / MSS patients ( Figure 1C ), depicting a graph of investigator-assessed progression-free survival (PFS) for dotalimumab plus chemotherapy versus placebo plus chemotherapy. Figure 1A-1C In each panel, the survival curve for the cohort of patients who received doritinab plus chemotherapy is the top curve; the survival curve for the cohort of patients who received placebo plus chemotherapy is the lower curve.

[0028] Figure 2 Progression-free survival (PFS) according to blinded independent central review (BICR) is shown for dotarimab plus chemotherapy versus placebo plus chemotherapy.

[0029] Figure 3A-3C For all participants (dMMR / MSI-H patients and MMRp / MSS patients) Figure 3A), dMMR / MSI-H patients ( Figure 3B ) and MMRp / MSS patients ( Figure 3C ), depicting overall survival (OS) with dotalimumab plus chemotherapy compared with placebo plus chemotherapy. Beginning approximately ten (10) months after randomization, Figure 3A-3C In each panel, the survival curve for the cohort of patients who received doritinab plus chemotherapy is the top curve; the survival curve for the cohort of patients who received placebo plus chemotherapy is the lower curve.

[0030] Figures 4A-4C For dMMR / MSI-H patients ( Figure 4A ), all participants (dMMR / MSI-H patients and MMRp / MSS patients) ( Figure 4B ) and MMRp / MSS patients ( Figure 4C ), depicting a graph of investigator-assessed duration of response (DoR) for dotalimumab plus chemotherapy versus placebo plus chemotherapy according to RECIST 1.1. Figures 4A-4C In each panel, the survival curve for the cohort of patients who received doritinab plus chemotherapy is the top curve; the survival curve for the cohort of patients who received placebo plus chemotherapy is the lower curve.

[0031] Figure 5 Hazard ratios (95% CI) for progression-free survival (PFS) and overall survival (OS) according to investigator assessment in the intention-to-treat population are shown. DETAILED DESCRIPTION

[0032] definition

[0033] As used herein and in the claims, the term "comprising" encompasses "including" or "consisting of," eg, a composition "comprising" X may consist exclusively of X or may include additional things, eg, X+Y.

[0034] Unless otherwise defined, all technical terms and scientific terms used herein have the same meaning as those generally understood by those of ordinary skill in the art to which the present disclosure belongs. Although any compositions and methods similar or equivalent to the compositions and methods described herein can be used to implement or test the methods of the present disclosure, exemplary compositions and methods are described herein. Any aspects and embodiments of the present disclosure described herein can also be combined. For example, the subject matter of any dependent claim or independent claim disclosed herein can be multiple combined (for example, one or more statements from each dependent claim can be combined into a single claim based on the independent claim to which it is dependent).

[0035] The ranges provided herein include all values within the specific range described as well as values around the endpoints of the specific range.The figures and tables of the present disclosure also describe ranges and discrete values, which can constitute elements of any method and use disclosed herein.

[0036] The concentrations described herein are determined at ambient temperature and pressure. For example, this may be at room temperature or at the temperature and pressure within a specific portion of a process stream. Generally, the concentrations are determined at standard conditions of 25°C and 1 bar pressure.

[0037] As used herein, the term "about" means within ±10% of the stated value.

[0038] As used herein, the term "antibody" refers to a polypeptide comprising classical immunoglobulin sequence elements sufficient to confer specific binding to a specific target antigen. As known in the art, naturally occurring complete antibodies are tetramers of approximately 150 kD, consisting of two identical heavy chain polypeptides (each approximately 50 kD) and two identical light chain polypeptides (each approximately 25 kD) that associate to form a structure commonly referred to as a "Y-shaped" structure. Each heavy chain consists of at least four domains (each approximately 110 amino acids in length): an amino-terminal variable (VH) domain (located at the tip of the Y structure), followed by three constant domains: CH1, CH2, and carboxyl-terminal CH3 (located at the base of the stem of the Y). A short region called a "hinge" connects the heavy chain variable region and the constant region. The "hinge" connects the CH2 and CH3 domains to the rest of the antibody. Two disulfide bonds in this hinge region connect the two heavy chain polypeptides to each other in the complete antibody. Each light chain is composed of two domains: an amino-terminal variable (VL) domain, followed by a carboxyl-terminal constant (CL) domain, separated from each other by another "hinge (switch). Those skilled in the art are familiar with antibody structure and sequence elements, recognize "variable" and "constant" regions in the provided sequences, and understand that there can be some flexibility in the definition of "boundaries" between such regions, so that different representations of the same antibody chain sequence can indicate such boundaries, for example, at positions shifted by one or several residues relative to different representations of the same antibody chain sequence. A complete antibody tetramer is composed of two heavy chain-light chain dimers, wherein the heavy chain and light chain are interconnected by a single disulfide bond; two additional disulfide bonds interconnect the heavy chain hinge region, allowing the dimers to interconnect and form a tetramer. Naturally produced antibodies are also glycosylated, typically at the CH2 domain. Each domain in a natural antibody has a structure characterized by an "immunoglobulin fold," which is formed by two β sheets (e.g., 3-, 4-, or 5-stranded sheets) stacked relative to each other in a compressed antiparallel β barrel. Each variable domain contains three hypervariable loops called "complementarity determining regions" (CDR1, CDR2, and CDR3) and four slightly invariant "framework" regions (FR1, FR2, FR3, and FR4). When a native antibody folds, the FR regions form a beta sheet that provides a structural framework for the domain, and the CDR loop regions from both the heavy and light chains come together in three-dimensional space so that they form a single hypervariable antigen binding site at the tip of the Y structure. The Fc region of a naturally occurring antibody binds to elements of the complement system and also to receptors on effector cells (including, for example, effector cells that mediate cytotoxicity). As is known in the art, the affinity and / or other binding properties of the Fc region for Fc receptors can be modulated by glycosylation or other modifications. In some embodiments, the antibodies produced and / or utilized according to the present disclosure include glycosylated Fc domains, including Fc domains with modified glycosylation or engineered glycosylation.For the purposes of this disclosure, in certain embodiments, any polypeptide or polypeptide complex comprising sufficient immunoglobulin domain sequences as found in natural antibodies may be referred to and / or used as an "antibody," regardless of whether such polypeptide is naturally produced (e.g., produced by an organism that reacts with an antigen) or produced by recombinant engineering, chemical synthesis, or other artificial systems or methods. In some embodiments, the antibody is polyclonal; in some embodiments, the antibody is monoclonal. In some embodiments, the antibody has a constant region sequence characteristic of mouse, rabbit, primate, or human antibodies. In some embodiments, as known in the art, antibody sequence elements are humanized, primatized, chimeric, fully human, and the like. In addition, in suitable embodiments (unless otherwise indicated or clearly derived from the context), as used herein, the term "antibody" may refer to any construct or format known or developed in the art for utilizing the structural and functional characteristics of antibodies in alternative presentation formats. For example, in some embodiments, the format of the antibodies utilized in accordance with the present disclosure is selected from, but not limited to, intact IgA, IgG, IgE, or IgM antibodies; bispecific or multispecific antibodies; antibody fragments, such as Fab fragments, Fab' fragments, F(ab')2 fragments, Fd' fragments, Fd fragments, and isolated CDRs or collections thereof; single-chain Fvs; polypeptide-Fc fusions; and single-domain antibodies. In some embodiments, the antibodies may lack covalent modifications that they would have when produced naturally (e.g., attachment of glycans). In some embodiments, the antibodies may contain covalent modifications (e.g., attachment of glycans, payloads (e.g., detectable moieties, therapeutic moieties, catalytic moieties, etc.), or other side groups (e.g., polyethylene glycol, etc.).

[0039] As used herein, the term "progression-free survival" refers to the period of time during which a subject with a disease (e.g., cancer) survives without a significant worsening of the disease state. Progression-free survival can be assessed as the period of time during which there is no progression of tumor growth and / or during which the patient's disease state is not determined to be a progressive disease. In some embodiments, the progression-free survival of a cancer patient is assessed by assessing tumor (lesion) size, tumor (lesion) number, and / or metastasis.

[0040] As used herein with reference to cancer states, the term "progression" or "progressive disease" ("PD") of tumor growth indicates an increase in the sum of the diameters of the target lesions (tumors). In some embodiments, progression of tumor growth refers to an increase of at least 20% in the sum of the diameters of the target lesions, with the minimum sum in the study (if the minimum sum in the study is the baseline sum, this includes the baseline sum) as a reference. In some embodiments, in addition to a relative increase of 20%, the sum of the diameters of the target lesions must also show an absolute increase of at least 5 mm. The appearance of one or more new lesions can also be a factor in determining the progression of tumor growth. For the purpose of determining progression-free survival, progression may also be defined when at least one of the following criteria is met: 1) tumor evaluation by CT / MRI clearly demonstrates progressive disease according to RECIST 1.1 or irRECIST criteria; or 2) additional diagnostic testing (e.g., histology / cytology, ultrasonography, endoscopy, positron emission tomography) identifies a new lesion or confirms that an existing lesion meets the Gynecologic Cancer Intergroup (GCIG) criteria for clear progressive disease and CA-125 progression (see Rustin et al., Int J Gynecol Cancer 2011;21:419-423, which is incorporated herein in its entirety); or 3) clear clinical signs and symptoms of PD unrelated to nonmalignant or iatrogenic causes ([i] intractable cancer-related pain; [ii] worsening malignant bowel obstruction / dysfunction; or [iii] clear symptomatic worsening of ascites or pleural effusion and CA-125 progression according to GCIG criteria).

[0041] As used herein, the term "complete response" or "CR" is used to indicate the disappearance of all or substantially all target lesions. Any pathological lymph node must be <10 mm on the short axis. In some embodiments, CR refers to a reduction in the sum of target lesion diameters (i.e., lesion loss) of approximately 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% with reference to the baseline sum diameter. In some embodiments, the total lesion diameter remaining after CR indication treatment is less than about 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less. Exemplary methods for assessing complete response are identified by RECIST guidelines. See, eg, EA Eisenhauer et al., “New response evaluation criteria in solid tumors: Revised RECIST guideline (version 1.1.),” Eur. J. of Cancer, 45:228-247 (2009).

[0042] As used herein, the term "partial response" or "PR" refers to a reduction in the progression of a subject's tumor as indicated by a reduction in the sum of the target lesion diameters, with reference to the baseline summation diameter. In some embodiments, PR refers to a reduction in the target lesion diameter summation by at least 30%, with reference to the baseline summation diameter. Exemplary methods for assessing partial responses are identified by RECIST guidelines. See, for example, EA Eisenhauer et al., " New response evaluation criteria in solid tumors: Revised RECIST guideline (version 1.1.), " Eur. J. of Cancer, 45: 228-247 (2009).

