Targeting DLL3 in cancer therapy

Abstract

The invention disclosed herein provides a method of treating DLL3 positive cancer or SCLC comprising administering an anti-DLL3 agent alone or in combination with an anti-PD-L1 antibody and / or a chemotherapeutic agent to a subject in need of such treatment. Phased administration or extended IV infusion of the anti-DLL3 agent is also disclosed.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Applications Nos. 63 / 313,119 and 63 / 429,311, filed February 23, 2022 and December 1, 2022, respectively, the contents of which are incorporated by reference in their entireties herein.

[0002] Submitting sequences as XML files The following XML file submission context is incorporated herein by reference in its entirety: 43,375 byte XML file named “10009-WO01-SEC_SequenceListing”; created on February 13, 2023.

[0003] This application relates to the dosage and administration of cancer therapies targeting DLL3, including combination therapies with PD-L1 targeted agents and / or chemotherapeutic agents. [Background technology]

[0004] Delta-like 3 (DLL3) is a type 1 transmembrane protein and non-canonical Notch ligand. DLL3 is a promising target for the development of T cell therapy due to its high cell surface expression in neuroendocrine tumors and minimal, mainly cytoplasmic localization in normal tissues (Owen et al., J Hematol Oncol., 12:61 (2019)). Neuroendocrine tumors typically begin in neuroendocrine cells and can arise in organs such as the lung, appendix, small intestine, rectum, and pancreas. Small cell lung cancer (SCLC) is a neuroendocrine cancer in which DLL3 is differentially expressed. Using immunohistochemistry (IHC), 85% of SCLC tumors stained positive for DLL3 in a pattern consistent with both membrane and cytoplasmic expression. In contrast, low levels of DLL3 protein expression were detected in normal brain, pancreatic islets, and pituitary gland with a cytoplasmic staining pattern (Saunders et al, Sci Transl Med. 7:302ra136 (2015)).

[0005] SCLC is an aggressive form of lung cancer with poor prognosis and limited treatment options, accounting for approximately 10-15% of lung cancers. Survival rates have remained low for decades, with only 5% of SCLC patients surviving 5 years, largely due to the lack of new therapies to combat this form of lung cancer. SCLC is characterized by neuroendocrine differentiation, high proliferation rates, rapid doubling times, and early establishment of widespread metastatic lesions. Approximately one-third of patients present with limited-stage disease. Most patients present with advanced-stage disease. These stages influence the available treatment regimens, limiting which stages are treated with chemotherapy and radiation, and extensive-stage disease is treated with chemotherapy alone.

[0006] Patients with SCLC have high response rates to first-line chemotherapy including etoposide and cisplatin and also radiation therapy, but invariably relapse rapidly. Although there are approved treatments for recurrent disease, chemotherapy resistance occurs where no therapeutic options are available. The prognosis in the relapsed refractory setting is extremely poor, with rapid disease progression and a short median survival of less than 6 months after patients receive third-line treatment. Patients with extensive-stage SCLC (ES-SCLC) develop drug resistance and die as a result of their disease with a median time of 10 to 12 months from diagnosis. AMG 757 (also known as tarlatamab) is a bispecific T cell engager (BiTE®) molecule that targets DLL3 on cancer cells and CD3 on T cells. It is being developed and evaluated in clinical trials for the treatment of DLL3-positive cancers such as SCLC and neuroendocrine prostate cancer (NEPC). [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] Owen et al.,J Hematol Oncol.,12:61(2019) [Non-Patent Document 2] Saunders et al, Sci Transl Med.7:302ra136(2015) Summary of the Invention [Problem to be solved by the invention]

[0008] Although efforts have been made to develop therapies for the treatment of DLL3-positive cancers such as SCLC, overall survival remains poor. There is an unmet medical need for the development of therapies for the treatment of DLL3-positive cancers such as SCLC. [Means for solving the problem]

[0009] Based on the disclosure provided herein, those of ordinary skill in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein, which equivalents are intended to be encompassed by embodiment (E) below.

[0010] E1: A method for treating DLL3-positive cancer, comprising administering an anti-DLL3 agent to a subject in need thereof, wherein the anti-DLL3 agent is administered at a dose of 10 mg to 100 mg twice every three weeks.

[0011] E2: A method for treating a DLL3-positive cancer, comprising administering an anti-DLL3 agent to a subject in need thereof, wherein the anti-DLL3 agent is administered at a dose of 20 mg to 200 mg once every three weeks.

[0012] E3: A method of treating DLL3 positive cancer comprising administering to a subject in need thereof an anti-DLL3 agent, wherein the anti-DLL3 agent is administered in the following regimen: a) a first cycle in which (i) the anti-DLL3 agent is administered by continuous intravenous infusion over 2 to 7 days at a dose of 1 mg to 200 mg, and (ii) following the continuous intravenous infusion, the anti-DLL3 agent is administered by bolus intravenous infusion on days 8, 15, or both 8 and 15; and b) i) to iii): i) a first cycle in which the anti-DLL3 agent is administered at a dose of 10 mg to 100 mg, and (ii) a second cycle in which the anti-DLL3 agent is administered at a dose of 10 mg to 100 mg, and (iii) a second cycle in which the anti-DLL3 agent is administered at a dose of 10 mg to 100 mg, and (iii) a second cycle in which the anti-DLL3 agent is administered at a dose of 10 mg to 100 mg, and (iv) a third cycle in which the anti-DLL3 agent is administered at a dose of 10 mg to 100 mg, and (v) a fourth cycle in which the anti-DLL3 agent is administered at a dose of 10 mg to 100 mg, and (vi ... 2) administering one or more subsequent doses of the anti-DLL3 agent at a dose of 10 mg to 100 mg starting on day 22 and once every three weeks thereafter; and iii) administering one or more subsequent doses of the anti-DLL3 agent at a dose of 20 mg to 200 mg starting on day 22 and once every three weeks thereafter.

[0013] E4: A method of treating a DLL3-positive cancer comprising administering to a subject in need thereof an anti-DLL3 agent, an anti-PD-L1 antibody, and optionally one or more chemotherapeutic agents, wherein the anti-DLL3 agent is administered according to any one of the following: a) administering the anti-DLL3 agent at a dose of 10 mg to 100 mg once every two weeks; b) administering the anti-DLL3 agent at a dose of 10 mg to 100 mg twice every three weeks; c) administering the anti-DLL3 agent at a dose of 20 mg to 200 mg once every three weeks.

[0014] E5: The method according to any one of E1 to E4, wherein the anti-DLL3 positive cancer is small cell lung cancer (SCLC).

[0015] E6: The method according to any one of E1 to E5, wherein the anti-DLL3 positive cancer is relapsed / refractory (RR) SCLC or extensive stage (ED) SCLC.

[0016] E7: The method of any one of E1 to E6, wherein the anti-DLL3 agent is a bispecific T cell-inducing antigen-binding polypeptide comprising two binding domains: a first domain that binds to human DLL3, and a second domain that binds to human CD3.

[0017] E8: The method of E7, wherein the DLL3-binding domain binds to an epitope of human DLL3 contained within the amino acid sequence of SEQ ID NO:29.

[0018] E9: The method described in E7 or E8, wherein the DLL3-binding domain comprises: (a) a heavy chain variable region (VH), comprising: (i) a VH complementarity determining region 1 (CDR-H1) comprising the amino acid sequence of SEQ ID NO: 1; (ii) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 2; and (iii) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 3; and (b) a light chain variable region (VL), comprising: (i) a VL complementarity determining region 1 (CDR-L1) comprising the amino acid sequence of SEQ ID NO: 4; (ii) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and (iii) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 6.

[0019] E10: A method described in any one of E7 to E9, wherein the DLL3-binding domain comprises (1) a VH having the amino acid sequence of SEQ ID NO: 7 and a VL having the amino acid sequence of SEQ ID NO: 8, or (2) a VH having the amino acid sequence of SEQ ID NO: 11 and a VL having the amino acid sequence of SEQ ID NO: 12.

[0020] E11: The method according to any one of E7 to E10, wherein the VH and VL of the DLL3-binding domain are linked by a linker to form a single chain Fv (scFv).

[0021] E12: The method according to any one of E7 to E11, wherein the DLL3-binding domain comprises the amino acid sequence of SEQ ID NO:9 or SEQ ID NO:13.

[0022] E13: The method described in any one of E7 to E12, wherein the CD3-binding domain comprises: (a) a VH comprising CDR-H1 comprising the amino acid sequence of SEQ ID NO: 18, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 19, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 20; and a VL comprising CDR-L1 comprising the amino acid sequence of SEQ ID NO: 15, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 16, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 17.

[0023] E14: The method according to any one of E7 to E13, wherein the CD3-binding domain comprises a VH comprising the amino acid sequence of SEQ ID NO: 21 and a VL comprising the amino acid sequence of SEQ ID NO: 22.

[0024] E15: The method described in E13 or E14, wherein the VH and VL of the CD3 binding domain are linked by a linker to form a single chain Fv (scFv).

[0025] E16: The method described in any one of E13 to E15, wherein the CD3 binding domain comprises the amino acid sequence of SEQ ID NO:23.

[0026] E17: The method according to any one of E7 to E16, wherein the DLL3-binding domain and the CD3-binding domain are linked by a linker.

[0027] E18: The method according to any one of E7 to E17, wherein the anti-DLL3 agent is a bispecific T cell-inducing antigen-binding polypeptide comprising a DLL3-binding domain and a CD3-binding domain. The DLL3-binding domain comprises: (a) a heavy chain variable region (VH), comprising: (i) a VH complementarity determining region 1 (CDR-H1) comprising the amino acid sequence of SEQ ID NO: 1; (ii) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 2; and (iii) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 3; and (b) a light chain variable region (VL), comprising: (i) a VL complementarity determining region 1 (CDR-L1) comprising the amino acid sequence of SEQ ID NO: 4; (ii) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and (iii) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 6. The CD3-binding domain comprises: (a) a VH comprising (i) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 18, (ii) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 19, and (iii) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 20; and (b) a VL comprising (i) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 15, (ii) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 16, and (iii) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 17.

[0028] E19: The method described in any one of E7 to E18, wherein the DLL3 binding domain comprises a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 8, and the CD3 binding domain comprises a VH comprising the amino acid sequence of SEQ ID NO: 21 and a VL comprising the amino acid sequence of SEQ ID NO: 22.

[0029] E20: The method described in any one of E7 to E18, wherein the DLL3-binding domain comprises a VH comprising the amino acid sequence of SEQ ID NO: 11 and a VL comprising the amino acid sequence of SEQ ID NO: 12, and the CD3-binding domain comprises a VH comprising the amino acid sequence of SEQ ID NO: 21 and a VL comprising the amino acid sequence of SEQ ID NO: 22.

[0030] E21: The method according to any one of E7 to E19, wherein the DLL3-binding domain comprises the amino acid sequence of SEQ ID NO:9, and the CD3-binding domain comprises the amino acid sequence of SEQ ID NO:23.

[0031] E22: The method according to any one of E7 to E18 or E20, wherein the DLL3-binding domain comprises the amino acid sequence of SEQ ID NO:13, and the CD3-binding domain comprises the amino acid sequence of SEQ ID NO:23.

[0032] E23: The method of E21 or E22, wherein the anti-DLL3 agent comprises the amino acid sequence of SEQ ID NO:10 or SEQ ID NO:14.

[0033] E24: The method according to any one of E7 to E23, wherein the anti-DLL3 agent comprises the amino acid sequence of SEQ ID NO:27 or SEQ ID NO:32.

[0034] E25: The method of any one of E1-E24, wherein the method further comprises administering to the subject one or more additional therapeutic agents.

[0035] E26: The method of E25, wherein the one or more additional therapeutic agents is a corticosteroid (e.g., dexamethasone), saline, or an anti-IL-6 antibody.

[0036] E27: The method of E25 or E26, wherein the one or more additional therapeutic agents are administered to the subject in the first cycle in which the anti-DLL3 agent is administered.

[0037] E28: The method of any one of E1 to E27, wherein the anti-DLL3 agent is prepared by a process of culturing a host cell comprising a nucleic acid encoding the anti-DLL3 agent of any one of E7 to E24 under conditions allowing expression of the anti-DLL3 agent, and then recovering the expressed anti-DLL3 agent from the cell culture.

[0038] E29: The method of any one of E1-E28, wherein the subject is a human. E30: The method of E29, wherein the subject has had at least one prior treatment for cancer and has relapsed, such as having had two or more prior treatments and has relapsed. E31: The method of E30, wherein the at least one prior treatment for cancer is platinum, chemotherapy, etoposide, and optionally an anti-PD-L1 antibody. E32: The method of E29, wherein the subject has not had a previous systemic treatment for cancer. E33: The method of any one of E1-E32, wherein the anti-DLL3 agent is tarlatamab. E34: The method of any one of E3, wherein the anti-PD-L1 antibody is atezolizumab or durvalumab.

[0039] E33: An anti-DLL3 agent for use in the treatment of a DLL3-positive cancer (e.g., SCLC), wherein the anti-DLL3 agent is administered as described in any one of embodiments E1-E29. [Brief description of the drawings]

[0040] [Figure 1A] Graph showing maximum percent change from baseline in tumor burden (defined by the sum of the longest diameter (SLD) of all target lesions) in 94 patients with a data cutoff date of at least 9 weeks after the date of first dose and for whom post-baseline tumor data were available. CR indicates complete response, PR indicates partial response, SD indicates stable disease, and NE indicates not evaluable. SD^ indicates the patient had an initial response but the response was not confirmed on subsequent scans, and PR** indicates the patient had an initial PR with the possibility of a future definitive scan. One confirmed subject in cohort 30 was missing sum of diameters for lesion measurements and was not included in the plot. †Stepwise dosing (i.e., 1 mg induction dose) was used in these cohorts. [Figure 1B] Graph showing time to response, duration of treatment, and patient status at data cutoff date by talutamab dose for all patients with confirmed response (N=25). [Figure 2A]Kaplan-Meier curves of progression-free survival for patients (N=107) whose data cutoff date was at least 9 weeks after the date of first dose. [Figure 2B] Kaplan-Meier curves of overall survival for patients (N=107) whose data cutoff date was at least 9 weeks after the date of first dose. [Figure 3A-B] Graphs showing that peak cytokine levels (6A: IL-6; 6B: IL-8; 6C: IL-10; 6D: TNF-α) tended to be higher in patients with CRS compared to patients without CRS. Biomarker-evaluable patients (N=86); patients with any grade of CRS at cycle 1 (n=45); patients without CRS (n=40). C1, cycle 1; CRS, cytokine release syndrome; G, grade. [Figure 3C-D] Graphs showing that peak cytokine levels (6A: IL-6; 6B: IL-8; 6C: IL-10; 6D: TNF-α) tended to be higher in patients with CRS compared to patients without CRS. Biomarker-evaluable patients (N=86); patients with any grade of CRS at cycle 1 (n=45); patients without CRS (n=40). C1, cycle 1; CRS, cytokine release syndrome; G, grade. [Figure 4] Graph showing longitudinal analysis of IL-10 expression in patients from the Phase I study described in Example 1. IL-10 was significantly elevated above the reference normal range and was higher in CRS patients. JT trend test adjusted P value=0.049 (significant at 95% confidence); KW test of association adjusted P value=0.096 (significant at 90% confidence; not significant at 95% confidence). Yellow dotted line indicates reference normal range. [Figure 5A-B]Graph showing analysis of IFN-γ expression in patients from the Phase I study described in Example 1. IFN-γ induction was above the physiological range, and induction was similar with and without cycle 1 CRS. JT trend test adjusted P value=0.234 (not significant at 95% confidence); KW test of association adjusted P value=0.317 (not significant at 90% or 95% confidence). Yellow dotted lines indicate reference normal range. [Figure 6] FIG. 1 is a schematic diagram of the clinical trial described in Example 5. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0041] AMG 757 is a half-life extended BiTE® (bispecific T cell engager) molecule developed for the treatment of DLL3-positive cancers such as SCLC. The activity of AMG 757 involves the expression of DLL3 in target cells ( + The pharmacological effect of AMG 757 is to bind to both DLL3 and T cells simultaneously. + Cytotoxic CD8 already primed to kill cells + or CD4 + AMG 757 was evaluated in a first-in-human study in subjects with SCLC (Study 20160323) and found to have antitumor activity starting at a dose level of 0.3 mg once every 2 weeks (Q2W) with an acceptable safety profile at doses up to 100 mg Q2W.