[0043] As used herein, "stabilization" or "stable disease" ("SD") of tumor growth refers to neither sufficient reduction to meet PR nor sufficient increase to meet PD. In some embodiments, stabilization refers to a change (increase or decrease) in the sum of the diameters of the target lesions of less than 30%, 25%, 20%, 15%, 10% or 5% with reference to the baseline sum diameter. Exemplary methods for assessing stabilization or stable disease of tumor growth are identified by RECIST guidelines. See, for example, EA Eisenhauer et al., "New response evaluation criteria in solid tumors: Revised RECIST guideline (version 1.1.)," Eur. J. of Cancer, 45: 228-247 (2009).

[0044] As used herein, the term "patient" refers to a human patient.

[0045] The term “biosimilar” means a biological drug or biological product that is highly similar to a reference biological product (e.g., dotarizumab) despite minor differences in clinically inactive components, and there are no clinically meaningful differences between the biological product and the reference product with respect to product safety, purity, and potency (section 351(i) of the Public Health Service Act (42 U.S.C. 262(i))).

[0046] Thus, the term "biosimilar" refers to a biological product that is highly similar to a reference product (e.g., dotarizumab) approved by a regulatory agency (e.g., the U.S. Federal Drug Administration (FDA) or the European Medicines Agency (EMA)) based on data from: (a) analytical studies demonstrating that the biological product is highly similar to the reference product despite minor differences in clinically inactive components; (b) animal studies (including assessments of toxicity); and / or (c) one or more clinical studies (including assessments of immunogenicity and pharmacokinetics or pharmacodynamics) sufficient to demonstrate safety, purity, and potency under one or more appropriate conditions of use for which the reference product has been approved and intended for use and for which approval is being sought (e.g., there are no clinically meaningful differences between the biological product and the reference product in terms of product safety, purity, and potency). In certain embodiments, a biosimilar product is an interchangeable product determined by a regulatory agency (e.g., FDA).

[0047] It should be broadly understood that biosimilars of dotalizumab will contain post-translational modifications that are critical to the function and efficacy of dotalizumab (as disclosed in International Publication No. WO 2021 / 126657). However, in certain embodiments, a biosimilar (e.g., a biosimilar of dotalizumab) may contain one or more molecular differences, such as post-translational modifications, such as, but not limited to, glycosylation, oxidation, deamidation, and / or truncation that are different from the post-translational modifications of a reference medicinal product (e.g., dotalizumab), provided that these differences do not result in a significant change in the safety and / or effectiveness of the medicinal product. In certain embodiments, a biosimilar (e.g., a biosimilar of dotalizumab) may have a glycosylation pattern that is the same as or different from that of a reference medicinal product (e.g., dotalizumab). In particular, although not exclusively, a biosimilar (e.g., a biosimilar of dotalizumab) may have a different glycosylation pattern, for example, if these differences address or are intended to address safety issues associated with a reference medicinal product (e.g., dotalizumab). In addition, a biosimilar (e.g., a biosimilar of dotalizumab) may differ from a reference medicinal product (e.g., dotalizumab) in, for example, its strength, pharmaceutical form, formulation, excipients, and / or presentation form, provided that the safety and effectiveness of the medicinal product are not compromised. In other embodiments, a biosimilar (e.g., a biosimilar of dotalizumab) may comprise differences in, for example, pharmacokinetic (PK) and / or pharmacodynamic (PD) spectra compared to a reference medicinal product (e.g., dotalizumab), but is still considered sufficiently similar to the reference medicinal product to be approved or considered suitable for approval. In certain embodiments, a biosimilar (e.g., a biosimilar of dotalizumab) may exhibit different binding characteristics compared to a reference medicinal product (e.g., dotalizumab), where regulatory agencies (such as the FDA and / or EMA) consider these different binding characteristics not to be an obstacle to approval as a similar biological product. The term "biosimilar" is also used synonymously by other national and regional regulatory agencies.

[0048] It should be understood that the International Nonproprietary Name (INN) of a drug (e.g., dotalizumab, pembrolizumab, nivolumab) should be interpreted to include generic versions, bioequivalent versions, subsequent biologic versions, and / or biosimilar versions of the drug, including but not limited to any drug that has received simplified regulatory approval by reference to an earlier regulatory approval of the drug. In addition, the INN of a drug optionally includes, but is not limited to, glycosylation variants of dotalizumab and its biosimilars.

[0049] Methods for treating cancer

[0050] Described herein are methods of treating cancer in patients who would benefit from administration of a PD-1 antagonist. Also described herein are uses of a PD-1 antagonist in treating cancer in a patient.

[0051] In one aspect, the present disclosure provides a method of treating cancer in a human patient, comprising administering to the human patient a therapeutically effective amount of a combination comprising a PD-1 antagonist (e.g., an anti-PD-1 antibody) and chemotherapy, e.g., wherein the chemotherapy is a platinum-based chemotherapy and paclitaxel.

[0052] In one aspect, the present disclosure provides a method of treating cancer in a human patient previously treated with one or more chemotherapeutic agents and / or radiation therapy, the method comprising administering to the human patient a therapeutically effective amount of a PD-1 antagonist (e.g., an anti-PD-1 antibody).

[0053] In one aspect, the present disclosure provides a method of treating cancer in a human patient, the method comprising: (a) selecting a human patient previously treated with one or more chemotherapeutic agents and / or radiation therapy; and (b) administering to the patient a therapeutically effective amount of a PD-1 antagonist (e.g., an anti-PD-1 antibody).

[0054] In one aspect, the present disclosure provides a method of treating gynecological cancer in a human patient who has not received prior immunotherapy treatment, the method comprising administering to the patient a therapeutically effective amount of a combination comprising a PD-1 antagonist (e.g., an anti-PD-1 antibody) and chemotherapy, e.g., wherein the chemotherapy is a platinum-based chemotherapy and paclitaxel.

[0055] The present disclosure provides a method for treating a patient's cancer. In some embodiments, the cancer is associated with a high tumor mutation burden (TMB). In some embodiments, the cancer is microsatellite stable (MSS). In some embodiments, the cancer is characterized by microsatellite instability. In some embodiments, the cancer has a high microsatellite instability state (MSI-H). In some embodiments, the cancer has a low microsatellite instability state (MSI-L). In some embodiments, the cancer is associated with high TMB and MSI-H. In some embodiments, the cancer is associated with high TMB and MSI-L or MSS. In some embodiments, the cancer is associated with high TMB and MSI-L. In some embodiments, the cancer is associated with high TMB and MSS. In some embodiments, the cancer has a defective DNA mismatch repair system. In some embodiments, the cancer has a defect in a DNA mismatch repair gene. In some embodiments, the cancer is a hypermutated cancer. In some embodiments, the cancer has homologous recombination repair deficiency / homologous repair deficiency ("HRD"). In some embodiments, the cancer comprises a mutation in polymerase δ (POLD). In some embodiments, the cancer comprises a mutation in polymerase ε (POLE).

[0056] In some embodiments, the cancer is endometrial cancer (e.g., MSI-H or MSS / MSI-L endometrial cancer). In some embodiments, the cancer is an MSI-H cancer comprising a mutation in POLE or POLD (e.g., an MSI-H non-endometrial cancer comprising a mutation in POLE or POLD). In some embodiments, the cancer is breast cancer (e.g., triple-negative breast cancer (TNBC)). In some embodiments, the cancer is lung cancer (e.g., non-small cell lung cancer). In some embodiments, the cancer is melanoma. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is anal squamous cell carcinoma, penile squamous cell carcinoma, cervical squamous cell carcinoma, vaginal squamous cell carcinoma, or vulvar squamous cell carcinoma.

[0057] In some embodiments, the cancer is adenocarcinoma, endometrial cancer, breast cancer, ovarian cancer, cervical cancer, fallopian tube cancer, testicular cancer, primary peritoneal cancer, colon cancer, colorectal cancer, stomach cancer, small intestine cancer, squamous cell carcinoma of the anogenital region (e.g., squamous cell carcinoma of the anus, penis, cervix, vagina, or vulva), soft tissue sarcoma (e.g., leiomyosarcoma), melanoma, renal cell carcinoma, lung cancer, non-small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, stomach cancer, bladder cancer, gallbladder cancer, liver cancer, thyroid cancer, laryngeal cancer, salivary gland cancer, esophageal cancer, head cancer, or Neck cancer, head and neck squamous cell carcinoma, prostate cancer, pancreatic cancer, mesothelioma, Merkel cell carcinoma, sarcoma, glioblastoma, hematologic cancers, multiple myeloma, B-cell lymphoma, T-cell lymphoma, Hodgkin lymphoma / primary mediastinal B-cell lymphoma, chronic myeloid leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, non-Hodgkin lymphoma, neuroblastoma, CNS tumors, diffuse intrinsic pontine glioma (DIPG), Ewing sarcoma, embryonal rhabdomyosarcoma, osteosarcoma, or Wilms' tumor. In some embodiments, the cancer is MSS or MSI-L, is characterized by microsatellite instability, is MSI-H, has high TMB, has high TMB and is MSS or MSI-L, has high TMB and is MSI-H, has a defective DNA mismatch repair system, has a defect in a DNA mismatch repair gene, is a hypermutated cancer, is an HRD cancer, contains a mutation in polymerase delta (POLD), or contains a mutation in polymerase epsilon (POLE).

[0058] In some embodiments, the cancer has homologous recombination repair deficiency / homologous repair deficiency ("HRD"). In some embodiments, the cancer is acute myeloid leukemia. In some embodiments, the cancer is acute lymphoblastic leukemia. In some embodiments, the cancer is non-Hodgkin lymphoma. In some embodiments, the cancer is Hodgkin lymphoma. In some embodiments, the cancer is neuroblastoma. In some embodiments, the cancer is a CNS tumor. In some embodiments, the cancer is diffuse intrinsic pontine glioma (DIPG). In some embodiments, the cancer is Ewing sarcoma. In some embodiments, the cancer is embryonal rhabdomyosarcoma. In some embodiments, the cancer is osteosarcoma. In some embodiments, the cancer is Wilms' tumor. In some embodiments, the cancer is a soft tissue sarcoma (e.g., leiomyosarcoma).

[0059] In some embodiments, the patient has cancer, such as head and neck cancer, lung cancer (e.g., non-small cell lung cancer (NSCLC)), kidney cancer, bladder cancer, melanoma, Merkel cell carcinoma, cervical cancer, vaginal cancer, vulvar cancer, uterine cancer, endometrial cancer, ovarian cancer, fallopian tube cancer, breast cancer, prostate cancer, salivary gland tumors, thymoma, adrenocortical carcinoma, esophageal cancer, gastric cancer, colorectal cancer, adnexal cancer, urothelial cell carcinoma, or squamous cell carcinoma (e.g., squamous cell carcinoma of the lung; squamous cell carcinoma of the anogenital region (including the anus, penis, cervix, vagina, or vulva); or squamous cell carcinoma of the esophagus). In certain embodiments, the patient has anal cancer, fallopian tube cancer, ovarian cancer, or lung cancer. In certain embodiments, the patient has anal cancer. In certain embodiments, the patient has fallopian tube cancer. In certain embodiments, the patient has ovarian cancer. In certain embodiments, the patient has lung cancer.

[0060] In some embodiments, the patient suffers from a cancer with microsatellite instability. In some embodiments, microsatellite instability is considered to be very high, wherein the instability is significantly higher than the instability observed in control cells (e.g., MSI-H status). In some embodiments, microsatellite instability is MSI-Low. In some embodiments, microsatellite instability is a microsatellite stable (e.g., MSS status). In some embodiments, the cancer with microsatellite instability is head and neck cancer, lung cancer (e.g., non-small cell lung cancer (NSCLC)), kidney cancer, bladder cancer, melanoma, Merkel cell carcinoma, cervical cancer, vaginal cancer, vulvar cancer, uterine cancer, endometrial cancer, ovarian cancer, fallopian tube cancer, breast cancer, prostate cancer, salivary gland tumors, thymoma, adrenocortical carcinoma, esophageal cancer, gastric cancer, colorectal cancer, adnexal cancer, urothelial cell carcinoma or squamous cell carcinoma (e.g., lung squamous cell carcinoma; anogenital region (including anus, penis, cervix, vagina or vulva) squamous cell carcinoma; or esophageal squamous cell carcinoma). In certain embodiments, the cancer with microsatellite instability is anal cancer, fallopian tube cancer, ovarian cancer, or lung cancer. In certain embodiments, the patient has endometrial cancer with microsatellite instability. In some embodiments, the patient has microsatellite stable (MSS) endometrial cancer.

[0061] In some embodiments, the patient has a cancer characterized by expression of PD-1 and / or PD-L1. In some embodiments, the cancer has high PD-1 and / or PD-L1 expression (e.g., by high PD-1 and / or high PD-L1 expression). In some embodiments, the cancer characterized by expression of PD-1 and / or PD-L1 is head and neck cancer, lung cancer (e.g., non-small cell lung cancer (NSCLC)), kidney cancer, bladder cancer, melanoma, Merkel cell carcinoma, cervical cancer, vaginal cancer, vulvar cancer, uterine cancer, endometrial cancer, ovarian cancer, fallopian tube cancer, breast cancer, prostate cancer, salivary gland tumors, thymoma, adrenocortical carcinoma, esophageal cancer, gastric cancer, colorectal cancer, adnexal cancer, urothelial cell carcinoma, or squamous cell carcinoma (e.g., squamous cell carcinoma of the lung; squamous cell carcinoma of the anogenital region (including anus, penis, cervix, vagina, or vulva); or squamous cell carcinoma of the esophagus). In certain embodiments, the cancer characterized by expression of PD-1 and / or PD-L1 is anal cancer, fallopian tube cancer, ovarian cancer, or lung cancer.

[0062] In some embodiments, the cancer is an advanced cancer. In some embodiments, the cancer is a metastatic cancer. In some embodiments, the cancer is an MSI-H cancer. In some embodiments, the cancer is an MSS cancer. In some embodiments, the cancer is a POLE mutant cancer. In some embodiments, the cancer is a POLD mutant cancer. In some embodiments, the cancer is a TMB-high cancer. In some embodiments, the cancer is associated with homologous recombination repair deficiency / homologous repair deficiency ("HRD").

[0063] In some embodiments, the cancer is a solid tumor. In some embodiments, the solid tumor is advanced. In some embodiments, the solid tumor is a metastatic solid tumor. In some embodiments, the solid tumor is an MSI-H solid tumor. In some embodiments, the solid tumor is an MSS solid tumor. In some embodiments, the solid tumor is a POLE mutant solid tumor. In some embodiments, the solid tumor is a POLD mutant solid tumor. In some embodiments, the solid tumor is a high TMB solid tumor. In some embodiments, the solid tumor is associated with homologous recombination repair deficiency / homologous repair deficiency ("HRD").

[0064] In some embodiments, the cancer is a non-endometrial cancer (e.g., a non-endometrial solid tumor). In some embodiments, the non-endometrial cancer is an advanced cancer. In some embodiments, the non-endometrial cancer is a metastatic cancer. In some embodiments, the non-endometrial cancer is an MSI-H cancer. In some embodiments, the non-endometrial cancer is an MSS cancer. In some embodiments, the non-endometrial cancer is a POLE mutant cancer. In some embodiments, the non-endometrial cancer is a solid tumor (e.g., an MSS solid tumor, an MSI-H solid tumor, a POLD mutant solid tumor, or a POLE mutant solid tumor). In some embodiments, the non-endometrial cancer is a high TMB cancer. In some embodiments, the non-endometrial cancer is associated with homologous recombination repair deficiency / homologous repair deficiency ("HRD").

[0065] In some embodiments, the cancer is endometrial cancer (e.g., a solid tumor). In some embodiments, the endometrial cancer is an advanced cancer. In some embodiments, the endometrial cancer is a metastatic cancer. In some embodiments, the endometrial cancer is an MSI-H endometrial cancer. In some embodiments, the endometrial cancer is an MSS endometrial cancer. In some embodiments, the endometrial cancer is a POLE mutant endometrial cancer. In some embodiments, the endometrial cancer is a POLD mutant endometrial cancer. In some embodiments, the endometrial cancer is a high TMB endometrial cancer. In some embodiments, the endometrial cancer is associated with homologous recombination repair deficiency / homologous repair deficiency ("HRD").

[0066] In some embodiments, the cancer is lung cancer (e.g., a solid tumor). In some embodiments, the lung cancer is advanced lung cancer. In some embodiments, the lung cancer is metastatic lung cancer. In some embodiments, the lung cancer is squamous cell carcinoma of the lung. In some embodiments, the lung cancer is small cell lung cancer (SCLC). In some embodiments, the lung cancer is non-small cell lung cancer (NSCLC). In some embodiments, the lung cancer is ALK translocation lung cancer (e.g., lung cancer with a known ALK translocation). In some embodiments, the lung cancer is EGFR mutant lung cancer (e.g., lung cancer with a known EGFR mutation). In some embodiments, the lung cancer is MSI-H lung cancer. In some embodiments, the lung cancer is MSS lung cancer. In some embodiments, the lung cancer is POLE mutant lung cancer. In some embodiments, the lung cancer is POLD mutant lung cancer. In some embodiments, the lung cancer is high TMB lung cancer. In some embodiments, the lung cancer is associated with homologous recombination repair deficiency / homologous repair deficiency ("HRD").

[0067] In some embodiments, the cancer is colorectal (CRC) cancer (e.g., a solid tumor). In some embodiments, the colorectal cancer is advanced colorectal cancer. In some embodiments, the colorectal cancer is metastatic colorectal cancer. In some embodiments, the colorectal cancer is MSI-H colorectal cancer. In some embodiments, the colorectal cancer is MSS colorectal cancer. In some embodiments, the colorectal cancer is POLE mutant colorectal cancer. In some embodiments, the colorectal cancer is POLD mutant colorectal cancer. In some embodiments, the colorectal cancer is high TMB colorectal cancer. In some embodiments, the colorectal cancer is associated with homologous recombination repair deficiency / homologous repair deficiency ("HRD").

[0068] In some embodiments, the cancer is melanoma. In some embodiments, the melanoma is advanced melanoma. In some embodiments, the melanoma is metastatic melanoma. In some embodiments, the melanoma is MSI-H melanoma. In some embodiments, the melanoma is MSS melanoma. In some embodiments, the melanoma is a POLE mutant melanoma. In some embodiments, the melanoma is a POLD mutant melanoma. In some embodiments, the melanoma is a TMB-high melanoma. In some embodiments, the melanoma is associated with homologous recombination repair deficiency / homologous repair deficiency ("HRD").

[0069] In some embodiments, the cancer is squamous cell carcinoma of the anogenital region (e.g., anus, penis, cervix, vagina, or vulva). In some embodiments, the squamous cell carcinoma of the anogenital region (e.g., anus, penis, cervix, vagina, or vulva) is an advanced cancer. In some embodiments, the squamous cell carcinoma of the anogenital region (e.g., anus, penis, cervix, vagina, or vulva) is a metastatic cancer. In some embodiments, the squamous cell carcinoma of the anogenital region (e.g., anus, penis, cervix, vagina, or vulva) is MSI-H. In some embodiments, the squamous cell carcinoma of the anogenital region (e.g., anus, penis, cervix, vagina, or vulva) is MSS. In some embodiments, the lung cancer is a POLE mutant cancer. In some embodiments, the squamous cell carcinoma of the anogenital region (e.g., anus, penis, cervix, vagina, or vulva) is associated with homologous recombination repair deficiency / homologous repair deficiency ("HRD").

[0070] In some embodiments, the cancer is ovarian cancer. In some embodiments, the ovarian cancer is advanced ovarian cancer. In some embodiments, the ovarian cancer is metastatic ovarian cancer. In some embodiments, the ovarian cancer is MSI-H ovarian cancer. In some embodiments, the ovarian cancer is MSS ovarian cancer. In some embodiments, the ovarian cancer is POLE mutant ovarian cancer. In some embodiments, the ovarian cancer is POLD mutant ovarian cancer. In some embodiments, the ovarian cancer is TMB-high ovarian cancer. In some embodiments, the ovarian cancer is associated with homologous recombination repair deficiency / homologous repair deficiency ("HRD"). In some embodiments, the ovarian cancer is serous cell ovarian cancer. In some embodiments, the ovarian cancer is clear cell ovarian cancer.

[0071] In some embodiments, the cancer is fallopian tube cancer. In some embodiments, the fallopian tube cancer is advanced fallopian tube cancer. In some embodiments, the fallopian tube cancer is metastatic fallopian tube cancer. In some embodiments, the fallopian tube cancer is MSI-H fallopian tube cancer. In some embodiments, the fallopian tube cancer is MSS fallopian tube cancer. In some embodiments, the fallopian tube cancer is POLE mutant fallopian tube cancer. In some embodiments, the fallopian tube cancer is POLD mutant fallopian tube cancer. In some embodiments, the fallopian tube cancer is high TMB fallopian tube cancer. In some embodiments, the fallopian tube cancer is associated with homologous recombination repair deficiency / homologous repair deficiency ("HRD"). In some embodiments, the fallopian tube cancer is serous cell fallopian tube cancer. In some embodiments, the fallopian tube cancer is clear cell fallopian tube cancer.