[0042] In preclinical studies, treatment with AMG 757 induces upregulation of PD-1 and programmed death ligand 1 (PD-L1) on T cells. The combination of AMG 757 and anti-PD-1 antibodies increases T cell-mediated redirected lysis of tumor cells expressing DLL3 compared to AMG 757 alone (Amgen Study Report R20190104). Upregulation of PD1 / PD-L1 in the tumor microenvironment may be a mechanism of resistance to BiTE therapy that may be mitigated by treatment with anti-PD1 or anti-PD-L1 therapy.

[0043] Combination therapy including BiTE molecules and cytotoxic chemotherapy is novel for the treatment of solid tumors. As disclosed and exemplified herein, a Phase 1 clinical trial for the treatment of SCLC was conducted using an agent targeting DLL3 (e.g., AMG 757) alone or in combination with an anti-PD-L1 agent and / or a chemotherapy agent. The methods disclosed herein can provide improved convenience, flexibility and efficacy, and / or reduce adverse effects to patients, compared to biweekly dosing regimens.

[0044] 1.Definition Some of the exemplary bispecific anti-DLL3 agents disclosed herein (such as BiTE® molecules) are bispecific T cell-inducing antigen-binding polypeptides. These polypeptides are recombinant proteins that contain two binding domains, each domain derived from an antigen-binding fragment of a full-length antibody. Such antigen-binding fragments retain the ability to specifically bind to an antigen (preferably with substantially the same binding affinity). Examples of antigen-binding fragments include: (i) a Fab fragment, which is a monovalent fragment consisting of the VL, VH, CL, and CH1 domains; (ii) an F(ab') fragment, which is a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region. 2 (iii) Fd fragments consisting of the VH and CH1 domains; (iv) Fv fragments consisting of the VL and VH domains of a single arm of an antibody; and (v) dAb fragments consisting of the VH domain (Ward et al., 1989 Nature 341:544-546). Furthermore, the two domains of the Fv fragment, VL and VH, are encoded by separate genes, but can be joined using recombinant methods by a synthetic linker that allows them to be produced as a single protein chain in which the VL and VH regions pair to form a monovalent molecule (known as single-chain Fv (scFv)); see, for example, Bird et al. Science 242:423-426 (1988) and Huston et al., 1988, Proc. Natl. Acad. Sci. USA 85:5879-5883.

[0045] "Variable domain" refers to either the variable region of an antibody light chain (VL) or the variable region of an antibody heavy chain (VH), either alone or in combination. As known in the art, the variable regions of the heavy and light chains each consist of four framework regions (FR) linked by three complementarity determining regions (CDRs), which contribute to the formation of the antigen-binding site of an antibody.

[0046] The "complementarity determining regions" (CDRs) of exemplary agents targeting DLL3 are listed in the sequence listing. CDRs can be defined according to Kabat, Chothia, both Kabat and Chothia accumulation, AbM, contact, North, and / or conformational definitions, or any method of determining CDRs well known in the art. See, for example, Kabat et al., 1991, Sequences of Proteins of Immunological Interest, 5th ed. (hypervariable regions); Chothia et al., 1989, Nature 342:877-883 (structural loop structures). The AbM definition of CDRs is a compromise between Kabat and Chothia, and uses Oxford Molecular's AbM antibody modeling software (Accelrys®). The identity of the amino acid residues of a particular antibody that make up a CDR can be determined using methods well known in the art.

[0047] The term "treatment" includes preventative treatment and / or therapeutic treatment. Treatment is considered preventative treatment when administered prior to clinical signs of a condition. Therapeutic treatment includes, for example, amelioration or reduction of disease severity or shortening of disease duration. Additionally, the term "treat" and related terms do not necessarily mean 100% or complete treatment. Rather, there are various degrees of treatment that one of skill in the art recognizes as having potential benefits or therapeutic effects. In this regard, the method of treating cancer of the present disclosure can provide any amount or level of treatment. Additionally, the treatment provided by the method of the present disclosure can include treatment of one or more pathologies or symptoms or signs of the cancer being treated. Additionally, the treatment provided by the method of the present disclosure can include slowing the progression of the cancer. For example, the method can treat cancer by enhancing T cell activity or immune response against the cancer, reducing tumor or cancer growth, reducing metastasis of tumor cells, increasing cell death of tumor or cancer cells, etc. In exemplary embodiments, the method treats to delay the onset or recurrence of cancer by 1 day, 2 days, 4 days, 6 days, 8 days, 10 days, 15 days, 30 days, 2 months, 4 months, 6 months, 1 year, 2 years, 4 years, or more. In exemplary embodiments, the method treats to extend the subject's survival. In various embodiments, the treatment provided by the method of the present disclosure provides a therapeutic response according to Response Evaluation Criteria in Solid Tumors (RECIST) or other similar criteria. RECIST is a set of criteria for evaluating the progression, stabilization, or response of tumors and / or cancer cells, jointly created by the National Cancer Institute of the United States, the National Cancer Institute of Canada Clinical Trials Group, and the European Organisation for Research and Treatment of Cancer. According to RECIST, a particular tumor is measured at the beginning of evaluation (e.g., a clinical trial) to provide a baseline for comparison after treatment with a drug.Tumor response assessments and assessment criteria are published in Eisenhauer et.al., Eur J Cancer 45:228-247 (2009) and Litiere et.al., Journal of Clinical Oncology 37(13):1102-1110 (2019) DOI:10.1200 / JCO.18.01100. In various instances, the treatment provided by the methods of the present disclosure provides a therapeutic response according to a modified RECIST tumor response assessment, as follows:

[0048] [Table 1]

[0049] Thus, provided herein are methods of delaying progression of a DLL3-positive cancer in a subject, enhancing T cell activity or immune response to a DLL3-positive cancer in a subject, reducing growth of a DLL3-positive tumor or cancer in a subject, reducing metastasis of DLL3-positive tumor cells in a subject, increasing cell death of a DLL3-positive tumor or cancer cells in a subject, delaying onset or recurrence of a DLL3-positive cancer in a subject, and / or prolonging survival of a subject. Also provided are methods of treating a DLL3-positive cancer to produce a complete response (CR), partial response (PR), or stable disease (SD) in a subject according to modified RECIST 1.1. In various aspects, the method comprises administering to the subject an anti-DLL3 agent, alone or in combination with an anti-PD-L1 antibody and / or one or more chemotherapeutic agents, in accordance with the present disclosure. For example, in various aspects, the method comprises administering to the subject an anti-DLL3 agent comprising the amino acid sequence of SEQ ID NOs: 13 and 23, alone or in combination with an anti-PD-L1 antibody and / or a chemotherapeutic agent.

[0050] "About" or "approximately," when used in connection with a measurable numerical variable, refers to the stated value of the variable and all values ​​of the variable that are within the experimental error of the stated value (e.g., within a 95% confidence interval of the mean) or ±10% of the stated value, whichever is greater. Numerical ranges include the numbers defining the range.

[0051] "First stage dose" or "induction dose", when used in connection with administration of an anti-DLL3 agent for the treatment of cancer (e.g., SCLC), refers to the initial dose of an anti-DLL3 agent in a step-dose schedule or regimen. Typically, the first stage dose or induction dose corresponds to a dose at or below which a first dose effect (e.g., cytokine release syndrome (CRS)) is observed. As known in the art, the first stage dose can be determined by modeling and simulation of safety and pharmacokinetic data. For example, the first stage dose can be the maximum tolerated dose (MTD) of the anti-DLL3 agent at which no CRS is observed or CRS of less than a certain grade (e.g., grade 2) is observed.

[0052] "Target dose," when used in connection with administration of an anti-DLL3 agent for the treatment of cancer (e.g., SCLC), refers to the dose at which the target effect of the anti-DLL3 agent (e.g., remission or reduction in the severity of SCLC, or shortening the duration of SCLC) is achieved.

[0053] "Step-up dose," when used in connection with administration of an anti-DLL3 agent for the treatment of cancer (e.g., SCLC), refers to a dose in an escalating dosing schedule or regimen that is higher than the previous dose at which the anti-DLL3 agent is administered. A step-up dose includes one or more doses that increase from a first step-up dose until a target dose is reached.

[0054] 2. Drugs that target DLL3 DLL3 is a non-canonical Notch ligand that is mainly expressed during embryogenesis and functions during somitogenesis. DLL3 accumulates in the Golgi apparatus in normal tissues (Geffers et al, J Cell Biol.178:465-476(2007)). DLL3 was identified as a tumor-associated antigen and a potential target for T cell-based therapy by analyzing the differential expression of this target in 28 SCLC tumors and a large panel of normal tissues (Study 123658).

[0055] The human DLL3 protein contains several extracellular domains: signal peptide, N-terminus, DSL, EGF1, EGF2, EGF3, EGF4, EGF5, EGF6, and membrane proximal domain. The amino acid sequences of human DLL3, EGF3 domain, EGF4 domain, combined EGF3 and EGF4 domain, and membrane proximal domain are shown in the sequence listing as SEQ ID NOs: 28, 29, 30, 31, and 33, respectively.

[0056] An exemplary agent targeting DLL3 is a bispecific T cell-inducing antigen-binding polypeptide that binds DLL3 and CD3, such as a BiTE® molecule. A BiTE® molecule is a recombinant protein formed from two flexibly linked binding domains, each derived from an antibody. One binding domain of the BiTE® molecule is specific for a tumor-associated surface antigen (e.g., DLL3), and the second binding domain is specific for CD3, a subunit of the T cell receptor complex on T cells. These designs make the BiTE® molecule uniquely suitable for transiently binding T cells to target cells while simultaneously potently activating the cytotoxicity of T cells against their natural target cells. See, for example, WO 99 / 54440, WO 2005 / 040220, and WO 2008 / 119567.

[0057] Thus, in some embodiments, the described DLL3 targeting agents comprise two binding domains: a first domain that binds to DLL3 (preferably human DLL3) and a second domain that binds to CD3 (preferably human CD3). Preferably, the first domain binds to an epitope of DLL3 contained in the amino acid sequence of SEQ ID NO: 31. More preferably, the first domain binds to an epitope of DLL3 contained in the amino acid sequence of SEQ ID NO: 29.

[0058] In certain embodiments, the DLL3 binding domain comprises (a) a heavy chain variable region (VH) comprising: (i) a VH complementarity determining region 1 (CDR-H1) comprising the amino acid sequence of SEQ ID NO: 1; (ii) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 2; and (iii) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 3; and (b) a light chain variable region (VL) comprising: (i) a VL complementarity determining region 1 (CDR-L1) comprising the amino acid sequence of SEQ ID NO: 4; (ii) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and (iii) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 6.

[0059] In certain embodiments, the DLL3-binding domain comprises a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 8. In certain preferred embodiments, the DLL3-binding domain comprises a VH comprising the amino acid sequence of SEQ ID NO: 11 and a VL comprising the amino acid sequence of SEQ ID NO: 12.

[0060] In some embodiments, the VH and VL are linked by a linker to form a single chain Fv (scFv). In certain embodiments, the DLL3 binding domain comprises the amino acid sequence of SEQ ID NO: 9. In certain preferred embodiments, the DLL3 binding domain comprises the amino acid sequence of SEQ ID NO: 13.

[0061] In certain embodiments, the CD3 binding domain comprises (a) a VH comprising a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 18, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 19, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 20, and a VL comprising a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 15, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 16, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 17.

[0062] In certain embodiments, the CD3 binding domain comprises a VH comprising the amino acid sequence of SEQ ID NO: 21 and a VL comprising the amino acid sequence of SEQ ID NO: 22. In certain embodiments, the CD3 binding domain comprises the amino acid sequence of SEQ ID NO: 23.

[0063] In certain embodiments, the anti-DLL3 agents disclosed herein comprise two domains: the first domain binds to DLL3 (preferably human DLL3) and comprises (a) a heavy chain variable region (VH) comprising (i) a VH complementarity determining region 1 (CDR-H1) comprising the amino acid sequence of SEQ ID NO:1; (ii) a CDR-H2 comprising the amino acid sequence of SEQ ID NO:2; and (iii) a CDR-H3 comprising the amino acid sequence of SEQ ID NO:3; and (b) a light chain variable region (VL) comprising (i) a VL complementarity determining region 1 (CDR-L1) comprising the amino acid sequence of SEQ ID NO:4; (ii) a CDR-L2 comprising the amino acid sequence of SEQ ID NO:5; and (iii) a CDR-L3 comprising the amino acid sequence of SEQ ID NO:6. The second domain binds to CD3 (preferably human CD3) and comprises (a) a VH comprising (i) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 18, (ii) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 19, and (iii) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 20, and (b) a VL comprising (i) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 15, (ii) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 16, and (iii) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 17.