[0072] In some embodiments, the cancer is primary peritoneal cancer. In some embodiments, the primary peritoneal cancer is advanced primary peritoneal cancer. In some embodiments, the primary peritoneal cancer is metastatic primary peritoneal cancer. In some embodiments, the primary peritoneal cancer is MSI-H primary peritoneal cancer. In some embodiments, the primary peritoneal cancer is MSS primary peritoneal cancer. In some embodiments, the primary peritoneal cancer is POLE mutant primary peritoneal cancer. In some embodiments, the primary peritoneal cancer is POLD mutant primary peritoneal cancer. In some embodiments, the primary peritoneal cancer is high TMB primary peritoneal cancer. In some embodiments, the primary peritoneal cancer is associated with homologous recombination repair deficiency / homologous repair deficiency ("HRD"). In some embodiments, the primary peritoneal cancer is serous cell primary peritoneal cancer. In some embodiments, the primary peritoneal cancer is clear cell primary peritoneal cancer.

[0073] In some embodiments, the cancer is acute lymphoblastic leukemia ("ALL"). In some embodiments, the acute lymphoblastic leukemia is late stage acute lymphoblastic leukemia. In some embodiments, the acute lymphoblastic leukemia is metastatic acute lymphoblastic leukemia. In some embodiments, the acute lymphoblastic leukemia is MSI-H acute lymphoblastic leukemia. In some embodiments, the acute lymphoblastic leukemia is MSS acute lymphoblastic leukemia. In some embodiments, the acute lymphoblastic leukemia is POLE mutant acute lymphoblastic leukemia. In some embodiments, the acute lymphoblastic leukemia is POLD mutant acute lymphoblastic leukemia. In some embodiments, the acute lymphoblastic leukemia is associated with homologous recombination repair deficiency / homologous repair deficiency ("HRD").

[0074] In some embodiments, the cancer is acute myeloid leukemia ("AML"). In some embodiments, the acute myeloid leukemia is advanced acute myeloid leukemia. In some embodiments, the acute myeloid leukemia is metastatic acute myeloid leukemia. In some embodiments, the acute myeloid leukemia is MSI-H acute myeloid leukemia. In some embodiments, the acute myeloid leukemia is MSS acute myeloid leukemia. In some embodiments, the acute myeloid leukemia is POLE mutant acute myeloid leukemia. In some embodiments, the acute myeloid leukemia is POLD mutant acute myeloid leukemia. In some embodiments, the acute myeloid leukemia is associated with homologous recombination repair deficiency / homologous repair deficiency ("HRD").

[0075] In some embodiments, the cancer is non-Hodgkin lymphoma (NHL). In some embodiments, the non-Hodgkin lymphoma is advanced non-Hodgkin lymphoma. In some embodiments, the non-Hodgkin lymphoma is metastatic non-Hodgkin lymphoma. In some embodiments, the non-Hodgkin lymphoma is MSI-H non-Hodgkin lymphoma. In some embodiments, the non-Hodgkin lymphoma is MSS non-Hodgkin lymphoma. In some embodiments, the non-Hodgkin lymphoma is POLE mutant non-Hodgkin lymphoma. In some embodiments, the non-Hodgkin lymphoma is POLD mutant non-Hodgkin lymphoma. In some embodiments, the non-Hodgkin lymphoma is associated with homologous recombination repair deficiency / homologous repair deficiency ("HRD").

[0076] In some embodiments, the cancer is Hodgkin lymphoma (HL). In some embodiments, the Hodgkin lymphoma is advanced Hodgkin lymphoma. In some embodiments, the Hodgkin lymphoma is metastatic Hodgkin lymphoma. In some embodiments, the Hodgkin lymphoma is MSI-H Hodgkin lymphoma. In some embodiments, the Hodgkin lymphoma is MSS Hodgkin lymphoma. In some embodiments, the Hodgkin lymphoma is POLE mutant Hodgkin lymphoma. In some embodiments, the Hodgkin lymphoma is POLD mutant Hodgkin lymphoma. In some embodiments, the Hodgkin lymphoma is associated with homologous recombination repair deficiency / homologous repair deficiency ("HRD").

[0077] In some embodiments, the cancer is neuroblastoma (NB). In some embodiments, the neuroblastoma is advanced neuroblastoma. In some embodiments, the neuroblastoma is metastatic neuroblastoma. In some embodiments, the neuroblastoma is MSI-H neuroblastoma. In some embodiments, the neuroblastoma is MSS neuroblastoma. In some embodiments, the neuroblastoma is POLE mutant neuroblastoma. In some embodiments, the neuroblastoma is POLD mutant neuroblastoma. In some embodiments, the neuroblastoma is TMB-high neuroblastoma. In some embodiments, the neuroblastoma is associated with homologous recombination repair deficiency / homologous repair deficiency ("HRD").

[0078] In some embodiments, the cancer is a CNS tumor. In some embodiments, the CNS tumor is advanced. In some embodiments, the CNS tumor is a metastatic CNS tumor. In some embodiments, the CNS tumor is an MSI-H CNS tumor. In some embodiments, the CNS tumor is an MSS CNS tumor. In some embodiments, the CNS tumor is a POLE mutant CNS tumor. In some embodiments, the CNS tumor is a POLD mutant CNS tumor. In some embodiments, the CNS tumor is a TMB-high CNS tumor. In some embodiments, the CNS tumor is associated with homologous recombination repair deficiency / homologous repair deficiency ("HRD").

[0079] In some embodiments, the cancer is diffuse intrinsic pontine glioma (DIPG). In some embodiments, the DIPG is advanced DIPG. In some embodiments, the DIPG is metastatic DIPG. In some embodiments, the DIPG is MSI-HDIPG. In some embodiments, the DIPG is MSSDIPG. In some embodiments, the DIPG is POLE mutant DIPG. In some embodiments, the DIPG is POLD mutant DIPG. In some embodiments, the DIPG is TMB-high DIPG. In some embodiments, DIPG is associated with homologous recombination repair deficiency / homologous repair deficiency ("HRD").

[0080] In some embodiments, the cancer is Ewing sarcoma. In some embodiments, the Ewing sarcoma is advanced Ewing sarcoma. In some embodiments, the Ewing sarcoma is metastatic Ewing sarcoma. In some embodiments, the Ewing sarcoma is MSI-H Ewing sarcoma. In some embodiments, the Ewing sarcoma is MSS Ewing sarcoma. In some embodiments, the Ewing sarcoma is POLE mutant Ewing sarcoma. In some embodiments, the Ewing sarcoma is POLD mutant Ewing sarcoma. In some embodiments, the Ewing sarcoma is TMB-high Ewing sarcoma. In some embodiments, the Ewing sarcoma is associated with homologous recombination repair deficiency / homologous repair deficiency ("HRD").

[0081] In some embodiments, the cancer is embryonal rhabdomyosarcoma (ERS). In some embodiments, embryonal rhabdomyosarcoma is late embryonal rhabdomyosarcoma. In some embodiments, embryonal rhabdomyosarcoma is metastatic embryonal rhabdomyosarcoma. In some embodiments, embryonal rhabdomyosarcoma is MSI-H embryonal rhabdomyosarcoma. In some embodiments, embryonal rhabdomyosarcoma is MSS embryonal rhabdomyosarcoma. In some embodiments, embryonal rhabdomyosarcoma is POLE mutant embryonal rhabdomyosarcoma. In some embodiments, embryonal rhabdomyosarcoma is POLD mutant embryonal rhabdomyosarcoma. In some embodiments, embryonal rhabdomyosarcoma is high TMB embryonal rhabdomyosarcoma. In some embodiments, embryonal rhabdomyosarcoma is associated with homologous recombination repair deficiency / homologous repair deficiency ("HRD").

[0082] In some embodiments, the cancer is osteosarcoma (OS). In some embodiments, the osteosarcoma is advanced osteosarcoma. In some embodiments, the osteosarcoma is metastatic osteosarcoma. In some embodiments, the osteosarcoma is MSI-H osteosarcoma. In some embodiments, the osteosarcoma is MSS osteosarcoma. In some embodiments, the osteosarcoma is POLE mutant osteosarcoma. In some embodiments, the osteosarcoma is POLD mutant osteosarcoma. In some embodiments, the osteosarcoma is TMB-high osteosarcoma. In some embodiments, the osteosarcoma is associated with homologous recombination repair deficiency / homologous repair deficiency ("HRD").

[0083] In some embodiments, the cancer is a soft tissue sarcoma. In some embodiments, the soft tissue sarcoma is an advanced soft tissue sarcoma. In some embodiments, the soft tissue sarcoma is a metastatic soft tissue sarcoma. In some embodiments, the soft tissue sarcoma is an MSI-H soft tissue sarcoma. In some embodiments, the soft tissue sarcoma is an MSS soft tissue sarcoma. In some embodiments, the soft tissue sarcoma is a POLE mutant soft tissue sarcoma. In some embodiments, the soft tissue sarcoma is a POLD mutant soft tissue sarcoma. In some embodiments, the soft tissue sarcoma is a high TMB soft tissue sarcoma. In some embodiments, the soft tissue sarcoma is associated with homologous recombination repair deficiency / homologous repair deficiency ("HRD"). In some embodiments, the soft tissue sarcoma is a leiomyosarcoma.

[0084] In some embodiments, the cancer is Wilms' tumor. In some embodiments, the Wilms' tumor is advanced Wilms' tumor. In some embodiments, the Wilms' tumor is metastatic Wilms' tumor. In some embodiments, the Wilms' tumor is MSI-H Wilms' tumor. In some embodiments, the Wilms' tumor is MSS Wilms' tumor. In some embodiments, the Wilms' tumor is a POLE mutant Wilms' tumor. In some embodiments, the Wilms' tumor is a POLD mutant Wilms' tumor. In some embodiments, the Wilms' tumor is a high TMB Wilms' tumor. In some embodiments, the Wilms' tumor is associated with homologous recombination repair deficiency / homologous repair deficiency ("HRD").

[0085] In some embodiments, the cancer is bile duct cancer.

[0086] In some embodiments, the cancer is of unknown primary.

[0087] In some embodiments, the cancer is a gynecological cancer. As used herein, "gynecological cancer" is a malignancy of the female reproductive tract, including but not limited to, the cervix, endometrium, fallopian tubes, ovaries, uterus, vagina, and breast.

[0088] In some embodiments, the cancer is a gynecological cancer selected from cervical cancer (e.g., squamous cell carcinoma, adenocarcinoma, adenosquamous cell carcinoma, small cell carcinoma), endometrial cancer (e.g., adenocarcinoma, sarcoma), ovarian / fallopian tube cancer (epithelial carcinoma, dysgerminoma, teratoma, endodermal sinus tumor, embryonal carcinoma, sex cord-stromal tumor), gestational trophoblastic tumor, primary peritoneal cancer, uterine sarcoma, uterine papillary serous carcinoma, adnexal tumor, vaginal cancer (e.g., squamous cell carcinoma, adenocarcinoma, clear cell adenocarcinoma, melanoma, sarcoma), or vulvar cancer (squamous cell carcinoma, adenocarcinoma, melanoma, sarcoma, verrucous carcinoma).

[0089] In some embodiments, the cancer is breast cancer selected from ductal carcinoma in situ, lobular carcinoma, inflammatory breast cancer, invasive ductal carcinoma, Paget's disease of the nipple, papillary breast cancer, medullary carcinoma, mammary carcinoma, a PAM-50 type (e.g., basal (triple negative) cancer, HER2 positive cancer, luminal A cancer, luminal B cancer, normal-like cancer), or a BRCA1 and / or BRCA2 mutation-positive cancer.

[0090] PD-1 antagonists

[0091] The present disclosure relates to methods for treating cancer in patients by administering programmed cell death protein 1 (PD-1) antagonists and uses thereof for treating cancer in patients. The PD-1 antagonists disclosed herein include biosimilars thereof.

[0092] As used herein, "PD-1 antagonist" refers to any compound or biological molecule that blocks the binding of programmed cell death ligand 1 (PD-L1) expressed on cancer cells to PD-1 expressed on immune cells (T cells, B cells, or natural killer T (NKT) cells) and can also block the binding of PD ligand 2 (PD-L2) expressed on cancer cells to PD-1 expressed by immune cells. Alternative names or synonyms for PD-1 and its ligands include: for PD-1, there are PDCD1, PD1, CD279, and SLEB2; for PD-L1, there are PDCD1L1, PDL1, B7H1, B7-4, CD274, and B7-H; and for PD-L2, there are PDCD1L2, PDL2, B7-DC, Btdc, and CD273. The human PD-1 amino acid sequence can be found in NCBI locus number: NP_005009. Human PD-L1 and PD-L2 amino acid sequences can be found in NCBI Locus Accession Numbers: NP_054862 and NP_079515, respectively.

[0093] PD-1 antagonists include monoclonal antibodies (mAbs) or antigen-binding fragments thereof that specifically bind to PD-1 or PD-L1 (e.g., specifically bind to human PD-1 or human PD-L1). mAbs can be human antibodies, humanized antibodies, or chimeric antibodies, and can include human constant regions. In some embodiments, the human constant region is selected from IgG1, IgG2, IgG3, or IgG4 constant regions, and in preferred embodiments, the human constant region is IgG1 or IgG4 constant region. In some embodiments, the antigen-binding fragment is selected from Fab, Fab'-SH, F(ab')2, scFv, or Fv fragments.

[0094] In one embodiment, the PD-1 antagonist is an anti-PD-1 antibody. In one embodiment, the anti-PD-1 antibody is selected from dotalizumab or a biosimilar thereof, pembrolizumab or a biosimilar thereof, nivolumab or a biosimilar thereof, and cemiplizumab or a biosimilar thereof. In one embodiment, the anti-PD-1 antibody is dotalizumab or a biosimilar thereof.

[0095] Dotalizumab is an IgG4 humanized monoclonal antibody that blocks PD-1 and is commercially available as JEMPERLI. Dotalizumab is indicated for the treatment of adult patients with mismatch repair-deficient (dMMR) recurrent or advanced endometrial cancer that has progressed on or after prior treatment with a platinum-containing regimen, as determined by an FDA-approved test, or (ii) a solid tumor that has progressed on or after prior treatment with no satisfactory alternative treatment options, as determined by an FDA-approved test.

[0096] Pembrolizumab is a humanized monoclonal anti-PD-1 antibody commercially available as KEYTRUDA. Pembrolizumab is indicated for the treatment of certain unresectable or metastatic melanomas. The amino acid sequence and methods of use of pembrolizumab are disclosed in U.S. Patent No. 8,168,757.

[0097] Nivolumab is a humanized monoclonal anti-PD-1 antibody commercially available as OPDIVO. Nivolumab is indicated for the treatment of some unresectable or metastatic melanomas. Nivolumab binds to the Ig superfamily transmembrane protein PD-1 through its ligands PD-L1 and PD-L2 and blocks PD-1 activation, leading to T cell activation and cell-mediated immune responses against tumor cells or pathogens. Activated PD-1 negatively regulates T cell activation and effector function by inhibiting activation of the P13k / Akt pathway. Other names for nivolumab include BMS-936558, MDX-1106, and ONO-4538. The amino acid sequence of nivolumab and methods of use and manufacture are disclosed in U.S. Patent No. 8,008,449.

[0098] Cemipril is a human monoclonal anti-PD-1 antibody commercially available as LIBTAYO. Cemipril is indicated for the treatment of non-small cell lung cancer (NSCLC), basal cell carcinoma (BCC), and cutaneous squamous cell carcinoma (CSCC).

[0099] Exemplary antibody heavy and light chain sequences are provided in Table 1. In one embodiment, dotalizumab comprises the heavy and light chain sequences of SEQ ID NO: 1 and SEQ ID NO: 2, respectively. In one embodiment, the anti-PD-1 antibody comprises the heavy and light chain sequences of SEQ ID NO: 3 and SEQ ID NO: 4, respectively. In one embodiment, the anti-PD-1 antibody comprises the heavy and light chain sequences of SEQ ID NO: 5 and SEQ ID NO: 6, respectively. In one embodiment, the anti-PD-1 antibody comprises the heavy and light chain sequences of SEQ ID NO: 7 and SEQ ID NO: 8, respectively.

[0100] Table 1

[0101]

[0102]

[0103] chemotherapy

[0104] The PD-1 antagonists disclosed herein can be administered in combination with one or more chemotherapeutic agents. Suitable chemotherapeutic agents include antimetabolite tumor agents (e.g., antifolate antitumor agents), platinum-based chemotherapy and other known chemotherapeutic agents, including but not limited to paclitaxel, docetaxel and nab-paclitaxel (ABRAXANE).

[0105] Antimetabolite tumor agents are phase-specific antitumor agents that act during the S phase (DNA synthesis) of the cell cycle by inhibiting DNA synthesis or by inhibiting purine or pyrimidine base synthesis and thereby limiting DNA synthesis. As a result, the S phase does not proceed and the cells subsequently die. Examples of antimetabolite antitumor agents include, but are not limited to, capecitabine, cladribine, clofarabine, cytarabine, decitabine, floxuridine, fludarabine, fluorouracil, gemcitabine, hydroxyurea, mercaptopurine, methotrexate, nelarabine, pemetrexed, pralatrexate, and thioguanine.

[0106] Platinum-based chemotherapeutic agents induce apoptosis in cancer cells in response to their covalent binding to DNA. Examples of platinum-based agents include, but are not limited to, cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, and satraplatin.

[0107] In one embodiment, the one or more chemotherapeutic agents are selected from antifolate antineoplastic agents, platinum-based chemotherapy, paclitaxel, or a combination thereof.

[0108] In one embodiment, the antifolate antitumor agent is pemetrexed.

[0109] In one embodiment, the platinum-based chemotherapy is cisplatin. In one embodiment, the platinum-based chemotherapy is carboplatin.

[0110] Dosage and administration schedule

[0111] PD-1 antagonists and chemotherapeutic agents

[0112] In some embodiments, the dose of the PD-1 antagonist (e.g., an anti-PD-1 antibody such as dotalizumab or a biosimilar thereof) is in the range of about 5 to about 5000 mg (e.g., about 5 mg, about 10 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 2000 mg, about 3000 mg, about 4000 mg, about 5000 mg, or a range defined by any two of the foregoing values). In some embodiments, the dose of the PD-1 antagonist (e.g., an anti-PD-1 antibody such as dotalizumab or a biosimilar thereof) is 500 mg or 1000 mg.

[0113] In some embodiments, the dosage is an amount relative to body weight. In some embodiments, the dosage of a PD-1 antagonist (e.g., an anti-PD-1 antibody, such as dotalimumab) is in the range of about 0.01 mg / kg to 100 mg / kg of animal or human body weight; however, dosages lower than or higher than this exemplary range are within the scope of the present disclosure. The daily dose can be from about 0.01 mg / kg to about 50 mg / kg of total body weight (e.g., about 0.1 mg / kg, about 0.5 mg / kg, about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 12 mg / kg, about 15 mg / kg, about 20 mg / kg, or a range defined by any two of the foregoing values).

[0114] In some embodiments, the dose is administered according to a regimen of delivering a dose once per week. In some embodiments, the dose is administered according to a regimen of delivering a dose once every two weeks. In some embodiments, the dose is administered according to a regimen of delivering a dose once every three weeks. In some embodiments, the dose is administered according to a regimen of delivering a dose once every four weeks. In some embodiments, the dose is administered according to a regimen of delivering a dose once every six weeks. In some embodiments, the dose is administered according to a regimen of delivering a dose once every eight weeks.

[0115] In some embodiments, the PD-1 antagonist (e.g., an anti-PD-1 antibody, such as dotalizumab or a biosimilar thereof) is administered according to a regimen of delivering a first dose of the PD-1 antagonist in the first 2 to 6 dosing cycles (e.g., the first 3, 4, or 5 dosing cycles), followed by delivery of a second dose of the PD-1 antagonist in subsequent dosing cycles until therapy is stopped (e.g., due to disease progression or side effects or as directed by a physician). In some embodiments, the duration of the first group of 2 to 6 dosing cycles (e.g., the first 3, 4, or 5 dosing cycles) is different from the duration of the subsequent dosing cycles. In some embodiments, the first dose and the second dose have the same duration and / or amount. In some embodiments, the first dose and the second dose have different durations and / or amounts.

[0116] In one embodiment, the PD-1 antagonist is administered at a dose of 500 mg. In one embodiment, the PD-1 antagonist is administered by infusion every 3 weeks. In one embodiment, the PD-1 antagonist is administered by infusion every 3 weeks over 30 minutes. In one embodiment, the PD-1 antagonist is administered by infusion every 3 weeks for up to three years. In one embodiment, the PD-1 antagonist is administered by infusion every 3 weeks until disease progression. In one embodiment, the PD-1 antagonist is administered by infusion every 3 weeks until a complete response.

[0117] In one embodiment, the PD-1 antagonist is administered at a dose of 1000 mg. In one embodiment, the PD-1 antagonist is administered by infusion every 6 weeks. In one embodiment, the PD-1 antagonist is administered by infusion every 6 weeks over 30 minutes. In one embodiment, the PD-1 antagonist is administered by infusion every 6 weeks for up to three years. In one embodiment, the PD-1 antagonist is administered by infusion every 6 weeks until disease progression. In one embodiment, the PD-1 antagonist is administered by infusion every 6 weeks until a complete response is achieved.

[0118] In one embodiment, pemetrexed is administered at 500 mg / m 2 In one embodiment, pemetrexed is administered Q3W. In one embodiment, pemetrexed is administered Q3W by 10-minute IV infusion.

[0119] In one embodiment, cisplatin is administered at 75 mg / m 2 In one embodiment, cisplatin is administered Q3W. In one embodiment, cisplatin is administered Q3W by 30-minute IV infusion for 4 to 6 cycles, such as 6 cycles.