[0064] In certain embodiments, the anti-DLL3 agents described herein comprise two domains: (a) a first domain that binds DLL3 (preferably human DLL3) and comprises a VH comprising the amino acid sequence of SEQ ID NO:7 and a VL comprising the amino acid sequence of SEQ ID NO:8, and (b) a second domain that binds CD3 (preferably human CD3) and comprises a VH comprising the amino acid sequence of SEQ ID NO:21 and a VL comprising the amino acid sequence of SEQ ID NO:22. In certain preferred embodiments, the anti-DLL3 agents described herein comprise two domains: (a) a first domain that binds DLL3 (preferably human DLL3) and comprises a VH comprising the amino acid sequence of SEQ ID NO:11 and a VL comprising the amino acid sequence of SEQ ID NO:12, and (b) a second domain that binds CD3 (preferably human CD3) and comprises a VH comprising the amino acid sequence of SEQ ID NO:21 and a VL comprising the amino acid sequence of SEQ ID NO:22.

[0065] In certain embodiments, the anti-DLL3 agents described herein comprise two domains: (a) a first domain that binds to DLL3 (preferably human DLL3) and comprises the amino acid sequence of SEQ ID NO: 9, and (b) a second domain that binds to CD3 (preferably human CD3) and comprises the amino acid sequence of SEQ ID NO: 23. In certain embodiments, the anti-DLL3 agents described herein comprise two domains: (a) a first domain that binds to DLL3 (preferably human DLL3) and comprises the amino acid sequence of SEQ ID NO: 13, and (b) a second domain that binds to CD3 (preferably human CD3) and comprises the amino acid sequence of SEQ ID NO: 23.

[0066] In certain embodiments, the anti-DLL3 agents described herein comprise the amino acid sequence of SEQ ID NO: 10. In certain embodiments, the anti-DLL3 agents described herein comprise the amino acid sequence of SEQ ID NO: 14.

[0067] In certain embodiments, the anti-DLL3 agents described herein comprise or consist of the amino acid sequence of SEQ ID NO: 27. In certain embodiments, the anti-DLL3 agents described herein comprise or consist of the amino acid sequence of SEQ ID NO: 33.

[0068] The anti-DLL3 agents described herein can be produced by recombinant DNA techniques known in the art. For example, the anti-DLL3 agents can be produced by a process in which a host cell (e.g., Chinese hamster ovary cell) containing a nucleic acid encoding the anti-DLL3 agent described herein is cultured under conditions that allow expression of the anti-DLL3 agent, and then the expressed anti-DLL3 agent is recovered from the cell culture. In various embodiments, the anti-DLL3 agent is taluratamab (International Nonproprietary Name (INN) for Pharmaceutical Substances: Proposed INN: List 123, WHO Drug Information 34(2):395-397(2020)), also known as AMG 757. Tarlatamab is a monoclonal antibody consisting of immunoglobulin scFv-scFv-scFc, anti-[Homo sapiens DLL3 (delta-like ligand 3)] and anti-[Homo sapiens CD3E (CD3ε, Leu-4)], monoclonal antibody single chain (scFv) 2-scFc, bispecific; IG single chain scFv-scFv-scFc, anti-DLL3 and anti-CD3E (1-982) [scFv-VH-V-κ] anti-DLL3 (1-241) [VH (Homo sapiens IGHV4-59 * 01 G49>C(44)(96.9%)-(IGHD)-IGHJ4 * 01 (100%)) CDR-IMGT[8.7.12](26-33.51-57.96-107)(1-118)-15-mer tris(tetraglycyl-seryl) linker(119-133)-V-κ(Homo sapiens IGKV3-20 * 01(91.7%)-IGKJ2 * 01 Q120>C(234)(90.9%))CDRIMGT[7.3.9](160-166.184-186.223-231)(134-241)]-6-mer seryl-tetraglycyl-seryl linker(242-247)-scFv-VH-V-λ anti-CD3E(248-496)[VH(Mus musculus IGHV10-1 *02(91.9%)-(IGHD)-IGHJ3 * 01 (86.7%) / Homo sapiens IGHV3-73 * 01(87.0%)-(IGHD)-IGHJ5 * 01 (100%)) CDR-IMGT[8.10.16](273-280.298-307.346-361)(248-372)-15-mer-tris(tetraglycyl-seryl) linker(373-387)-V-λ(Homo sapiens IGLV7-43 * 01 (85.1%) - IGLJ3 * 02 (100%)) CDR-IMGT[9.3.9](413-421.439-441.478-486)(388-496)]-4-mer-tetraglycyl linker(497-500)-scFc(h-CH2-CH3)-(h-CH2-CH3)(501-982) [Homo sapiens IGHG1 * 03h-CH2-CH3, nG1m1 (hinge 6-15 (501-510), CH2 R83>C (572), N84.4>G (577), V85>C (582) (511-620), CH3 E12 (636), M14 (638) (621-725), CHS>del) (501-725) - 30-mer hexakis(tetraglycyl-seryl) linker (726-755) - Homo sapiens IGHG1 * 03 h-CH2-CH3, nG1m1 (hinge 6-15(756-765), CH2 R83>C(827), N84.4>G(832), V85>C(837)(766-875), CH3 E12(891), M14(893)(876-980), CHS(981-982))(756-982)]], nonglycosylated, produced in Chinese hamster ovary (CHO) cells; immunomodulatory and antineoplastic agent.

[0069] In certain embodiments, an exemplary anti-DLL3 agent is a DLL3 (e.g., human DLL3) binding molecule, such as those disclosed in WO2019234220, WO2020 / 069028, WO2019 / 131988, WO2021 / 200898, and WO2021 / 155380, all of which are incorporated by reference in their entirety. In certain embodiments, the anti-DLL3 agent is a protein comprising: (a) a first domain that is a single chain variable fragment that specifically binds human CD3; (b) a second domain that is a single domain antibody that specifically binds human serum albumin protein; and (c) a third domain that is a single domain antibody that specifically binds DLL3 protein. In certain embodiments, the anti-DLL3 agent comprises or consists of the amino acid sequence of SEQ ID NO: 34 or 35. In certain embodiments, the anti-DLL3 agent is a protein comprising: (a) a first antigen binding domain that specifically binds human DLL3; (b) a second antigen binding domain that specifically binds human CD3, and (c) a first and a second Fc domain, where the first Fc domain is covalently linked to the first antigen binding domain and the second Fc domain is covalently linked to the second antigen binding domain. In certain embodiments, the first binding domain specifically binds to a membrane proximal region of human DLL3 (e.g., SEQ ID NO: 33). In certain embodiments, the first binding domain comprises, from its N-terminus to its C-terminus, a first light chain variable domain, a first light chain constant domain, a first peptide linker, a first heavy chain variable domain, and a first heavy chain constant CH1 domain, and the second binding domain comprises, from its N-terminus to its C-terminus, a second light chain variable domain, a second light chain constant domain, a second peptide linker, a second heavy chain variable domain, and a second heavy chain constant CH1 domain. In certain embodiments, the anti-DLL3 agent comprises a first antigen binding domain and a second antigen binding domain, wherein the first antigen binding domain comprises or consists of the amino acid sequence of SEQ ID NO:36 and the second binding domain comprises or consists of the amino acid sequence of SEQ ID NO:37.In certain embodiments, the anti-DLL3 agent comprises a first binding domain and a second binding domain, where at least one of the first and second domains binds human CD3 and the third binding domain binds human DLL3. In certain embodiments, one of the first or second binding domains binds human CD3, one of the first or second binding domains binds human CD137, and the third binding domain binds human DLL3. In certain embodiments, the first and second binding domains are identical and bind human CD3, and the third binding domain binds human DLL3. In certain embodiments, the first and second binding domains are identical and bind human CD137, and the third binding domain binds human DLL3. Examples of such anti-DLL3 agents are disclosed in WO2021200898.

[0070] The DLL3-targeting agents disclosed herein can be used alone or in combination with other anti-cancer agents disclosed herein to treat DLL3-positive cancers (e.g., lung cancer, small cell lung cancer).

[0071] 3. Other anticancer drugs Drugs that target PD-L1 Programmed cell death protein 1 (PD-1), also known as CD279, SLEB2, and hSLE1, is a transmembrane protein expressed on activated T, natural killer (NK) and B lymphocytes, macrophages, dendritic cells (DC), and monocytes. In particular, PD-1 is highly expressed on tumor-specific T cells (Han et al., Am J Cancer Res 10(3):727-742(2020)). PD-1 binds to B7 protein family members, PD-1 ligand 1 (PD-L1; also known as CD279 and B7-H1), and PD-1 ligand 2 (PD-L2, also known as CD273 and B7-DC). PD-L1 is constitutively expressed on T and B cells, macrophages, and dendritic cells, whereas PD-L2 expression is typically restricted to activated DCs and macrophages (Xing et al., Oncoimmunology 7(3):e1356144(2017)(doi:10.1080 / 2162402X.2017.1356144)). PD-1 inhibits both adaptive and innate immune responses. The PD-1 / PD-L1 axis is involved in suppressing T cell immune responses in cancer. Antagonists of this pathway are being clinically validated in many solid tumor indications. PD-1 inhibitors, such as nivolumab, pembrolizumab, and cemiplimab, and PD-L1 inhibitors, such as atezolizumab, avelumab, and durvalumab, target the PD-1 / PD-L1 pathway and each have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of various cancers. In various embodiments, agents that target PD-L1 (e.g., PD-L1 blocking agents) can be used in the methods disclosed herein to treat DLL3-positive cancers. Exemplary agents that target PD-L1 include anti-PD-L1 antibodies, such as atezolizumab, avelumab, and durvalumab.

[0072] In certain embodiments, the anti-PD-L1 antibody is atezolizumab (International Nonproprietary Name (INN) for Pharmaceutical Substances, WHO Drug Information, Vol. 29, No. 3, 2015, Recommended INN: List 74). Atezolizumab is a humanized PD-L1 blocking antibody. It is an immunoglobulin G1-kappa anti-[Homo sapiens CD274 (Programmed Death Ligand 1, PDL1, PD-L1, B7 Homolog 1, B7H1)] humanized monoclonal antibody; gamma 1 heavy chain (1-448) [humanized VH (Homo sapiens IGHV3-23 * 04(86.70%)-(IGHD)-IGHJ4 * 01) [8.8.11] (1-118) - Homo sapiens IGHG1 * 03 (CH1 R120>K(215)(119~216), hinge(217~231), CH2 N84.4>A(298)(232~341), CH3(342~446), CHS(447~448))(119-448)], (221-214')-disulfide with κ light chain (1'-214') [humanized V-κ (Homo sapiens) IGKV1-5 * 01(87.90%)-IGKJ1 * 01) [6.3.9] (1'-107') - Homo sapiens IGKC * 01(108'-214')]; dimer (227-227":230-230")-bis ​​disulfide. Atezolizumab is commercially available, for example as Tecentriq®.

[0073] In certain embodiments, the anti-PD-L1 antibody is avelumab (International Nonproprietary Name (INN) for Pharmaceutical Substances, WHO Drug Information Vol. 30, No. 1, 2016, Recommended INN: List 75). Avelumab is a PD-L1 blocking monoclonal antibody produced in CHO cells. It is composed of immunoglobulin G1-lambda1, anti-[Homo sapiens CD274 (Programmed Death Ligand 1, PDL1, PD-L1, B7 Homolog 1, B7H1)], Homo sapiens monoclonal antibody; gamma1 heavy chain (1-450) [Homo sapiens VH (IGHV3-23 * 01(90.80%)-(IGHD)-IGHJ4 * 01)[8.8.13](1-120)-IGHG1 * 01, Gm17, 1 (CH1(121-218), hinge(219-233), CH2(234-343), CH3(344-448), CHS(449-450)(121-450)], with λ1 light chain (223-215')-disulfide(1'-216') [Homo sapiens V-λ (IGLV2-14 * 01(99.00%)-IGLJ1 * 01)[9.3.10](1'-110')-IGLC1 * 02(111'-216')]; dimer(229-229):232-232''-bisdisulfide. Avelumab is commercially available, for example as Bavencio®.

[0074] In certain embodiments, the anti-PD-L1 antibody is durvalumab (International Nonproprietary Name (INN) for Pharmaceutical Substances, WHO Drug Information, Vol. 29, No. 3, 2015, Recommended INN: List 74). Durvalumab is a PD-L1 blocking monoclonal antibody produced in CHO cells. It is an immunoglobulin G1-kappa anti-[Homo sapiens CD274 (Programmed Death Ligand 1, PDL1, PD-L1, B7 Homolog 1, B7H1)], Homo sapiens monoclonal antibody; gamma 1 heavy chain (1-451) [Homo sapiens VH (IGHV3-7 * 01(99.00%)-(IGHD)-IGHJ4 * 01)[8.8.14](1-121)-IGHG1 * 03 (CH1(122-219), hinge(220-234), CH2(235-344) L1.3>F(238), L1.2>E(239), P116>S(335), CH3(345-449), CHS(450-451))(122-451)], (224-215')-κ light chain with disulfide(1'-215') [Homo sapiens V-κ (IGKV3-20 * 01(96.90%)-IGKJ1 * 01)[7.3.9](1'-108')-IGKC * 01(109'-215')]; dimer (230-230":233-233")-bis ​​disulfide. Durvalumab is commercially available, for example as Imfinzi®.

[0075] B. Chemotherapeutic agents "Chemotherapeutic agents," also referred to as antineoplastic agents, include compounds useful in the treatment of cancer. Chemotherapeutic agents can be classified according to their mechanism of action and further divided into subgroups within each class. Exemplary classes of chemotherapeutic agents include alkylating agents, antimetabolites, topoisomerase inhibitors, antitumor antibiotics, mitotic inhibitors, and protein kinase inhibitors. Alkylating agents include subgroups such as oxazaphosphorines, nitrogen mustards, imidazotetrazines, nitrosoureas, alkylsulfonates, hydrazines, and platinum-based agents. Platinum-based agents include cisplatin, carboplatin, and oxaliplatin. Topoisomerase inhibitors include topoisomerase I inhibitors and topoisomerase II inhibitors. Mitotic inhibitors include vinca alkaloids, taxanes, and nontaxane microtubule inhibitors. Antitumor antibiotics include bleomycin, actinomycin D (dactinomycin), and mitomycin. Protein kinase inhibitors include BCR-ABL and c-KIT tyrosine kinase inhibitors, EGFR tyrosine kinase inhibitors, ALK tyrosine kinase inhibitors, V600E mutant BRAF oncogene inhibitors, MEK inhibitors, Bruton's kinase inhibitors, Janus kinase inhibitors, and CDK inhibitors.

[0076] In certain embodiments, the chemotherapeutic agent that can be used in the methods disclosed herein is an alkylating agent. In certain embodiments, the alkylating agent is a platinum-based agent, such as cisplatin, carboplatin, or oxaliplatin. In certain embodiments, the alkylating agent is lurbinectedin. Lurbinectedin is commercially available, for example, as Zepzelca™. In certain embodiments, the chemotherapeutic agent that can be used in the methods disclosed herein is a topoisomerase inhibitor, for example, a topoisomerase II inhibitor (e.g., etoposide). In certain embodiments, the chemotherapeutic agent that can be used in the methods disclosed herein includes a platinum-based agent (cisplatin, carboplatin, or oxaliplatin), a topoisomerase II inhibitor (etoposide), or a combination of a platinum-based agent and a topoisomerase II inhibitor.