[0120] In one embodiment, carboplatin is administered at a dose of 5 mg / mL / min (mg / mL / min) area under the concentration time curve. In one embodiment, carboplatin is administered Q3W. In one embodiment, carboplatin is administered Q3W by IV infusion over 15 to 60 minutes for 4 to 6 cycles, such as 6 cycles.

[0121] In one embodiment, paclitaxel is administered at 175 mg / m 2 In one embodiment, paclitaxel is administered Q3W. In one embodiment, paclitaxel is administered Q3W for 4 to 6 cycles, such as 6 cycles.

[0122] Dotarizumab and optional chemotherapeutic agents

[0123] In some embodiments, the dose of dotalitumumab or its biosimilar is in the range of about 5 to about 5000 mg (e.g., about 5 mg, about 10 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 2000 mg, about 3000 mg, about 4000 mg, about 5000 mg, or a range defined by any two of the foregoing values). In some embodiments, the dose of dotalitumumab or its biosimilar is 500 mg or 1000 mg.

[0124] In some embodiments, the dosage is an amount relative to body weight. In some embodiments, the dosage of dotalizumab or its biosimilar is in the range of about 0.01 mg / kg to 100 mg / kg of animal or human body weight; however, dosages below or above this exemplary range are within the scope of the present disclosure. The daily dose can be from about 0.01 mg / kg to about 50 mg / kg of total body weight (e.g., about 0.1 mg / kg, about 0.5 mg / kg, about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 12 mg / kg, about 15 mg / kg, about 20 mg / kg, or a range defined by any two of the foregoing values).

[0125] In some embodiments, the dose is administered according to a regimen of delivering a dose every two weeks. In some embodiments, the dose is administered according to a regimen of delivering a dose every three weeks. In some embodiments, the dose is administered according to a regimen of delivering a dose every four weeks. In some embodiments, the dose is administered according to a regimen of delivering a dose every six weeks. In some embodiments, the dose is administered according to a regimen of delivering a dose every eight weeks.

[0126] In some embodiments, the composition for delivering dotalizumab or a biosimilar thereof is administered to a patient at a dose of about 400 mg. In some embodiments, dotalizumab or a biosimilar thereof is administered according to a regimen of delivering a dose of about 400 mg every two weeks. In some embodiments, dotalizumab or a biosimilar thereof is administered according to a regimen of delivering a dose of about 400 mg every three weeks. In some embodiments, dotalizumab or a biosimilar thereof is administered according to a regimen of delivering a dose of about 400 mg every four weeks. In some embodiments, dotalizumab or a biosimilar thereof is administered according to a regimen of delivering a dose of about 400 mg every six weeks. In some embodiments, dotalizumab or a biosimilar thereof is administered according to a regimen of delivering a dose of about 400 mg every eight weeks.

[0127] In some embodiments, the composition for delivering dotalizumab or a biosimilar thereof is administered to a patient at a dose of about 500 mg. In some embodiments, dotalizumab or a biosimilar thereof is administered according to a regimen of delivering a dose of about 500 mg every two weeks. In some embodiments, dotalizumab or a biosimilar thereof is administered according to a regimen of delivering a dose of about 500 mg every three weeks. In some embodiments, dotalizumab or a biosimilar thereof is administered according to a regimen of delivering a dose of about 500 mg every four weeks. In some embodiments, dotalizumab or a biosimilar thereof is administered according to a regimen of delivering a dose of about 500 mg every six weeks. In some embodiments, dotalizumab or a biosimilar thereof is administered according to a regimen of delivering a dose of about 500 mg every eight weeks.

[0128] In some embodiments, the composition delivering dotalizumab or a biosimilar thereof is administered to a patient at a dose of about 800 mg. In some embodiments, dotalizumab or a biosimilar thereof is administered according to a regimen of delivering about 800 mg of a dose every two weeks. In some embodiments, dotalizumab or a biosimilar thereof is administered according to a regimen of delivering about 800 mg of a dose every three weeks. In some embodiments, dotalizumab or a biosimilar thereof is administered according to a regimen of delivering about 800 mg of a dose every four weeks. In some embodiments, dotalizumab or a biosimilar thereof is administered according to a regimen of delivering about 800 mg of a dose every six weeks. In some embodiments, dotalizumab or a biosimilar thereof is administered according to a regimen of delivering about 800 mg of a dose every eight weeks.

[0129] In some embodiments, the composition for delivering dotalizumab or a biosimilar thereof is administered to a patient at a dose of about 1000 mg. In some embodiments, dotalizumab or a biosimilar thereof is administered according to a regimen of delivering a dose of about 1000 mg every two weeks. In some embodiments, dotalizumab or a biosimilar thereof is administered according to a regimen of delivering a dose of about 1000 mg every three weeks. In some embodiments, dotalizumab or a biosimilar thereof is administered according to a regimen of delivering a dose of about 1000 mg every four weeks. In some embodiments, dotalizumab or a biosimilar thereof is administered according to a regimen of delivering a dose of about 1000 mg every six weeks. In some embodiments, dotalizumab or a biosimilar thereof is administered according to a regimen of delivering a dose of about 1000 mg every eight weeks.

[0130] In some embodiments, dotalizumab or a biosimilar thereof is administered according to a regimen that delivers a dose of about 500 mg every three weeks. In some embodiments, dotalizumab or a biosimilar thereof is administered according to a regimen that delivers a dose of about 1000 mg every six weeks.

[0131] In some embodiments, dotalizumab or its biosimilar is administered according to a regimen of administering a first dose of dotalizumab or its biosimilar in the first 2 to 6 dosing cycles (e.g., the first 3, 4, or 5 dosing cycles), followed by administering a second dose of dotalizumab or its biosimilar in subsequent dosing cycles until treatment is stopped (e.g., due to disease progression or side effects or as directed by a physician). In some embodiments, the duration of the first group of 2 to 6 dosing cycles (e.g., the first 3, 4, or 5 dosing cycles) is different from the duration of the subsequent dosing cycles. In some embodiments, dotalizumab or its biosimilar is administered according to a regimen of delivering a first dose of dotalizumab or its biosimilar every three weeks in the first three dosing cycles, followed by delivering a second dose of dotalizumab or its biosimilar every six weeks or more in the remaining dosing cycles (e.g., delivering a second dose of dotalizumab or its biosimilar every six weeks in the remaining dosing cycles). In some embodiments, dotalitumumab or a biosimilar thereof is administered according to a regimen of delivering dotalitumumab or a biosimilar thereof every three weeks for the first four dosing cycles, followed by delivering a second dose of dotalitumumab or a biosimilar thereof every six weeks or more for the remaining dosing cycles (e.g., delivering a second dose of dotalitumumab or a biosimilar thereof every six weeks for the remaining dosing cycles). In some embodiments, dotalitumumab or a biosimilar thereof is administered according to a regimen of delivering a first dose of dotalitumumab or a biosimilar thereof every three weeks for the first five dosing cycles, followed by delivering a second dose of dotalitumumab or a biosimilar thereof every six weeks or more for the remaining dosing cycles (e.g., delivering a second dose of dotalitumumab or a biosimilar thereof every six weeks for the remaining dosing cycles). In some embodiments, dotalizumab or its biosimilar is administered according to a regimen of delivering dotalizumab or its biosimilar once every three weeks for the first six dosing cycles, followed by delivering a second dose of dotalizumab or its biosimilar once every six weeks or more for the remaining dosing cycles (e.g., delivering a second dose of dotalizumab or its biosimilar once every six weeks for the remaining dosing cycles).

[0132] In some embodiments, dotalitimumab or its biosimilar is administered according to a regimen in which a first dose of dotalitimumab or its biosimilar is delivered every three weeks for the first 2 to 6 dosing cycles (e.g., the first 3, 4, or 5 dosing cycles), followed by a second dose of dotalitimumab or its biosimilar every six weeks or until therapy is discontinued (e.g., due to disease progression or side effects, or as directed by a physician). In some embodiments, dotalitimumab or its biosimilar is administered according to a regimen in which a first dose of dotalitimumab or its biosimilar is delivered every three weeks for the first 3, 4, 5, or 6 dosing cycles (e.g., the first 4 dosing cycles or the first 6 dosing cycles), followed by a second dose of dotalitimumab or its biosimilar every six weeks or longer until therapy is discontinued (e.g., due to disease progression or side effects, or as directed by a physician). In some embodiments, the method comprises delivering a second dose of dotalitimumab or its biosimilar every six weeks until therapy is discontinued.

[0133] In some embodiments, the first dose and / or the second dose of dotalitamab or its biosimilar is about 100 mg to about 2000 mg (e.g., about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, or about 2000 mg). In some embodiments, the first dose and the second dose are the same. In some embodiments, the first dose and the second dose are different. In some embodiments, the first dose is about 500 mg of dotalitamab or its biosimilar. In some embodiments, the second dose is about 1000 mg of dotalitamab or its biosimilar.

[0134] In some embodiments, dotalizumab or its biosimilar is administered according to a regimen comprising administering a dose of about 500 mg every 3 weeks for a total of four doses, followed by at least one dose of about 1000 mg every six weeks after the fourth dose of about 500 mg. In some embodiments, dotalizumab or its biosimilar is administered according to a regimen comprising administering a dose of about 500 mg every 3 weeks for a total of six doses, followed by at least one dose of about 1000 mg every six weeks after the sixth dose of about 500 mg. In some embodiments, an additional dose of about 1000 mg is administered every six weeks after the first dose of about 1000 mg until no further clinical benefit is achieved. In some embodiments, dotalizumab or its biosimilar is administered according to a dosing regimen comprising 500 mg for 4 cycles Q3W, followed by 1000 mg Q6W. In some embodiments, dotalizumab or its biosimilar is administered according to a dosing regimen comprising 500 mg for 6 cycles Q3W, followed by 1000 mg Q6W.

[0135] In one embodiment, dotalizumab or its biosimilar is administered at a dose of 500 mg. In one embodiment, dotalizumab or its biosimilar is administered every 3 weeks. In one embodiment, dotalizumab or its biosimilar is administered intravenously every 3 weeks by infusion over 30 minutes. In one embodiment, dotalizumab or its biosimilar is administered at a dose of 1000 mg starting 3 weeks after dose 4. In one embodiment, dotalizumab or its biosimilar is administered at a dose of 1000 mg starting 3 weeks after dose 6. In one embodiment, dotalizumab or its biosimilar is administered every 6 weeks.

[0136] In one embodiment, the patient stops administering at least one of the one or more chemotherapeutic agents and / or radiation therapy prior to initiating administration of dotarimab or a biosimilar thereof.

[0137] Measuring tumor response

[0138] Tumor response can be measured by, for example, solid tumor response evaluation criteria (RECIST) v1.1 guidelines. This guideline is provided by EA Eisenhauer et al., " New response evaluation criteria in solid tumors: Revised RECIST guideline (version 1.1.), " Eur. J. of Cancer, 45: 228-247 (2009). In some embodiments, the RECIST guidelines can be used as the basis of all regimen guidelines relevant to the disease state. In some embodiments, the RECIST guidelines are used to assess the date of tumor response and / or disease progression for treatment.