[0077] 4. Dosing regimens for DLL3-targeted cancer therapy Disclosed herein are methods of treating DLL3-positive cancers (e.g., lung cancer, SCLC, neuroendocrine prostate cancer (NEPC)), comprising administering to a subject in need thereof an agent that targets DLL3, or a combination of an agent that targets DLL3 and PD-L1, and / or a chemotherapeutic agent. The method comprises administering to a subject in need thereof a DLL3-targeting agent, alone or in combination with a PD-L1-targeting agent and / or a chemotherapeutic agent, according to a particular dose / regimen disclosed herein. In certain embodiments, the method further comprises administering to the subject one or more additional therapeutic agents that prevent, reduce, or mitigate the risk of adverse effects associated with administration of the DLL3-targeting agent. In various embodiments, the DLL3-targeting agent is administered by parenteral administration. In various embodiments, the DLL3-targeting agent is administered by intravenous (IV) infusion. Unless otherwise specified herein, the DLL3-targeting agent is administered by bolus IV infusion (e.g., infusion over about 60 minutes). Similarly, the PD-L1-targeting agent is administered by bolus IV infusion, unless otherwise specified.

[0078] Dosage regimen for DLL3-targeting drugs In one aspect, disclosed herein is a method of treating a DLL3-positive cancer, comprising administering to a subject in need thereof an agent that targets DLL3. Agents that target DLL3 include the anti-DLL3 agents disclosed above. In certain embodiments, disclosed herein is a method of treating a DLL3-positive cancer, comprising administering to a subject in need thereof an anti-DLL3 agent at a dose of about 3 mg to about 100 mg twice every three weeks (21 days). In certain embodiments, the anti-DLL3 agent is administered at a dose of about 10 mg to about 100 mg twice every three weeks. In certain embodiments, the anti-DLL3 agent is administered at a dose of about 3 mg, about 10 mg, about 30 mg, 50 mg, about 80 mg, or about 100 mg, particularly about 10 mg, about 30 mg, or about 100 mg twice every three weeks. In certain embodiments, the anti-DLL3 agent is administered on days 1 and 8 of a 21-day cycle.

[0079] In certain embodiments, disclosed herein are methods of treating DLL3 positive cancer, comprising administering to a subject in need thereof an anti-DLL3 agent at a dose of about 6 mg to about 200 mg once every three weeks (21 days, Q3W). In certain embodiments, the anti-DLL3 agent is administered at a dose ranging from about 6 mg to about 50 mg, or about 20 mg to about 100 mg, or about 80 mg to about 150 mg, or about 100 mg to about 200 mg, once every three weeks. In certain embodiments, the anti-DLL3 agent is administered at a dose of about 6 mg, about 20 mg, about 60 mg, about 100 mg, about 180 mg, or about 200 mg, particularly about 20 mg, about 60 mg, or about 200 mg, once every three weeks. In certain embodiments, the anti-DLL3 agent is administered at a dose of about 20 mg once every three weeks. In certain embodiments, the anti-DLL3 agent is administered on day 1 of a 21 day cycle.

[0080] Subjects may be at increased risk of cytokine release syndrome (CRS) during the initiation of treatment with an anti-DLL3 agent (e.g., a DLL3-targeting agent disclosed above) due to its mechanism of action, and a step-dosing approach may be implemented. Thus, in certain embodiments, the anti-DLL3 agent is administered using a step-dosing approach during the initiation of treatment with the agent (e.g., the first cycle of treatment) before the anti-DLL3 agent is administered according to the above-mentioned twice every three weeks or once every three weeks regimen. In such embodiments, the anti-DLL3 is administered in a 21-day cycle during the initiation of treatment (cycle 1) according to the following one-step dosing regimen: a first step-dosing or induction dose on day 1, a step-dosing dose equal to the target dose on day 8, and a target dose on day 15. Alternatively, the anti-DLL3 agent is administered in a 21-day cycle during the initiation of treatment (cycle 1) according to the following: a first dose or induction dose on day 1, a step-up dose equal to the target dose on day 8, and a step-up dose where no anti-DLL3 agent is administered on day 15; or no anti-DLL3 agent is administered on day 1, a first dose or induction dose on day 8, and a step-up dose equal to the target dose on day 15.

[0081] In certain embodiments, the anti-DLL3 agent is administered in 21 day cycles according to the following schedule: a) cycle 1: a first dose of 0 mg or 1 mg on day 1, a second dose on day 8, and a third dose on day 15, b) starting with cycle 2 of the 21 day cycle, one or more subsequent doses administered twice per cycle thereafter, where each of the second, third, and one or more subsequent doses are the same and are between about 3 mg and about 100 mg. ... a) Cycle 1: a first dose of 1 mg on day 1, a second dose on day 8, and a third dose on day 15, b) starting with cycle 2 of a 21 day cycle, one or more subsequent doses administered twice per cycle thereafter, where each of the second, third, and one or more subsequent doses are the same and are about 10 mg to about 100 mg (e.g., 10 mg, 30 mg, or 100 mg). In certain embodiments, an anti-DLL3 agent is administered on days 1 and 8 of cycle 2 and beyond.

[0082] In certain embodiments, the anti-DLL3 agent is administered in 21 day cycles according to the following schedule: a) Cycle 1: a first dose of 0 mg or 1 mg on day 1, a second dose on day 8, and a third dose on day 15; b) starting with cycle 2 of the 21 day cycle, one or more subsequent doses are administered once per cycle thereafter, where each of the second, third and one or more subsequent doses are the same and are between about 6 mg and about 200 mg. In certain embodiments, the anti-DLL3 agent is administered in 21 day cycles according to the following schedule: a) cycle 1: a first dose of 1 mg on day 1, a second dose on day 8, and a third dose on day 15, b) starting with cycle 2 of the 21 day cycle, one or more subsequent doses administered once per cycle thereafter, where each of the second, third, and one or more subsequent doses are the same and are about 20 mg to about 200 mg (e.g., 20 mg, 60 mg, or 200 mg). In certain embodiments, the anti-DLL3 agent is administered on day 1 and thereafter of cycle 2.

[0083] In certain embodiments, the anti-DLL3 agent is administered in 21 day cycles according to the following schedule: a) cycle 1: a first dose of 1 mg on day 1, a second dose on day 8, b) starting with cycle 2 of the 21 day cycle, one or more subsequent doses administered once per cycle thereafter, where each of the second dose and the one or more subsequent doses are the same and are from about 6 mg to about 100 mg (e.g., 20 mg). In such embodiments, the anti-DLL3 agent is not administered on day 15 of cycle 1.

[0084] In certain embodiments, the anti-DLL3 agent is administered in 21 day cycles according to the following schedule: a) cycle 1: a first dose of 1 mg on day 8, a second dose on day 15, b) starting with cycle 2 of the 21 day cycle, one or more subsequent doses administered once per cycle thereafter, where each of the second dose and the one or more subsequent doses are the same and are from about 6 mg to about 100 mg (e.g., 20 mg). In such embodiments, the anti-DLL3 agent is not administered on day 1 of cycle 1.

[0085] In various embodiments, the anti-DLL3 agent is administered parenterally, for example, by bolus IV infusion (e.g., infusion over about 60 minutes). The twice every three weeks and once every three weeks dosing regimens described above can provide improved convenience and flexibility for patients and can improve activity of the anti-DLL3 agent, as compared to twice every two weeks dosing regimens.

[0086] In addition to the step-dosing approach, the anti-DLL3 agent can be administered by IV infusion over an extended period (eIV), e.g., over 2-7 days, during the initiation of treatment of the agent (e.g., cycle 1 of treatment). Compared to bolus IV administration (e.g., IV infusion over about 60 minutes), eIV can achieve similar or higher cumulative serum exposure of the anti-DLL3 agent with a lower Cmax. Thus, eIV can be used to reduce the intensity and / or frequency of symptoms associated with CRS while achieving similar or enhanced pharmacodynamic activity (e.g., efficacy). eIV is also referred to herein as continuous intravenous infusion.

[0087] In certain embodiments, the anti-DLL3 agent is administered using an eIV approach during treatment initiation of the agent (first cycle of treatment) before the anti-DLL3 agent is administered according to the twice every three weeks or once every three weeks regimen described above. In such embodiments, the anti-DLL3 agent is administered in 21 day cycles, where in cycle 1, the anti-DLL3 agent is administered by continuous intravenous infusion starting on day 1 for 2 to 7 days at a dose of about 1 mg to about 200 mg, optionally by bolus intravenous infusion on days 8, 15, or both 8 and 15 at a dose of about 10 mg to about 200 mg.

[0088] In certain embodiments, the anti-DLL3 agent is administered in 21 day cycles according to the following regimen: a) starting with cycle 1 on day 1, the anti-DLL3 agent is administered by continuous intravenous infusion for 2 to 7 days at a dose of about 1 mg to about 200 mg, and b) starting with cycle 2, the anti-DLL3 agent is administered by bolus intravenous infusion thereafter as follows: i) twice every 3 weeks at a dose of about 10 mg to about 100 mg, or ii) once every 3 weeks at a dose of about 20 mg to about 200 mg. In certain embodiments, the anti-DLL3 agent is administered in a) at a dose of about 10 mg to about 100 mg, or about 30 mg to about 100 mg, for 2, 3, 5, or 7 days. In certain embodiments, the anti-DLL3 agent is administered in a) at a dose of about 100 mg to about 200 mg for 2, 3, 5, or 7 days. In certain embodiments, the anti-DLL3 agent is administered in a) at a dose of 30 mg, 50 mg, or 100 mg over 3 days, 5 days, or 7 days. In certain embodiments, the anti-DLL3 agent is administered in a) at a dose of 30 mg or 100 mg over 3 days. In certain embodiments, the method further comprises a) administering the anti-DLL3 agent by bolus IV infusion at a dose of about 10 mg to about 200 mg on days 8, 15, or 8 and 15 of cycle 1.

[0089] In certain embodiments, the anti-DLL3 agent is administered in 28 day cycles according to the following regimen: a) starting with cycle 1 on day 1, the anti-DLL3 agent is administered at a dose of about 1 mg to about 100 mg by continuous intravenous infusion for 2 to 7 days, and b) starting with cycle 2, the anti-DLL3 agent is administered at a dose of about 10 mg to about 100 mg by bolus intravenous infusion once every 2 weeks thereafter. In certain embodiments, the anti-DLL3 agent is administered in a) at a dose of about 10 mg to about 100 mg, or about 30 mg to about 100 mg, for 2, 3, 5, or 7 days. In certain embodiments, the anti-DLL3 agent is administered in a) at a dose of 30 mg, 50 mg, or 100 mg for 3, 5, or 7 days. In certain embodiments, the anti-DLL3 agent is administered in a) at a dose of 30 mg or 100 mg for 3 days. In certain embodiments, the method further includes a) administering an anti-DLL3 agent at a dose of about 10 mg to about 100 mg by bolus IV infusion on days 8, 15, or 8 and 15 of cycle 1.

[0090] The anti-DLL3 agent includes any of the above DLL3 targeting agents. For example, the anti-DLL3 agent includes the amino acid sequence of SEQ ID NO: 13 and 23, or includes or consists of the amino acid sequence of SEQ ID NO: 14, 27, or 32. In various embodiments, the anti-DLL3 agent is AMG 757. In various embodiments, the DLL3 positive cancer includes lung cancer, such as SCLC or NEPC. In certain embodiments, the SCLC is relapsed / refractory SCLC (RR SCLC) or extensive stage SCLC (ED SCLC) or limited stage SCLC. In certain embodiments, the subject is a human with SCLC (e.g., RR SCLC or ED SCLC).

[0091] b. Dosage regimens for agents targeting DLL3 and PD-L1 Disclosed herein is a method of treating DLL3-positive cancer comprising administering to a subject in need thereof a combination of agents targeting DLL3 and PD-L1. Agents targeting DLL3 include anti-DLL3 agents disclosed herein, and agents targeting PD-L1 include anti-PD-L1 antibodies disclosed herein. In one aspect, disclosed herein is a method of treating DLL3-positive cancer comprising administering to a subject in need thereof an anti-DLL3 agent, an anti-PD-L1 antibody, and optionally one or more chemotherapeutic agents, wherein the anti-DLL3 agent is administered once every two weeks at a dose of about 10 mg to about 100 mg. In certain embodiments, the anti-DLL3 agent is administered once every two weeks at a dose of about 10 mg, about 30 mg, about 50 mg, or about 100 mg. In certain embodiments, the anti-DLL3 agent is administered on days 1 and 15 of a 28-day cycle.

[0092] In one aspect, disclosed herein is a method of treating a DLL3 positive cancer comprising administering to a subject in need thereof an anti-DLL3 agent, an anti-PD-L1 antibody, and optionally one or more chemotherapeutic agents, wherein the anti-DLL3 agent is administered twice every three weeks at a dose of about 10 mg to about 100 mg, or once every three weeks at a dose of about 20 mg to about 200 mg. In certain embodiments, the anti-DLL3 agent is administered twice every three weeks at a dose of about 10 mg, about 30 mg, about 50 mg, or about 100 mg, e.g., on days 1 and 8 of a 21 day cycle. In certain embodiments, the anti-DLL3 agent is administered once every three weeks at a dose of about 20 mg to about 100 mg (e.g., about 20 mg, about 60 mg, or about 100 mg), e.g., on day 1 of a 21 day cycle. In certain embodiments, the anti-DLL3 agent is administered at a dose of about 100 mg to about 200 mg (eg, about 120 mg, or about 200 mg) once every three weeks, eg, on day 1 of a 21-day cycle.

[0093] In various embodiments in which an anti-DLL3 agent is administered together with an anti-PD-L1 antibody and optionally one or more chemotherapeutic agents, the anti-DLL3 agent can be administered according to a stepped dosing regimen during initiation of treatment (e.g., cycle 1) to minimize potential adverse effects (e.g., CRS) associated with the anti-DLL3 agent. Thus, in certain embodiments, the anti-DLL3 agent is administered in a 21-day cycle according to the following regimen in cycle 1 of treatment: a first dose of 0 mg or about 1 mg on day 1, a second dose of about 1 mg to about 100 mg on day 8, and a third dose of about 10 mg to about 200 mg on day 15. In certain embodiments, the anti-DLL3 agent is administered according to the following regimen in cycle 1: a first dose of about 1 mg on day 1, a second dose of about 10 mg to about 100 mg on day 8, and a third dose of about 10 mg to about 100 mg on day 15. In certain embodiments, the anti-DLL3 agent is administered according to the following regimen for Cycle 1: a first dose of about 1 mg on day 1, a second dose of about 10 mg to about 100 mg on day 8, and a third dose of about 20 mg to about 200 mg on day 15. Each of the Cycle 1 regimens can be used prior to the once every 2 weeks, twice every 3 weeks, or once every 3 weeks regimen of the anti-DLL3 agent described above.

[0094] In certain preferred embodiments in which an anti-DLL3 agent is administered in combination with an anti-PD-L1 agent and optional chemotherapy, the anti-DLL3 agent is administered in a 21 day cycle according to the following regimen in cycle 1 of treatment: a first dose of about 1 mg is administered on day 1, a second dose of about 10 mg to about 100 mg (e.g., 20 mg) is administered on day 8, and no anti-DLL3 agent is administered on day 15. Alternatively, the anti-DLL3 agent is administered in a 21 day cycle according to the following regimen in cycle 1 of treatment: no anti-DLL3 agent is administered on day 1, a first dose of about 1 mg is administered on day 8, and a second dose of about 10 mg to about 100 mg (e.g., 20 mg) is administered on day 15. In such embodiments, the anti-PD-L1 agent (durvalumab or atezolizumab) is administered first, followed by one or more chemotherapy agents and, if administered on the same day, the anti-DLL3 agent.

[0095] In certain embodiments, disclosed herein are methods of treating a DLL3 positive cancer comprising administering to a subject in need thereof an anti-DLL3 agent, an anti-PD-L1 antibody, and optionally one or more chemotherapeutic agents, wherein the anti-DLL3 agent is administered according to the following regimen: a) Cycle 1 (21 days): a first dose of about 1 mg on day 1, a second dose on day 8, and a third dose on day 15; b) Cycle 2 and Cycle 3 (each cycle being 21 days): a fourth dose on day 1 and a fifth dose on day 8 of each cycle; and c) starting with Cycle 4, one or more subsequent doses once every two weeks for each subsequent 28 day cycle, wherein the second, third, fourth, fifth and one or more subsequent doses are the same and are each about 10 mg to about 100 mg (e.g., about 10 mg, about 30 mg, or about 100 mg).

[0096] In certain embodiments, disclosed herein are methods of treating DLL3 positive cancer, comprising administering to a subject in need thereof an anti-DLL3 agent, an anti-PD-L1 antibody, and optionally one or more chemotherapeutic agents, wherein the anti-DLL3 agent is administered in 21 day cycles according to the following regimen: a) Cycle 1: a first dose of about 1 mg on day 1, a second dose on day 8, and a third dose on day 15; b) Cycle 2 and Cycle 3: a fourth dose on day 1 and a fifth dose on day 8 of each cycle; and c) starting with Cycle 4, one or more subsequent doses once every three weeks thereafter, wherein the second, third, fourth, and fifth doses are the same, each being about 10 mg to about 100 mg (e.g., about 10 mg, about 30 mg, or about 100 mg), and one or more subsequent doses are the same, each being about 20 mg to about 200 mg (e.g., about 20 mg, about 60 mg, or about 200 mg).

[0097] In certain embodiments, disclosed herein are methods of treating DLL3 positive cancer, comprising administering to a subject in need thereof an anti-DLL3 agent, an anti-PD-L1 antibody, and optionally one or more chemotherapeutic agents, where the anti-DLL3 agent is administered in 21 day cycles according to the following regimen: a) Cycle 1: a first dose of about 1 mg on day 1, a second dose of about 10 mg to about 100 mg on day 8, and a third dose on day 15; b) Cycle 2 and Cycle 3: a fourth dose on day 1 of each cycle, and c) starting with Cycle 4, one or more subsequent doses once every three weeks thereafter, where the third, fourth, and one or more subsequent doses are the same and are each about 20 mg to about 200 mg (e.g., about 20 mg, about 60 mg, or about 200 mg).

[0098] In certain embodiments, disclosed herein are methods of treating DLL3 positive cancer, comprising administering to a subject in need thereof an anti-DLL3 agent, an anti-PD-L1 antibody, and optionally one or more chemotherapeutic agents, where the anti-DLL3 agent is administered in 21 day cycles according to the following regimen: a) Cycle 1: a first dose of about 1 mg on day 1, a second dose of about 10 mg to about 100 mg (e.g., about 20 mg) on ​​day 8, b) Cycle 2 and Cycle 3: a third dose on day 1 of each cycle, and c) starting with Cycle 4, one or more subsequent doses once every three weeks thereafter, where the third and one or more subsequent doses are the same and are each about 10 mg to about 100 mg (e.g., about 20 mg), each subsequent dose being about 10 mg to about 100 mg.

[0099] In certain embodiments, disclosed herein are methods of treating DLL3 positive cancer, comprising administering to a subject in need thereof an anti-DLL3 agent, an anti-PD-L1 antibody, and optionally one or more chemotherapeutic agents, where the anti-DLL3 agent is administered in 21 day cycles according to the following regimen: a) Cycle 1: a first dose of about 1 mg on day 8, a second dose of about 10 mg to about 100 mg (e.g., 20 mg) on ​​day 15, b) Cycle 2 and Cycle 3: a third dose on day 1 of each cycle, and c) starting with Cycle 4, one or more subsequent doses once every three weeks thereafter, where the third and one or more subsequent doses are the same and are each about 10 mg to about 100 mg (e.g., about 20 mg).

[0100] In various embodiments in which the anti-DLL3 agent is administered together with an anti-PD-L1 antibody and optionally one or more chemotherapeutic agents, the anti-PD-L1 antibody is a PD-L1 blocking antibody. Examples of such anti-PD-L1 antibodies include atezolizumab, durvalumab, and avelumab. In certain embodiments, the anti-PD-L1 antibody is atezolizumab or durvalumab. In certain embodiments, the anti-PD-L1 antibody is durvalumab. When used in the methods disclosed herein, the dose and regimen of the anti-PD-L1 antibody are the same as those approved by regulatory authorities (e.g., FDA). For example, atezolizumab can be administered at a dose of about 840 mg every 2 weeks, or about 1200 mg every 3 weeks, or about 1680 mg every 4 weeks. For example, durvalumab can be administered at a dose of about 10 mg / kg every 2 weeks, or about 1500 mg every 3 weeks, or about 1500 mg every 4 weeks.

[0101] In various embodiments in which an anti-DLL3 agent is administered together with an anti-PD-L1 antibody and optionally one or more chemotherapeutic agents, the one or more chemotherapeutic agents include an alkylating agent, a topoisomerase inhibitor, or a combination thereof. In certain embodiments, the one or more chemotherapeutic agents include a platinum-based agent (e.g., cisplatin, carboplatin, or oxaliplatin), a topoisomerase II inhibitor (e.g., etoposide), or a combination thereof. In certain embodiments, the one or more chemotherapeutic agents include cisplatin or carboplatin and etoposide. In certain embodiments, the one or more chemotherapeutic agents are etoposide. In various embodiments, the one or more chemotherapeutic agents are administered according to a dose and / or regimen approved by a regulatory agency (e.g., FDA). For example, in various embodiments, carboplatin is administered at a dose sufficient to achieve AUC=5 mg / ml / min and etoposide is administered at a dose sufficient to achieve AUC=100 mg / m 2 is administered at a dose of

[0102] The anti-DLL3 agent includes any of the above DLL3 targeting agents. For example, the anti-DLL3 agent includes the amino acid sequence of SEQ ID NO: 13 and 23, or includes or consists of the amino acid sequence of SEQ ID NO: 14, 27, or 32. In various embodiments, the DLL3 positive cancer includes lung cancer, such as SCLC or NEPC. In certain embodiments, the SCLC is relapsed / refractory SCLC (RR SCLC) or extensive stage SCLC (ED SCLC) or limited stage SCLC. In certain embodiments, the subject is a human with SCLC, such as RR SCLC or ED SCLC or limited stage SCLC.

[0103] In various embodiments, the anti-DLL3 agent, the anti-PD-L1 antibody, and any one or more chemotherapeutic agents are each administered by IV infusion, hi certain embodiments, the anti-DLL3 agent is administered after the administration of the anti-PD-L1 antibody and the one or more chemotherapeutic agents if they are administered on the same day.

[0104] In various embodiments disclosed herein, "combination therapy" or "in combination with" refers to the administration of one therapeutic modality (e.g., an anti-DLL3 agent) in addition to another therapeutic modality (e.g., an anti-PD-L1 antibody and optionally one or more chemotherapeutic agents) to a subject (e.g., a human) with a DLL3-positive cancer. In combination therapies involving an anti-DLL3 agent and an anti-PD-L1 antibody, one therapeutic modality can be administered before, during, or after the administration of the other therapeutic modality to the subject. However, such combination therapy does not include situations in which 28 days or more elapse between the end of administration of one therapeutic modality and the start of administration of another therapeutic modality.

[0105] c. Anti-DLL3 agent and chemotherapy drug dosing regimen Disclosed herein is a method for treating DLL3 positive cancer, comprising administering to a subject in need thereof a combination of an anti-DLL3 agent and one or more chemotherapeutic agents.The agent that targets DLL3 includes the anti-DLL3 agent disclosed herein, and the chemotherapeutic agent includes the alkylating agent disclosed herein.In certain embodiments, the alkylating agent is lurbinectedin.

[0106] In certain embodiments, disclosed herein are methods of treating DLL3 positive cancer, comprising administering to a subject in need thereof an anti-DLL3 agent and an alkylating agent, wherein the anti-DLL3 agent is administered to the subject once every two weeks at a dose of about 10 mg to about 200 mg (e.g., 10 mg, 20 mg, 60 mg, or 100 mg). In certain embodiments, the anti-DLL3 agent is administered twice every three weeks at a dose of about 10 mg to about 100 mg (e.g., 10 mg, 20 mg, 60 mg, or 100 mg). In certain embodiments, the anti-DLL3 agent is administered once every three weeks at a dose of about 20 mg to about 200 mg (e.g., 20 mg, 60 mg, 100 mg, or 200 mg). In certain embodiments, the anti-DLL3 agent is administered on day 1 of a 21-day cycle. In various embodiments, the alkylating agent is lurbinectedin.

[0107] In certain embodiments, the methods include administering to a subject in need thereof an anti-DLL3 agent and an alkylating agent, where the anti-DLL3 agent is administered to the subject in a 21 day cycle according to the following: a first dose of 0 mg or about 1 mg on day 1, a second dose of about 10 mg to about 100 mg on day 8, a third dose of about 10 mg to about 200 mg on day 15, and one or more subsequent doses of about 10 mg to about 200 mg starting on day 22 and once every three weeks thereafter. In certain embodiments, the first dose is 1 mg, the second dose is 10 mg to 100 mg (e.g., 10 mg, 20 mg, 60 mg, or 100 mg), the third dose is 10 mg to 200 mg (e.g., 10 mg, 20 mg, 60 mg, 100 mg, or 200 mg), and one or more subsequent doses are the same and are the same as the third dose (e.g., 10 mg, 20 mg, 60 mg, 100 mg, or 200 mg). In certain embodiments, the method includes administering only an alkylating agent in cycle 1 and cycle 2, and administering an alkylating agent and an anti-DLL3 agent in cycle 3 and beyond. In various embodiments, the alkylating agent is lurbinectedin. In various embodiments, lurbinectedin is administered according to a dose and / or regimen approved by a regulatory agency (e.g., FDA), e.g., at about 3.2 mg / m once every three weeks. 2 , 2.6 mg / m 2 , or 2 mg / m 2 can be administered at a dose of

[0108] Anti-DLL3 agents include any of the DLL3 targeting agents described above. For example, anti-DLL3 agents include the amino acid sequences of SEQ ID NOs: 13 and 23, or include or consist of the amino acid sequences of SEQ ID NOs: 14, 27, or 32.

[0109] In various embodiments, the DLL3 positive cancer includes lung cancer, such as SCLC. In certain embodiments, the SCLC is relapsed / refractory SCLC (RR SCLC) or extensive stage SCLC (ED SCLC). In certain embodiments, the subject is a human with SCLC (e.g., RR SCLC or ED SCLC).

[0110] In various embodiments, the anti-DLL3 agent and the alkylating agent (e.g., lurbinectedin) are each administered by IV infusion. In certain embodiments, the anti-DLL3 agent is administered after administration of the alkylating agent if administered on the same day.

[0111] In various embodiments disclosed herein, "combination therapy" or "in combination with" refers to the administration of one therapeutic modality (e.g., an anti-DLL3 agent) in addition to another therapeutic modality (e.g., an alkylating agent such as lurbinectedin) to a subject (e.g., a human) with a DLL3-positive cancer. In combination therapies involving an anti-DLL3 agent and lurbinectedin, one therapeutic modality can be administered before, during, or after the other therapeutic modality is administered to the subject. However, such combination therapy does not include situations in which 28 days or more elapse between the end of administration of one therapeutic modality and the start of administration of another therapeutic modality.

[0112] 5. Additional Therapeutic Agents In some embodiments, the methods disclosed herein further include the use of one or more additional therapeutic agents to prevent, reduce, or mitigate the risk of adverse effects associated with administration of an anti-DLL3 agent alone or in combination with an anti-PD-L1 antibody and / or a chemotherapeutic agent. The main adverse effect associated with the use of an anti-DLL3 agent is CRS. One or more additional therapeutic agents useful for preventing, reducing, or mitigating the risk of CRS include corticosteroids (e.g., dexamethasone), fluids (e.g., saline), and anti-IL6 antibodies (e.g., tocilizumab or siltuximab). Dexamethasone may be administered by IV administration prior to all cycle 1 doses of an anti-DLL3 agent (e.g., AMG 757), including all step doses, saline (e.g., 1 liter) may be administered IV after all cycle 1 doses of an anti-DLL3 agent (e.g., AMG 757), and anti-IL6 antibodies (e.g., tocilizumab or siltuximab) may be administered as needed (e.g., to subjects not responsive to IV fluids). Further corticosteroid prophylaxis with oral dexamethasone may be administered as needed. Exemplary doses of dexamethasone include 8 mg / administration (maximum 24 mg / day). Exemplary doses of tocilizumab include 8 mg / kg (not to exceed 800 mg). Symptoms of CRS include fever, nausea, fatigue, headache, myalgia, malaise, and therapeutic agents useful for treating these symptoms (e.g., paracetamol / acetaminophen for fever) may also be used. In certain embodiments, one or more additional therapeutic agents that may also be used to reduce or alleviate adverse effects associated with anti-DLL3 agent therapy include granulocyte colony stimulating factors (e.g., filgrastim or pegfilgrastim).