[0139] RECIST guidelines require that, first, the overall tumor burden at baseline be estimated, which is used as a comparator for subsequent measurements. Tumors can be measured using any imaging system known in the art, such as by CT scan or X-ray. Measurable disease is defined by the presence of at least one measurable lesion.

[0140] The following examples are provided to illustrate the claimed disclosure, but not to limit it.

[0141] Example

[0142] Example 1: Dolimab plus standard of care in patients with primary advanced or recurrent endometrial cancer A phase 3 study of standard-of-care chemotherapy versus placebo plus standard-of-care chemotherapy.

[0143] A phase 3 study was conducted in patients with primary advanced or recurrent endometrial cancer to compare the efficacy of dotarilimab plus carboplatin-paclitaxel followed by dotarilimab versus carboplatin-paclitaxel plus placebo followed by placebo. The primary endpoints were progression-free survival (PFS) assessed by investigators according to RECIST v1.1 and overall survival (OS). Secondary endpoints included PFS by blinded independent central review (BICR), overall response rate (ORR), duration of response (DoR), disease control rate (DCR), patient-reported outcomes (PROs), and safety and tolerability.

[0144] Patients in the experimental group received dotalizumab, carboplatin, and paclitaxel Q3W for 6 cycles, followed by dotalizumab Q6W for up to 3 years. Patients in the control group received placebo, carboplatin, and paclitaxel Q3W for 6 cycles, followed by placebo Q6W for up to 3 years. Dotalizumab was administered intravenously at a dose of 500 mg Q3W for 6 cycles, followed by a dose of 1000 mg Q6W for up to 3 years. Carboplatin was administered Q3W for 6 cycles at an area under the concentration-time curve of 5 mg / mL / min. Paclitaxel was administered at a dose of 175 mg per square meter (mg / m 2 ) was administered Q3W for 6 cycles.

[0145] Surprisingly and unexpectedly, as shown in Figures 1 and Figure 2 As shown in the , dotalizumab plus carboplatin-paclitaxel followed by dotalizumab significantly improved progression-free survival compared with carboplatin-paclitaxel plus placebo followed by placebo. Figure 1A As shown in the mismatch repair deficient (dMMR) / microsatellite instability-high (MSI-H) subgroup, and as Figure 1B In a total population of adult patients with primary advanced or recurrent endometrial cancer, administration of dotarilimab plus carboplatin-paclitaxel followed by dotarilimab demonstrated statistically significant and clinically meaningful benefit. Figure 1CAs shown in Figure 3, a clinically relevant benefit in PFS was also observed in the mismatch repair intact (MMRp) / microsatellite stable (MSS) subgroup. In addition, as shown in Figure 3, good overall survival data were observed in all subgroups. As shown in Figure 4, compared with chemotherapy alone, dotalimab plus chemotherapy resulted in deeper and more durable responses, with a higher rate of complete responses and longer duration of response.

[0146] The patients' medical history of endometrial cancer is provided in Table 2 .

[0147] Table 2

[0148]

[0149] The safety and tolerability profile of dotarumab was consistent with that of similar regimens in clinical trials. The most common treatment-emergent adverse events in patients receiving dotarumab plus chemotherapy were nausea, alopecia, fatigue, peripheral neuropathy, anemia, arthralgia, constipation, and diarrhea.

[0150] Example 2: Endometrial Treatment with Dotarizumab in Patients Previously Treated with Standard of Care Chemotherapy cancer.

[0151] Endometrial cancer patients previously treated with standard-of-care chemotherapy (e.g., carboplatin-paclitaxel) are switched to treatment with dotalimumab or its biosimilars, optionally in combination with standard-of-care chemotherapy. In some cases, the patient's treatment is switched because the patient exhibits progressive disease after receiving standard-of-care chemotherapy. In some cases, the patient's treatment is switched because the patient exhibits only stable disease after receiving standard-of-care chemotherapy. After switching to treatment with dotalimumab or its biosimilars (optionally in combination with standard-of-care chemotherapy), the patient exhibits an improved response.

[0152] Unless otherwise indicated, all numbers used in the specification and claims expressing the amounts of ingredients, properties (such as molecular weight, reaction conditions, etc.) should be understood as being modified in all cases by the term "about". Therefore, unless otherwise indicated to the contrary, the numerical parameters listed in the specification and the appended claims are approximate values, which may vary depending on the desired properties sought to be obtained by the present disclosure. At the very least, and not attempting to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be interpreted in light of the number of reported significant digits and by applying ordinary rounding techniques.

[0153] Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the disclosure are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

[0154] The terms "one", "the", "said" and similar references used in the context of describing the present disclosure (especially in the context of the claims) are to be interpreted as covering both the singular and the plural, unless otherwise stated herein or clearly contradicted by the context. The enumeration of numerical ranges herein is intended only as a simplified method of individually referring to each individual value falling within the range. Unless otherwise stated herein, each individual value is incorporated into this specification as if it were individually quoted herein. Unless otherwise stated herein or clearly contradicted by the context, all methods described herein may be performed in any suitable order. The use of any and all examples or exemplary language (e.g., "such as") provided herein is intended only to better illustrate the present disclosure and does not constitute a limitation on the scope of the present disclosure otherwise requested. Any language in the specification should not be interpreted as indicating any unclaimed element that is essential to the practice of the present disclosure.

[0155] The grouping of alternative elements or embodiments of the present disclosure disclosed herein should not be construed as limiting. Each group member may be mentioned and requested individually, or may be mentioned and requested in any combination with other members of the group or other elements present herein. For convenience and / or patentability reasons, it is estimated that one or more members of a group may be included in the group or deleted from the group. When any such inclusion or deletion occurs, the specification is deemed to contain the group as modified, thereby satisfying the written description of all Markush groups used in the appended claims.

[0156] Certain embodiments of the present disclosure are described herein, including the best mode of implementing the present disclosure known to the inventors. Of course, variations of these described embodiments will become apparent to those of ordinary skill in the art after reading the foregoing description. The inventors expect that skilled artisans will adopt such variations where appropriate, and the inventors intend that the present disclosure be implemented in a manner different from that specifically described herein. Therefore, the present disclosure includes all modifications and equivalents to the subject matter described in the claims appended hereto as permitted by applicable law. In addition, unless otherwise indicated herein or clearly contradicted by the context, any combination of the above elements in all their possible variations is encompassed by the present disclosure.

[0157] Specific embodiments disclosed herein may be further limited in the claims using "consisting of" or "consisting essentially of" language. When used in a claim (whether as filed or added by amendment), the transition term "consisting of" excludes any element, step, or ingredient not specified in the claim. The transition term "consisting essentially of" limits the scope of the claim to the specified materials or steps and those that do not materially affect the basic and novel feature(s). The embodiments of the present disclosure so claimed are inherently or expressly described and enabled herein.

[0158] It should be understood that the embodiments of the present disclosure disclosed herein are illustrative of the principles of the present disclosure. Other modifications that may be employed are also within the scope of the present disclosure. Therefore, by way of example and not limitation, alternative configurations of the present disclosure may be utilized in accordance with the teachings herein. Therefore, the present disclosure is not limited to what is precisely shown and described.

[0159] Although the present disclosure is described and illustrated herein by reference to various specific materials, procedures, and embodiments, it should be understood that the present disclosure is not limited to the specific combination of materials and procedures selected for this purpose. As will be understood by those skilled in the art, various changes in such details may be implied. It is hoped that this description and examples are considered merely exemplary, with the true scope and spirit of the present disclosure being indicated by the claims. All references, patents, and patent applications mentioned in this application are incorporated herein by reference in their entirety.

Claims

1. A method of treating cancer in a human patient, the method comprising: A therapeutically effective amount of a combination comprising 500 mg to 1000 mg of dotarimab or a biosimilar thereof, a platinum-based chemotherapy, and paclitaxel is administered to the human patient, for example, wherein the platinum-based chemotherapy is cisplatin or carboplatin.

2. The method of claim 1, wherein the platinum-based chemotherapy is carboplatin.

3. The method of claim 1 or 2, wherein the administration comprises a first dose of 500 mg of dotarumab or its biosimilar once every 3 weeks (Q3W) for 4 to 6 cycles, followed by a second dose of 1000 mg of dotarumab or its biosimilar once every 6 weeks (Q6W).

4. The method of claim 3, wherein the second dose of dotarizumab or a biosimilar thereof is Q6W for up to 3 years.

5. The method of claim 3 or 4, wherein the first dose and / or the second dose of dotarizumab or a biosimilar thereof is administered by intravenous infusion, for example by intravenous infusion over 30 minutes.

6. The method of any one of the preceding claims, wherein the administration comprises a carboplatin dose having an area under the concentration time curve of 5 mg / mL / min once every 3 weeks (Q3W) for 4 to 6 cycles.

7. The method of any one of the preceding claims, wherein the administration comprises 175 mg / m 2 ) of paclitaxel once every 3 weeks (Q3W) for 4 to 6 cycles.

8. The method of any one of the preceding claims, wherein the administering comprises: The first dose of 500 mg of dotalimumab or its biosimilar once every 3 weeks (Q3W) for 6 cycles, a carboplatin dose with an area under the concentration-time curve of 5 mg / mL / min once every 3 weeks (Q3W) for 6 cycles, and 175 mg per square meter (mg / m 2 ) every 3 weeks (Q3W) for 6 cycles, followed by a second dose of 1000 mg of dotalimumab or its biosimilar every 6 weeks (Q6W).

9. The method of claim 8, wherein the first dose of dotarizumab or a biosimilar thereof, the carboplatin dose, and the paclitaxel dose are all administered on day 1 of a 21-day cycle.

10. The method of claim 9, wherein the second dose of dotarizumab or a biosimilar thereof is administered on day 1 of a 42-day cycle.

11. The method of any one of the preceding claims, wherein the patient has not previously received treatment for the cancer.

12. The method of any one of the preceding claims, wherein the cancer is a gynecological cancer.

13. The method of claim 12, wherein the gynecological cancer is selected from the group consisting of endometrial cancer, ovarian cancer, fallopian tube cancer, cervical cancer, vaginal cancer, vulvar cancer, uterine cancer, papillary serous carcinoma of the uterus, primary peritoneal cancer, adnexal tumors, gestational trophoblastic tumors, and breast cancer.

14. The method of any one of the preceding claims, wherein the cancer is mismatch repair deficient (dMMR) endometrial cancer.

15. The method of any one of the preceding claims, wherein the cancer is microsatellite instability-high (MSI-H) endometrial cancer.