[0113] Thus, in certain embodiments, the methods disclosed herein further comprise administering one or more additional therapeutic agents selected from a corticosteroid (e.g., prednisone, hydrocortisone, and dexamethasone), a fluid (saline), and an anti-IL6 antibody (e.g., tocilizumab or siltuximab). In certain embodiments, the methods further comprise one or more additional therapeutic agents selected from a corticosteroid (e.g., dexamethasone), a fluid (saline), and tocilizumab or siltuximab. In certain embodiments, one or more of the corticosteroid, fluid, and tocilizumab are administered in cycle 1 in which the anti-DLL3 agent (e.g., AMG 757) is administered.

[0114] In certain embodiments of any one of the methods of administering one or more additional therapeutic agents, the subject is a human.

[0115] 6.Treatment success The efficacy of the disclosed methods for treating DLL3-positive cancers (such as SCLC) may be evaluated by various clinical outcomes, endpoints, and / or measurements. In this regard, clinical outcomes that may be evaluated include, but are not limited to, progression-free survival (PFS), overall survival (OS), objective response (ORR), disease control rate (DCR), and duration of response (DOR). As used herein, the term "progression-free survival (PFS)" refers to the time from randomization to first evidence of disease progression or death. As used herein, the term "overall survival (OS)" refers to the time from randomization to death. As used herein, the term "objective response rate (ORR)" is a measure of how a particular treatment affects the tumor burden in patients with a history of solid tumors and refers to the proportion of patients who respond partially or completely to the treatment. As used herein, the term "duration of response (DoR)" refers to the time from randomization to disease progression or death in patients who achieve a complete or partial response. As used herein, the term "disease control rate (DCR)" refers to the proportion of patients with advanced cancer in whom a therapeutic intervention resulted in a complete response, partial response, or stable disease. Clinical endpoints for cancer treatment are further described, for example, in Delgado A. and Guddati, AK, et al., Am J Cancer Res 2021;11(4):1121-1131.

[0116] In some embodiments, the disclosed methods desirably increase one or more of progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and / or disease control rate (DCR) and duration of response (DOR) compared to standard of care (SOC). For example, when an anti-DLL3 agent is used as a first-line treatment for SCLC (e.g., an anti-DLL3 agent in combination with an anti-PD L1, and optionally a chemotherapy agent, treating a patient who has not received prior systemic therapy), the disclosed methods desirably result in an ORR of at least about 65% (e.g., about 65% to about 70%), a median PFS of greater than about 5 months (e.g., 7 months or more), and a median OS of at least about 13 months, e.g., about 13-15 months or about 16-18 months. When the anti-DLL3 agent is administered as a third-line treatment for SCLC (e.g., anti-DLL3 agent monotherapy to treat patients who have received two or more prior therapies and have relapsed), the method desirably results in an ORR of at least about 20% (e.g., about 24% or more), a median PFS of greater than about 6 months, and a median OS of at least about 7.5 months (e.g., 8 months or more).

[0117] 7. Manufactured articles Disclosed herein is an article of manufacture that includes: (a) a container containing an anti-DLL3 agent (e.g., AMG 757); and (b) a package insert having instructions for treating a DLL3 positive cancer (or treating SCLC or NEPC) in a subject by administering the anti-DLL3 agent (e.g., AMG 757), the instructions providing for administering the anti-DLL3 agent to the subject at a dose of about 10 mg to about 100 mg (e.g., 10 mg, 30 mg, or 100 mg) twice every three weeks, e.g., on days 1 and 8 of a 21 day cycle. In certain embodiments, the instructions provide for administering the anti-DLL3 agent to the subject at a dose of about 20 mg to about 200 mg (e.g., 20 mg, 60 mg, 100 mg, 160 mg, or 200 mg) once every three weeks, e.g., on day 1 of a 21 day cycle. In certain embodiments, the instructions further specify that in a first cycle in which the anti-DLL3 agent is administered to the subject, the anti-DLL3 agent is administered by extended intravenous infusion over 2-7 days (e.g., over 3 days). In certain embodiments, the instructions further specify that the anti-DLL3 agent is administered in cycle 1 (a 21 day cycle) according to a one-stage dosing regimen: 1 mg on day 1, a second dose on day 8, and a third dose on day 15, wherein the second and third doses are the same and are each about 10 mg to about 100 mg.

[0118] In certain embodiments, the article of manufacture includes: (a) a container containing an anti-DLL3 agent (e.g., AMG 757); and (b) a mailing with instructions for treating a DLL3 positive cancer (or treating SCLC) in a subject by administering to the subject the anti-DLL3 agent (e.g., AMG 757) in combination with an anti-PD-L1 antibody (e.g., atezolizumab or durvalumab), the instructions specifying administering the anti-DLL3 agent to the subject at a dose of about 20 mg to about 200 mg (e.g., 20 mg, 60 mg, 100 mg, 160 mg, or 200 mg) once every three weeks, e.g., on day 1 of a 21 day cycle. In certain embodiments, the instructions specify administering to the subject at a dose of about 10 mg to about 100 mg twice every three weeks, e.g., on days 1 and 8 of a 21 day cycle. In certain embodiments, the instructions provide for administering the anti-DLL3 agent to the subject at a dose of about 10 mg to about 100 mg once every two weeks, e.g., on days 1 and 15 of a 28-day cycle. In certain embodiments, the instructions further provide for one or more chemotherapeutic agents (e.g., carboplatin or cisplatin and / or etoposide) to be administered to the subject in combination with the anti-DLL3 agent and the anti-PD-L1 agent. In various embodiments, the package insert may provide for the administration of the anti-DLL3 agent (e.g., AMG 757) in combination with chemo-immunotherapy, followed by a maintenance cycle of the anti-DLL3 agent plus the anti-PD-L1 agent. Alternatively, the package insert may provide for the administration of the anti-DLL3 agent (e.g., AMG 757) in combination with the anti-PD-L1 agent as maintenance therapy only following standard of care chemo-immunotherapy. In embodiments in which the anti-DLL3 agent and the anti-PD-L1 agent are used as maintenance therapy only, the package insert may further specify that subjects who have received at least four (e.g., 4-6 cycles) of platinum-based chemotherapy, etoposide, and an anti-PD-L1 agent and have not experienced disease progression are eligible, as well as subjects who have received 4-6 cycles of platinum-based chemotherapy and etoposide without access to a first-line anti-PD-L1 agent. Additionally, for maintenance therapy only, the package insert may further specify that day 1 of cycle 1 of treatment begins within 8 weeks of the start of the last cycle of chemotherapy.The package insert may further specify that prophylactic cranial radiation is permitted if radiation is completed at least 7 days prior to day 1 of cycle 1 when the anti-DLL3 agent is administered and the subject does not require steroids for management of central nervous system (CNS) symptoms.

[0119] In various embodiments, the package insert may further instruct to hospitalize and monitor the subject for up to about 48 hours (e.g., about 24 hours, 12 hours, or 8 hours) after administration of the anti-DLL3 agent (e.g., AMG 757) on cycle 1 and / or cycle 2. For example, the package insert may instruct to hospitalize and monitor the subject for up to about 48 hours (e.g., about 24 hours, 12 hours, or 8 hours) after the first two or three doses of the anti-DLL3 agent on cycle 1. In various embodiments, the package insert may further instruct to measure or test the subject's one or more cytokines (e.g., levels of one or more cytokines in the subject's blood or serum), such as IL-6, IL-8, IL-10, TNF-α, and IFN-g, after administration of the anti-DLL3 agent (e.g., AMG 757) on cycle 1, and if any of the levels of any of the cytokines are above normal baseline levels, to hospitalize and monitor the subject for up to about 48 hours (e.g., about 24 hours, 12 hours, or 8 hours). For example, the package insert may instruct to measure or test the subject's IL-10 after administration of an anti-DLL3 agent (e.g., AMG 757) in cycle 1, and if the level of IL-10 is above normal baseline levels, to hospitalize and monitor the subject for up to about 48 hours (e.g., about 24 hours, 12 hours, or 8 hours). Cytokines can be measured or tested using methods known in the art.

[0120] In certain embodiments, the article of manufacture includes: (a) a container containing an anti-DLL3 agent (e.g., AMG 757); and (b) a package insert having instructions for treating a DLL3 positive cancer (or treating SCLC) in a subject by administering the anti-DLL3 agent (e.g., AMG 757) in combination with an alkylating agent (e.g., lurbinectedin), the instructions specifying that the anti-DLL3 agent is administered to the subject at a dose of about 20 mg to about 200 mg (e.g., 20 mg, 60 mg, 100 mg, 160 mg, or 200 mg) once every three weeks, e.g., on day 1 of a 21-day cycle.

[0121] In various embodiments, the container comprises an amount of the anti-DLL3 agent (e.g., AMG 757) of about 1 mg, 5 mg, 10 mg, or 25 mg, e.g., the anti-DLL3 agent is supplied as a sterile, single-use, preservative-free, lyophilized formulation containing 1, 5, 10, or 25 mg of anti-DLL3 agent per container (e.g., vial). In various embodiments, the instructions specify that the lyophilized formulation is to be reconstituted with sterile water for injection. In various embodiments, the instructions specify that the subject is a human (e.g., a human with SCLC).

[0122] 8. Target In various cases of the methods disclosed herein, the subject is a human subject. In exemplary embodiments, the human subject has a DLL3-positive cancer. In exemplary embodiments, the DLL3-positive cancer is small cell lung cancer (SCLC) or neuroendocrine prostate cancer (NEPC). In exemplary cases, the human subject has SCLC, optionally histologically or cytologically confirmed SCLC. In various aspects, the human is male or female and / or is 18 years of age or older with SCLC. In exemplary aspects, the human subject has undergone platinum-based chemotherapy. In exemplary aspects, the human subject optionally has RR SCLC that has progressed or relapsed after at least one platinum-based chemotherapy with or without a PD-L1 inhibitor. In exemplary aspects, the human subject has ES-SCLC, optionally histologically or cytologically confirmed ES SCLC. In exemplary aspects, the human subject has ES-SCLC and has not received prior systemic treatment for ES-SCLC. In exemplary cases, the human subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 (Oken et al., Am J Clin Oncol 5:649-655 (1982)). In various embodiments, the human subject has one or more brain metastases that are undergoing treatment. In various embodiments, the human subject has liver metastases. In various embodiments, the platinum-based chemotherapy comprises carboplatin or cisplatin or platinum-irinotecan. In other exemplary examples, the human subject has NEPC, such as metastatic de novo or treatment-emerging NEPC. Optionally, the subject has received at least one prior systemic treatment including a platinum-containing regimen for de novo NEPC (having no prior diagnosis or treatment of prostate cancer at the time of NEPC diagnosis) or an androgen signaling inhibitor (e.g., abiraterone, enzalutamide, darolutamide and / or apalutamide) if treatment-emerging (having a prior diagnosis of prostate cancer prior to NEPC diagnosis).

[0123] 9. Cancer In various embodiments, the cancer treated by the methods of the present disclosure is a DLL3 positive cancer (e.g., SCLC and NEPC). In various examples, the cancer treated by the methods of the present disclosure is a lung cancer, such as small cell lung cancer (SCLC). In an exemplary embodiment, the SCLC is a histologically or cytologically confirmed SCLC. Optionally, the SCLC is measurable by modified Response Criteria in Solid Tumors (RECIST) 1.1, where measurable lesions include (a) non-nodal lesions with clear boundaries that can be precisely and continuously measured in one dimension of the axial plane (longest diameter ≧10 mm measured by magnetic resonance imaging / computed tomography (MRI / CT) with a scan slice thickness ≦5 mm) and / or (b) nodal lesions with a longest diameter ≧15 mm perpendicular to the long axis (short axis) on MRI / CT, ​​and / or exclude simple cysts, pleural / pericardial effusions, and ascites. In various embodiments, the cancer treated by the methods of the present disclosure is neuroendocrine prostate cancer (NEPC), such as metastatic de novo or therapeutically emerging NEPC. In exemplary embodiments, NEPC is histologically diagnosed small cell NEPC or prostate cancer with neuroendocrine differentiation defined by positive immunohistochemical staining for chromogranin and / or synaptophysin in the majority of tumor samples, or alterations in two or more of Tp53, RB1, and / or PTEN by immunohistochemistry (IHC) or genomic analysis of baseline tumor tissue or circulating tumor DNA (ctDNA). EXAMPLES

[0124] Example 1 Clinical trial using AMG 757 Study 20160232 is an open-label, escalation, multiple-dose Phase 1 study evaluating AMG 757 in subjects with SCLC. The study has two indications: A: recurrent / refractory small cell lung cancer (RR SCLC), and B: extensive stage SCLC (ED SCLC).

[0125] Primary endpoints: dose-limiting toxicities (DLTs), treatment-emergent adverse events (AEs), treatment-related AEs, and clinically significant changes in vital signs, ECGs, physical examinations, and laboratory tests.

[0126] Secondary Endpoints: For Indications A and B: (1) PK parameters of AMG 757 following intravenous administration, including but not limited to maximum observed concentration (C max ), minimum observed concentration (C min ), area under the concentration-time curve (AUC) over a 2-week dosing interval, accumulation after multiple doses, and, where available, half-life (t 1 / 2 ), (2) objective response (OR) according to modified Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, (3) duration of response (DOR), (4) 1-year progression-free survival (PFS), and (5) 1-year overall survival (OS). For indication B only: recurrence-free survival (RFS).

[0127] Exploratory Endpoints: For indications A and B: (1) Incidence of anti-AMG 757 antibody formation, (2) Changes in protein, nucleic acid and cellular biomarkers in blood (e.g., cytokines, lymphocyte status, CTCs, sDLL3), (3) Cell surface protein expression (e.g., DLL3) and tumor infiltrating lymphocyte status in tumor tissue at baseline. For indication B only: Effect of prior chemotherapy on T cell cytokine production prior to AMG 757 treatment. Incidence of CRS (only in the portion evaluating CRS mitigation strategies).

[0128] Key eligibility criteria for Study 20160323 are summarized in Table 3 below.

[0129] [Table 3-1]

[0130] AMG 757 (0.003-100.0 mg) was administered intravenously every 2 weeks ± stepwise to patients with SCLC that had progressed after one or more platinum-based regimens. Antitumor activity was assessed using modified RECIST 1.1. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Tumor DLL3 expression was assessed by immunohistochemistry. T-cell activation and cytokine profiles were evaluated. Administration of AMG 757 or tarlatamab continued until disease progression, unacceptable side effects, or withdrawal of consent.