16. The method of any one of the preceding claims, wherein the cancer is recurrent or advanced endometrial cancer.

17. The method of any one of the preceding claims, wherein the cancer is primary advanced endometrial cancer.

18. The method of any one of the preceding claims, wherein the cancer is stage III or stage IV endometrial cancer.

19. The method of any one of the preceding claims, wherein the administration results in improved progression-free survival (PFS) relative to administration of the platinum-based chemotherapy and paclitaxel in the absence of dotarizumab or a biosimilar thereof.

20. The method of any one of the preceding claims, wherein the administration results in improved overall survival (OS) relative to administration of the platinum-based chemotherapy and paclitaxel in the absence of dotarizumab or a biosimilar thereof.

21. The method of any one of the preceding claims, wherein the administration results in improved duration of response (DoR) relative to administration of the platinum-based chemotherapy and paclitaxel in the absence of dotarizumab or a biosimilar thereof.

22. A method of treating cancer in a human patient previously treated with one or more chemotherapeutic agents and / or radiation therapy, the method comprising administering to the human patient a therapeutically effective amount of dotarizumab or a biosimilar thereof.

23. The method of claim 22, wherein the chemotherapeutic agent is a platinum-based chemotherapy.

24. The method of claim 23, wherein the platinum-based chemotherapy is cisplatin or carboplatin.

25. The method of any one of claims 22 to 24, wherein the patient stops administering the radiation therapy prior to starting administration of dotarizumab or a biosimilar thereof.

26. The method of any one of claims 22 to 25, wherein the patient stops administering the one or more chemotherapeutic agents prior to initiating administration of dotarimab or a biosimilar thereof.

27. The method of any one of claims 22 to 26, wherein platinum-based chemotherapy and paclitaxel are co-administered to the patient with dotarizumab or a biosimilar thereof, eg, wherein the platinum-based chemotherapy is cisplatin or carboplatin.

28. The method of claim 27, wherein the platinum-based chemotherapy is carboplatin.

29. The method of any one of claims 22 to 28, wherein the administration comprises a first dose of 500 mg of dotarumab or a biosimilar thereof once every 3 weeks (Q3W) for 4 to 6 cycles, followed by a second dose of 1000 mg of dotarumab or a biosimilar thereof once every 6 weeks (Q6W).

30. The method of claim 29, wherein the second dose of dotarizumab or a biosimilar thereof is Q6W for up to 3 years.

31. The method of claim 29 or 30, wherein the first dose and / or the second dose of dotarizumab or a biosimilar thereof is administered by intravenous infusion, for example by intravenous infusion over 30 minutes.

32. The method of any one of claims 27 to 31, wherein the administration comprises a carboplatin dose comprising an area under the concentration time curve of 5 mg / mL / min once every 3 weeks (Q3W) for 4 to 6 cycles.

33. The method of any one of claims 27 to 32, wherein the administration comprises 175 milligrams per square meter (mg / m 2 ) of paclitaxel once every 3 weeks (Q3W) for 4 to 6 cycles.

34. The method of any one of claims 27 to 33, wherein the administering comprises: The first dose of 500 mg of dotalimumab or its biosimilar once every 3 weeks (Q3W) for 6 cycles, a carboplatin dose with an area under the concentration-time curve of 5 mg / mL / min once every 3 weeks (Q3W) for 6 cycles, and 175 mg per square meter (mg / m 2 ) every 3 weeks (Q3W) for 6 cycles, followed by a second dose of 1000 mg of dotalimumab or its biosimilar every 6 weeks (Q6W).

35. The method of claim 34, wherein the first dose of dotarizumab or a biosimilar thereof, the carboplatin dose, and the paclitaxel dose are all administered on day 1 of a 21-day cycle.

36. The method of claim 35, wherein the second dose of dotarizumab or a biosimilar thereof is administered on day 1 of a 42-day cycle.

37. The method of any one of claims 22 to 36, wherein the cancer is a gynecological cancer.

38. The method of claim 37, wherein the gynecological cancer is selected from endometrial cancer, ovarian cancer, fallopian tube cancer, cervical cancer, vaginal cancer, vulvar cancer, uterine cancer, uterine papillary serous carcinoma, primary peritoneal cancer, adnexal tumor, gestational trophoblastic tumor, or breast cancer.

39. The method of any one of claims 22 to 38, wherein the cancer is mismatch repair deficient (dMMR) endometrial cancer.

40. The method of any one of claims 22 to 39, wherein the cancer is microsatellite instability-high (MSI-H) endometrial cancer.

41. The method of any one of claims 22 to 40, wherein the cancer is recurrent or advanced endometrial cancer.

42. The method of any one of claims 22 to 41, wherein the cancer is primary advanced endometrial cancer.

43. The method of any one of claims 22 to 42, wherein the cancer is stage III or stage IV endometrial cancer.

44. The method of any one of claims 27 to 43, wherein the administration results in improved progression-free survival (PFS) relative to administration of the platinum-based chemotherapy and paclitaxel in the absence of dotarizumab or a biosimilar thereof.

45. The method of any one of claims 27 to 44, wherein the administration results in improved overall survival (OS) relative to administration of the platinum-based chemotherapy and paclitaxel in the absence of dotarizumab or a biosimilar thereof.

46. The method of any one of claims 27 to 45, wherein the administration results in improved duration of response (DoR) relative to administration of the platinum-based chemotherapy and paclitaxel in the absence of dotarizumab or a biosimilar thereof.

47. A method of treating cancer in a human patient, the method comprising: (a) selecting a human patient previously treated with one or more chemotherapeutic agents and / or radiation therapy; and (b) administering a therapeutically effective amount of dotarizumab or a biosimilar thereof to the patient.

48. The method of claim 47, wherein the chemotherapeutic agent is a platinum-based chemotherapy.

49. The method of claim 48, wherein the platinum-based chemotherapy is cisplatin or carboplatin.

50. The method of any one of claims 47 to 49, wherein the patient stops administering the radiation therapy prior to initiating administration of dotarizumab or a biosimilar thereof.

51. The method of any one of claims 47 to 50, wherein the patient stops administering the one or more chemotherapeutic agents prior to initiating administration of dotarizumab or a biosimilar thereof.

52. The method of any one of claims 47 to 51, wherein platinum-based chemotherapy and paclitaxel are co-administered to the patient with dotarilimab or a biosimilar thereof, e.g., wherein the platinum-based chemotherapy is cisplatin or carboplatin.

53. The method of claim 52, wherein the platinum-based chemotherapy is carboplatin.

54. The method of any one of claims 47 to 53, wherein the administration comprises a first dose of 500 mg of dotarumab or its biosimilar once every 3 weeks (Q3W) for 4 to 6 cycles, followed by a second dose of 1000 mg of dotarumab or its biosimilar once every 6 weeks (Q6W).

55. The method of claim 54, wherein the second dose of dotarizumab or a biosimilar thereof is Q6W for up to 3 years.

56. The method of claim 54 or 55, wherein the first dose and / or the second dose of dotarizumab or a biosimilar thereof is administered by intravenous infusion, for example by intravenous infusion over 30 minutes.

57. The method of any one of claims 52 to 56, wherein the administration comprises a carboplatin dose comprising an area under the concentration time curve of 5 milligrams per milliliter per minute (mg / mL / min) once every three weeks (Q3W) for four to six cycles.

58. The method of any one of claims 52 to 57, wherein the administration comprises 175 milligrams per square meter (mg / m 2 ) of paclitaxel once every 3 weeks (Q3W) for 4 to 6 cycles.

59. The method of any one of claims 47 to 58, wherein the administering comprises: The first dose of 500 mg of dotalimumab or its biosimilar once every 3 weeks (Q3W) for 6 cycles, a carboplatin dose with an area under the concentration-time curve of 5 mg / mL / min once every 3 weeks (Q3W) for 6 cycles, and 175 mg per square meter (mg / m 2 ) every 3 weeks (Q3W) for 6 cycles, followed by a second dose of 1000 mg of dotalimumab or its biosimilar every 6 weeks (Q6W).

60. The method of claim 59, wherein the first dose of dotarizumab or a biosimilar thereof, the carboplatin dose, and the paclitaxel dose are all administered on day 1 of a 21-day cycle.

61. The method of claim 60, wherein the second dose of dotarizumab or a biosimilar thereof is administered on day 1 of a 42-day cycle.

62. The method of any one of claims 47 to 61, wherein the cancer is a gynecological cancer.

63. The method of claim 62, wherein the gynecological cancer is selected from endometrial cancer, ovarian cancer, fallopian tube cancer, cervical cancer, vaginal cancer, vulvar cancer, uterine cancer, uterine papillary serous carcinoma, primary peritoneal cancer, adnexal tumor, gestational trophoblastic tumor, or breast cancer.

64. The method of any one of claims 47 to 63, wherein the cancer is mismatch repair deficient (dMMR) endometrial cancer.

65. The method of any one of claims 47 to 64, wherein the cancer is microsatellite instability-high (MSI-H) endometrial cancer.

66. The method of any one of claims 47 to 65, wherein the cancer is recurrent or advanced endometrial cancer.

67. The method of any one of claims 47 to 66, wherein the cancer is primary advanced endometrial cancer.

68. The method of any one of claims 47 to 67, wherein the endometrial cancer is stage III or stage IV endometrial cancer.

69. The method of any one of claims 47 to 68, wherein the administration results in improved progression-free survival (PFS) relative to administration of the platinum-based chemotherapy and paclitaxel in the absence of dotarizumab or a biosimilar thereof.

70. The method of any one of claims 47 to 69, wherein the administration results in improved overall survival (OS) relative to administration of the platinum-based chemotherapy and paclitaxel in the absence of dotarizumab or a biosimilar thereof.

71. The method of any one of claims 47 to 70, wherein the administration results in improved duration of response (DoR) relative to administration of the platinum-based chemotherapy and paclitaxel in the absence of dotarizumab or a biosimilar thereof.

72. A method of treating gynecological cancer in a human patient who has not received prior immunotherapy treatment, the method comprising administering to the patient a therapeutically effective amount of a combination comprising 500 mg to 1000 mg of dotarizumab or a biosimilar thereof, a platinum-based chemotherapy, and paclitaxel.

73. The method of claim 72, wherein the gynecological cancer is a microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) gynecological cancer.

74. A method of treating a gynecological cancer in a patient who has been previously treated with a platinum-based chemotherapeutic agent, the method comprising administering 500 mg to 1000 mg of dotarizumab or a biosimilar thereof.

75. The method of claim 74, wherein the dotarizumab or a biosimilar thereof is administered at a dose of 1000 mg once every six (6) weeks (Q6W).

76. The method of claim 74, wherein the dotarizumab or a biosimilar thereof is administered at a dose of 500 mg once every six (3) weeks (Q3W).

77. The method of claim 74, wherein the gynecological cancer is a microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) gynecological cancer.

78. A method of treating microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) endometrial cancer in a patient previously treated with pembrolizumab, the method comprising administering 500 mg to 1000 mg of dotalimumab or a biosimilar thereof.

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