[0131] The analysis included patients enrolled in the escalation and expansion cohorts. The data cutoff was July 19, 2022. A two-parameter Bayesian logistic regression model (BLRM) model guided dose exploration. Safety data were reviewed continuously. At dose-level review meetings (DLRMs), the sponsor, in consultation with the site investigators, reviewed all available cumulative data by BLRM-recommended dose level and cohort before making dose escalation decisions. AEs and DLTs observed in all subjects were evaluated continuously and fully integrated into all DLRMs. Based on the overall benefit-risk profile of 100 mg, we elected to further evaluate this as an expansion dose. Descriptive statistics are provided for selected demographic, safety, pharmacokinetic (PK), pharmacodynamic, and biomarker data. Kaplan-Meier methods were used to estimate median and percentile times to event endpoints with confidence intervals (CIs) calculated using the Brookmeyer and Crowley method.

[0132] The maximum tolerated dose (MTD) is the highest dose considered safe as determined jointly by the investigator and study team taking into account the Bayesian logistic regression model (BLRM).

[0133] Adverse events were graded using the Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. CRS events were graded using the Lee criteria.

[0134] Additionally, cytokine release syndrome (CRS), neutropenia, and neurological events were monitored as events of interest in this study using the Amgen MedDRA Query narrow (AMQN) search approach. All events were coded using MedDRA version 24.1. Cytokine release syndrome by AMQN search includes cytokine abnormality, cytokine release syndrome, cytokine storm, and cytokine test. CRS events were graded using the CRS Lee et al. (2014) criteria. Neutropenia was graded using CTCAE version 4.0 based on the AMQN search. Neurological events were graded using CTCAE version 4.0 based on the "Central neuropsychiatric events due to direct neurotoxicity" AMQN search.

[0135] The efficacy data disclosed herein was based on local investigator assessment. Patients were defined as evaluable for efficacy if the data cutoff date was at least 9 weeks after the first dose date to allow time for evaluation.

[0136] Exploratory analyses of T cell and peripheral cytokines were performed on serially collected blood samples.

[0137] For immunogenicity assessment, blood samples from patients receiving tarlatamab were collected on study day 1 (pre-dose) and at multiple time points during the study for detection of anti-tarlatamab binding antibodies using a validated electrochemiluminescence bridging immunoassay.

[0138] Immune cell and cytokine analysis Whole blood samples collected in EDTA tubes were collected according to the evaluation schedule specified in the study protocol. Flow cytometry validation panels were used to stain whole blood samples using fluorescently labeled antibodies CD4 BV510 (clone SK3, BD Biosciences), CD8 BV605 (clone SK1, BD Biosciences), CD3 Alexa Fluor 700 (clone SK7, BioLegend), and CD279 (PD-1) BB515 (clone EH12.1, BD Biosciences). Data were acquired centrally at Q2 Solutions Laboratories Europe on a BD FACSCanto flow cytometer. To assess cytokine production, serum samples were collected and IFNγ levels were assessed using a Meso Scale Discovery (MSD) V-plex pro-inflammatory panel 1. The assay was performed according to the manufacturer's instructions. Briefly, samples were diluted 1:2 in diluent 2 (MSD). Diluted samples and standards were added in duplicate to a 96-well plate containing capture antibodies independently pre-coated on 10 defined spots and incubated for 2 hours at ambient temperature. The plate was washed 3 times with wash buffer, detection antibody mixture was added to each well, and the plate was incubated for 2 hours at ambient temperature. The plate was washed 3 times with wash buffer, 2x Read Buffer T (MSD) was added to each well, and read on an MSD plate reader. Concentrations were extrapolated from a standard curve within an established range of 2.61-542,720 pg / mL.

[0139] Characterization of Cytokine Release Syndrome (CRS) An analysis was performed to examine the correlation between cytokine levels within 24 hours after the first dose of tarlatamab and the occurrence of CRS in cycle 1. Cohorts receiving 1 mg of tarlatamab as the first dose and 1–100 mg in subsequent doses in cycle 1 were included in this analysis.

[0140] Serum was collected for cytokine analysis at time points up to 24 hours. Incidence, time to onset, severity, management, and recurrence of CRS were assessed. Serum peak levels and rate of rise within 24 hours after the first dose of talutamab were evaluated for a range of soluble factors in patients with CRS vs. those without CRS in cycle 1. Patients from the 1 mg initial dose cohort were included.

[0141] Kruskal Wallis (KW) rank-based test with false discovery rate correction was used to identify whether analyte values ​​from the CRS and no CRS categories were derived from different distributions. Jonckheere-Terpstra (JT) trend test with false discovery rate correction was used to identify increasing trends in analyte values ​​from no CRS to CRS buckets. Univariate logistic regression was used to determine whether the rate of expansion and peak of each analyte predicted the occurrence of CRS at cycle 1 after dosing.

[0142] result As of July 19, 2022, 107 patients have received tarlatamab in the dose escalation (0.003–100 mg; n=73) and expansion (100 mg; n=34) cohorts (Figure 1). Stepwise dosing was utilized starting with the 3 mg cohort (using 1 mg as an induction dose, followed by target doses on days 8, 15, and Q2W thereafter) due to cytokine release syndrome (CRS) observed in the previous cohort. Cytokine release syndrome (CRS) is an expected risk of tarlatamab due to its mechanism of action (MOA).

[0143] Baseline characteristics are summarized in Table 3. Median age was 63 years (range, 32–80). ECOG performance status was 0–1 in 99% of patients. More than 70% had received two or more prior lines of therapy, 25% were platinum-refractory, and 50% had received prior PD-1 / PD-L1 inhibitors.

[0144] Median follow-up was 8.7 months (range, 0.2-31.8). Treatment was discontinued in 92 patients (86%), most commonly due to disease progression (n=77 [72%]). At data cutoff, 47 patients (43.9%) had discontinued the study due to death. The median number of treatment cycles initiated was 3 (interquartile range [IQR]: 1, 8) and the median number of doses of talutamab administered was 6 (IQR: 3, 16).

[0145] [Table 3-2]

[0146] [Table 3-3]

[0147] Retrospective DLL3 immunohistochemistry was performed on fresh or archived biopsies as described above. DLL3 was expressed (≥1%) in 85 (94%) of 90 evaluable patients. The median H-score was 186 (range, 0-300), and the median tumor cell positivity was 95% (range, 0-100%).

[0148] Safety and Tolerability DLTs occurred in six patients, including pneumonitis (n=1 [previous dose 0.3 mg]), increased alanine aminotransferase (n=1 [1 mg]), CRS (n=1 [1 mg]), encephalopathy (n=1 [10 mg]), chills, fever, and neutropenia (n=1 each [100 mg]). The maximum tolerated dose (MTD) was not reached, and the highest dose (100 mg) was evaluated in the expansion cohort. Four patients (3.7%) discontinued talutamab due to AEs of encephalopathy (n=1), immune effector cell-associated neurotoxicity (ICANS) (n=1), and pneumonitis (n=2), all of which were treatment-related. A single G5 pneumonitis event was recorded in a 70-year-old man with a history of previous carboplatin / etoposide chemotherapy, chronic obstructive pulmonary disease, and radiation to lung and pleural nodules. The onset of the event was on day 18 of cycle 1, 3 days after the second taluratamab treatment (both at a dose of 0.3 mg), and was confounded by clinically significant disease progression at the time of pneumonitis requiring urgent palliative radiation to a soft tissue mass of the thoracic spine causing lung and spinal cord compression. The cause of death was attributed by the investigator to disease progression and pneumonitis. A further G3 of pneumonitis and three further G2 TEAEs were observed (overall incidence of pneumonitis 5 / 107 [4.7%]). Of the patients with G2 pneumonitis, one patient discontinued treatment due to neurotoxicity (not pneumonitis), one patient had resolution of pneumonitis before interruption for PD, and one patient resumed treatment without dose modification.

[0149] TEAEs of any cause / grade occurred in 107 patients (100%). The most common were CRS (56 patients [52.3%]), fever (43 [40.2%]), constipation (33 [30.8%]), and fatigue (32 [29.9%]). Grade ≥3 AEs occurred in 61 patients (57.0%), the most common being neutropenia (8.4%), decreased lymphocyte count (6.5%), and hypertension (5.6%). Serious adverse events (SAEs) occurred in 55 patients (51.4%). TEAEs led to dose reductions in 9 patients (8.4%), and 4 (3.7%) had CRS-related reductions. Dose interruptions occurred in 20 patients (18.7%), most commonly neutropenia and decreased neutrophil count. Any grade and grade ≥3 TRAEs occurred in 97 (90.7%) and 33 (30.8%) patients, respectively.

[0150] CRS, neutropenia, and neurological events were monitored as events of interest based on preclinical, clinical, and mechanistic data with talutamab, other BiTE™ molecules, and other T cell-related therapies. An Amgen MedDRA Query narrow (AMQN) search was performed to supplement standard system organ class single preferred term safety reports (defined above and summarized in Table 4). Measures to improve the likelihood of CRS included prophylactic corticosteroids (cycle 1 only) and IV hydration in some patients. Grade 2 or higher treatment-emergent CRS was reported in 15 patients (14.0%), grade 3 CRS was reported in one patient (0.9%), and no grade 4 or 5 CRS was reported. For CRS of any grade (n=56), the median time to first onset was 2 days (range, 1-30 days) after first dose based on the recorded date, and more precise time-based reporting was implemented to better characterize CRS, with median time to onset being 17.5 hours in the subset of patients for whom hourly data were available (n=47). CRS was transient (median duration, 3 days [IQR: 2-4 days]) and resolved in all cases. Eight patients (7.5%) received tocilizumab for CRS. CRS was primarily limited to cycle 1. A total of five patients (4.7%) had CRS in cycle 2, and four of these patients also had CRS in cycle 1, while one patient experienced CRS for the first time after cycle 2. Treatment-emergent neurological AEs of any grade occurred in 75 patients (70.1%), most were grade 1, with dysgeusia (29.0%), headache (19.6%), and dizziness (10.3%) being the most common. Grade 3 or higher treatment-emergent neurological events occurred in 12 patients (11.2%), including confusional state (4.7%), delirium (1.9%), and encephalopathy (1.9%). One subject had a grade 4 neurological event (confusion) and none had a grade 5. All grade 3 or higher neurological AEs resolved, one subject discontinued talutamab due to G3 encephalopathy, and two other subjects continued treatment at a lower dose.G2 ICANS was the other neurological cause leading to discontinuation in one subject. The first onset of any grade neurological event was mostly within the first 30 days of treatment (median, 9 days [IQR, 2-29 days], with a median duration of 5 days (IQR, 2-15 days). Grade ≥3 neutropenia occurred in 11 patients (10.3%). Onset of any grade neutropenia occurred a median of 30 days (IQR, 21-31 days) after the first taluratamab dose, with a median duration of 7 days (IQR, 4-13); overall, 10 patients (9.3%) received G-CSF. Febrile neutropenia occurred in one patient and was not considered related to treatment.

[0151] [Table 4-1]

[0152] [Table 4-2]

[0153] Effectiveness The confirmed ORR was 23.4% (95% confidence interval [CI]: 15.7, 32.5), including 2 complete responses and 23 partial responses (Table 5).

[0154] [Table 5]

[0155] Figure 1A shows the best percent change from baseline in sum of diameters for patients with evaluable postbaseline assessments (n=94). Disease control rate was 51.4% (95% CI: 41.5, 61.2). Responses were seen from the 0.3 mg dose, and higher response rates were generally observed with doses of 3 mg or higher. At least 30% tumor shrinkage in target lesions at postbaseline assessment was observed in 39 patients (36.4%). Among confirmed responders, median TTR was 1.8 months (range, 1.2-7.4), and median DOR was 12.3 months (95% CI: 6.6, 14.9) (Figure 1B). The longest response duration was 14.9 months, with 11 patients (44% of responders) showing ongoing responses at data cutoff. The median PFS was 3.7 months (95%CI: 2.1, 5.4), and the median OS was 13.2 months (95%CI: 10.5, NE), respectively (Figure 2).A total of 28 patients (26.2%) received subsequent anticancer therapy after talutamab.

[0156] Clinical Pharmacokinetics As of April 15, 2022, preliminary pharmacokinetic data from dose escalation and dose expansion cohorts were available for 101 patients. Briefly, tarlatamab demonstrated an approximately dose-proportional increase in serum exposure. Approximate steady state in serum tarlatamab exposure was achieved within 4 weeks of initiating the biweekly target regimen, with minimal accumulation. The mean (±SD) terminal elimination half-life estimated at steady state across the evaluated target dose range was approximately 5.7 (±2.2) days, which is consistent with the intended half-life extension of the HLE platform relative to non-HLE BiTE™ molecules.

[0157] immunogenicity Among patients with available samples, 10 of 97 (10.3%) developed anti-tarlatamab antibodies after tarlatamab administration. Two of 99 (2.0%) patients had preexisting antibodies at baseline. In these patients, there was no apparent impact of anti-drug antibodies (ADAs) on tarlatamab exposure or safety profile.

[0158] Pharmacodynamics The pharmacodynamic response after the first dose of talutamab infusion was characterized by early T cell redistribution, T cell activation, and a transient IFN-γ rise. For the step-dose cohorts, the pharmacodynamic response was maximal after the first administration of the 1 mg step-dose and was not exceeded by administration of the target dose.

[0159] Overview of Clinical CRS CRS was mostly grade 1 (39%), occurred in cycle 1, and was reversible in all patients (see Table 6). CRS was clinically manageable.

[0160] [Table 6]

[0161] Cytokine and CRS analysis In biomarker-evaluable patients, the ratios of peak levels within 24 hours to baseline levels for IL-6, IL-8, IL-10, and TNF-α tended to be higher in patients with CRS in cycle 1 than in those without (Figure 3A-Figure 3D). IL-10 showed a significant elevation above the reference normal range and was higher in CRS patients (Figure 4). The effector cytokine IFN-γ was investigated for its potent induction in preclinical experiments (e.g., Giffin MJ, et al. Clin Cancer Res. 2021;27:1526-1537). As expected from the mechanism of action of tarlatamab, IFN-γ induction was above the physiological range and induction was similar between those with CRS in cycle 1 and those without CRS in cycle 1 (Figures 5A and 5B).

[0162] Consideration Tarlatamab demonstrated a manageable safety profile across a wide dose range through the 100 mg expansion dose and was associated with encouraging response rates in a heavily pretreated population of SCLC patients. Confirmed responses were durable and OS appeared promising. Across all doses (N=107), tarlatamab was discontinued in only 4 patients (3.7%) and dose reductions were performed in 9 patients due to AEs. The MTD was not reached and the highest dose (100 mg) was further evaluated in dose expansion cohorts.

[0163] CRS was expected based on the MOA of tarlatamab. CRS was the most frequent TEAE observed in this study (56% of patients), but was generally low-grade and transient, typically occurring in the first cycle. CRS was typically reversible and managed with steroids, IV fluids, and antipyretics, and tocilizumab was used to treat CRS in 8 of 107 patients (7.5%) who received tarlatamab. Neutropenia is a risk associated with tarlatamab observed in this study that was unexpected based on preclinical data and the mechanism is not understood. The study protocol was updated accordingly for specific monitoring and management. Further evaluation of neutropenia will be relevant for testing the use of tarlatamab in combination with other myelosuppressive therapies. Because of the known association with immune effector cell therapy, neurological evaluations were performed as part of frequent clinical evaluations to evaluate study patients for CRS and / or neurological AEs. Most neurological AEs were mild and self-limited without requiring treatment discontinuation or dose reduction, however 12 patients (11.2%) had grade 3 or higher neurological AEs. Two patients discontinued talutamab due to neurological AEs (encephalopathy, ICANS). Careful evaluation of neurological AEs is ongoing to better characterize these events and identify risk factors or interventions that may specifically improve management.

[0164] There are few approved therapies for SCLC after first-line therapy. A phase 2 trial of lurbinectedin in second-line SCLC found an ORR of 35% and a median DOR of 5.3 months. A randomized trial of topotecan versus combination chemotherapy in recurrent SCLC found a topotecan ORR of 24% and a median DOR of 3.3 months. Prior conditional US FDA approval of nivolumab and pembrolizumab for third-line or later SCLC was based on response rates of 12% and 19%, respectively, with more than 60% of responding patients experiencing durable responses for ≥12 months. These approvals were subsequently revoked for failure to demonstrate survival benefit. Tarlatamab's ORR of 23% and median DOR of 12.3 months compares well with other therapies, especially considering that more than 70% of patients had at least two prior lines of therapy. Half of the patients in this study (50%) had received prior PD-1 / PD-L1 therapy, which represents current practice in first-line SCLC. Despite the median PFS seen with tarlatamab (3.7 months), the median OS (13.2 months) is relatively high and compares favorably with the median OS of 9.3 months previously reported with lurbinectedin or approximately 6 months with topotecan, although the value of the comparison is limited by differences in study design and patient population. The encouraging OS benefit may reflect the long durability of response seen thus far in those responding to tarlatamab, although further follow-up is required in larger randomized trials. An alternative explanation for the relatively long OS with short PFS could be an OS benefit derived from post-tarlatamab therapy, although this is unlikely to be the major factor as only 26.2% of patients received such therapy in this heavily pretreated cohort. Efforts are currently underway to identify clinical, demographic, and biological factors (e.g., prior treatment, DLL3 expression) that predict response and / or toxicity. Increased DLL3 expression appears to be associated with a greater magnitude of clinical benefit.

[0165] The results of this example demonstrate promising activity of tarlatamab in patients with high unmet medical need and have led to several ongoing trials of tarlatamab as monotherapy in SCLC and other neuroendocrine cancers.

[0166] Example 2 Study Design of Extended Intravenous Infusion of AMG 757 in a Phase 1 Study Evaluating the Safety, Tolerability, and Pharmacokinetics of AMG 757 in Patients with Small Cell Lung Cancer Study 20160232 is an open-label, escalation, multiple-dose Phase 1 study evaluating AMG 757 in subjects with SCLC. The study has two indications: A: recurrent / refractory small cell lung cancer (RR SCLC), and B: extensive stage SCLC (ED SCLC).

[0167] The primary, secondary, and exploratory endpoints and key inclusion and exclusion criteria of the study are listed in Example 1.

[0168] To reduce the incidence of CRS, the dosing schedule of cycle 1 is adapted to administer AMG 757 over a longer infusion period as described herein. Specifically, AMG 757 is administered by continuous intravenous (eIV) infusion (e.g., infusion period ranges from 2-7 days) at a dose on day 1 of cycle 1 to reduce the incidence and / or severity of CRS. eIV infusion administration includes an induction dose or target dose administered via eIV infusion for 2, 3, 5, or 7 days, followed by a step-up dose (equal to the target dose) on day 8 and a bolus IV infusion (e.g., 60 minute IV infusion) of the target dose on day 15, or a bolus IV infusion of the target dose on day 15. Dose levels for the eIV approach starting on day 1 of cycle 1 include doses of about 1 mg to about 200 mg (e.g., 30 mg, or 100 mg) infused over 72 hours followed by a bolus IV infusion on days 8 and 15, or on day 15 only. Thereafter, AMG 757 is administered Q2W (e.g., starting on day 29), twice every 3 weeks (e.g., starting on day 22), or Q3W (e.g., starting on day 22). The eIV dosing schedule (Cycle 1 only) is outlined in the table below.

[0169] [Table A]

[0170] Example 3. Extended IV Administration to Patients with SCLC and Outcomes Patients with SCLC were enrolled in the eIV cohort for dose exploration and expansion of AMG 757 monotherapy. As of January 3, 2023, thirty-one (31) patients were enrolled in the eIV cohort. Starting on day 1 of cycle 1, 30 mg or 100 mg of AMG 757 was administered by eIV infusion for 3 days (72 hours), followed by a bolus infusion of AMG 757 at a dose of 100 mg on days 8 and 15 of cycle 1, then 100 mg once every 2 weeks thereafter. Of the 31 patients, 6 received the 30 mg eIV dose (cohort 26) and 25 received the 100 mg eIV dose (cohorts 27 and 31). On day 1 of cycle 1, dexamethasone 8 mg IV (or equivalent) was administered 1 hour prior to the start of the AMG 757 infusion. In addition, saline (1 L) was administered over 4-5 hours from the start of the AMG 757 infusion on Day 1 of Cycle 1. Treatment results are summarized in Table 7 below.

[0171] [Table 7-1]

[0172] [Table 7-2]

[0173] Treatment-emergent adverse events of any grade were observed in all patients in the eIV cohort. Adverse events led to AMG 757 dose reduction in one patient (3.8%) and drug discontinuation in one patient (3.8%) in cohorts 27 and 31. They did not lead to dose reduction or discontinuation in any patients in cohort 26.

[0174] Example 4 Three-week dosing regimen of AMG 757 in a Phase 1 study evaluating the safety, tolerability and pharmacokinetics of AMG 757 in subjects with small cell lung cancer Study 20160232 is an open-label, escalation, multiple-dose Phase 1 study evaluating AMG 757 in subjects with SCLC. The study has two indications: A: recurrent / refractory small cell lung cancer (RR SCLC), and B: extensive stage SCLC (ED SCLC).

[0175] The primary, secondary, and exploratory endpoints and key inclusion and exclusion criteria of the study are listed in Example 1.

[0176] In subjects with SCLC, two 21-day dose regimens of AMG 757 are investigated. Starting with cycle 2, subjects receive AMG 757 twice every 3 weeks for a 21-day cycle (e.g., days 1 and 8 of a 21-day cycle) or once every 3 weeks for a 21-day cycle (e.g., day 1 of a 21-day cycle). Tiered doses, such as the first tiered dose on day 1, the tiered dose equal to the target dose on day 8, and the target dose on day 15, are administered in cycle 1.

[0177] Days 1 and 8 of a 21-day cycle (D1 / D8): Subjects receive 1 mg of AMG 757 on day 1, followed by target doses of 100 mg on days 8 and 15. Starting on day 1 of cycle 2, subjects receive the AMG 757 target dose on days 1 and 8. The starting target dose of AMG 757 is 100 mg.

[0178] Once every 3 weeks (Q3W): Subjects receive 1 mg of AMG 757 on day 1 of cycle 1, followed by a step-up dose on day 8, and a target dose on day 15. Starting on or after day 1 of cycle 2, subjects receive the target dose Q3W. The starting Q3W target dose is 200 mg. A Q3W dosing schedule can provide improved convenience and flexibility to patients and healthcare providers. It can also positively impact resource utilization (e.g., fewer days per month at a treatment center). Subjects in the 200 mg Q3W cohort receive 100 mg of AMG 757 on day 8 of cycle 1. Dose escalation target doses for Q3W dosing of AMG 757 include 100 mg Q3W and 60 mg Q3W.

[0179] As of January 3, 2023, 11 patients were treated in the Q3W dosing cohort (Cohort 37) and 1 patient was treated on days 1 and 8 of the 21-day cycle cohort (Cohort 38). Briefly, for Q3W dosing, 1 mg AMG 757 was administered on day 1 of cycle 1, followed by 100 mg on day 8 of cycle 1, and 200 mg on day 15 of cycle 1. From day 1 of cycle 2 onwards, 200 mg AMG 757 was administered Q3W. For D1 / D8 dosing, 1 mg AMG 757 was administered on day 1 of cycle 1, followed by 100 mg on days 8 and 15 of cycle 1. From day 1 of cycle 2 onwards, 100 mg AMG 757 was administered on D1 / D8 of a 21-day cycle. The response for patients receiving D1 / D8 dosing was stable disease. The treatment outcomes for patients receiving Q3W dosing are summarized in Table 8 below.

[0180] [Table 8-1]

[0181] [Table 8-2]

[0182] Treatment-emergent adverse events of any grade were observed in 10 patients (83.3%) in cohort 37, the dose of AMG 757 was reduced in 1 patient, and the drug was discontinued in 1 patient due to an adverse event. In cohort 38, treatment-emergent adverse events of any grade were observed in 3 patients (100%), with no dose reductions or interruptions.

[0183] Example 5. A Phase 1B Study Evaluating the Safety and Efficacy of First-Line Tarlatamab (AMG 757) in Combination with Carboplatin, Etoposide, and a PD-L1 Inhibitor in Subjects with Advanced Small Cell Lung Cancer This study (Study 20200469) is a Phase 1b, multicenter, open-label study evaluating the safety, tolerability, PK, pharmacokinetics (PD), and preliminary efficacy of first-line tarlatamab in combination with standard of care chemoimmunotherapy in subjects with ES-SCLC. Tarlatamab will be evaluated in combination with induction chemotherapy + anti-PD-L1 (e.g., atezolizumab) followed by maintenance cycles of tarlatamab + anti-PD-L1 (e.g., atezolizumab), and as just-for-all maintenance therapy with tarlatamab administered in combination with anti-PD-L1 (e.g., atezolizumab) after standard of care chemoimmunotherapy. The indication for this study is SCLC.

[0184] The study objectives and endpoints are listed in Table 9 below.

[0185] [Table 9-1]

[0186] [Table 9-2]

[0187] The main inclusion and exclusion criteria are summarized below. Key inclusion criteria Age 18 or older Subjects with histologically or cytologically confirmed ES SCLC and have not received prior systemic treatment for ES-SCLC other than first-line therapy as described below. Subjects with prior treatment for limited-stage SCLC are permitted. Parts 1-4 and 7: Subjects must have received one cycle of platinum chemotherapy, etoposide, and a PD-L1 inhibitor. Subjects who did not access a PD-L1 inhibitor are eligible. Parts 5, 6, 8, and 9: Subjects must have received 4-6 cycles of first-line platinum chemotherapy, etoposide, and a PD-L1 inhibitor and have not experienced disease progression. If there is no access to a first-line PD-L1 inhibitor, subjects who have received 4-6 cycles of platinum chemotherapy + etoposide are eligible. Measurable disease by modified Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 (excluding Parts 5, 6, 8, and 9). Eastern Cooperative Oncology Group 0~1 Subjects with treated asymptomatic brain metastases are eligible as long as they meet the protocol criteria. Adequate organ function per local laboratory defined as: Absolute neutrophil count ≥ 1.5 × 10 9 / L Platelet count ≥ 100 × 10 9 / L Hemoglobin ≥ 9g / dL Modification of diet in renal disease: Estimated glomerular filtration rate >60mL / min / 1.73m based on calculations 2 Aspartate aminotransferase and alanine aminotransferase less than or equal to 3 times the upper limit of normal (ULN) (or less than or equal to 5 times the ULN in subjects with hepatic involvement). Total bilirubin ≤ 1.5 x ULN (or ≤ 2 x ULN in subjects with liver metastases) Prothrombin time (PT) / international normalized ratio and partial thromboplastin time or activated partial thromboplastin time ≤ 1.5 x institutional ULN Pulmonary function: There were no clinically significant pleural effusions on Study Day 1. Treatment of pleural effusions to meet eligibility is permitted. Baseline oxygen saturation >90% on room air. Cardiac function: Cardiac ejection fraction ≥ 50% Key Exclusion Criteria Subjects will be excluded from the study if any of the following criteria apply: Untreated or symptomatic brain metastases and / or leptomeningeal disease History or evidence of interstitial lung disease or active non-infectious pneumonia Have a diagnosis of immunodeficiency or are receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment. History of immune-related colitis Subjects with symptoms and / or clinical and / or radiological signs indicating acute and / or uncontrolled active systemic infection within 7 days prior to the first dose of study treatment. History of arterial thrombosis (e.g., stroke or transient ischemic attack) within 6 months of enrollment Myocardial infarction and / or symptomatic congestive heart failure (New York Heart Association > Class II) or unstable angina within 6 months of Study Day 1. Unstable cardiac arrhythmia within 3 months of Study Day 1. Clinically significant pericardial effusion. Active autoimmune disease that has required systemic treatment (excluding replacement therapy) within the past 2 years, or any other disease requiring immunosuppressive therapy during the study. Subjects with type 1 diabetes, vitiligo, psoriasis, hypothyroidism or hyperthyroidism not requiring immunosuppressive therapy will be accepted. Live vaccine therapy within 4 weeks prior to study drug administration History of solid organ transplant History or evidence of other clinically significant disorders, conditions or diseases that, in the opinion of the investigator or an Amgen physician, if discussed, pose a risk to the subject's safety or interfere with the evaluations, procedures or completion of the study.

[0188] Example 6 Study design and results of study 2020469 Overall Design: This is a Phase 1b, multicenter, open-label study evaluating the safety, tolerability, PK, pharmacokinetics (PD), and preliminary efficacy of first-line tarlatamab in combination with standard of care chemoimmunotherapy in subjects with ES-SCLC. Tarlatamab will be evaluated in combination with induction chemotherapy + anti-PD-L1 (e.g., atezolizumab) followed by maintenance cycles of tarlatamab + anti-PD-L1 (e.g., atezolizumab), and as just-maintenance therapy with tarlatamab administered in combination with anti-PD-L1 (e.g., atezolizumab) after standard of care chemoimmunotherapy.

[0189] Tarlatamab is administered as a short-term intravenous (IV) infusion over 60 minutes followed by a flush. A stepped dosing approach is implemented during the first cycle of tarlatamab administration in each part to reduce the risk of cytokine release syndrome (CRS). Three different dosing schedules of tarlatamab are evaluated: once every 2 weeks (Q2W), days 1 and 8 (D1 / D8) of a 21-day cycle, and once every 3 weeks (Q3W). For all dosing schedules, tarlatamab administration begins with 1 mg administered on day 1 of cycle 1, followed by one or more step doses to reach the target dose. Premedication with dexamethasone 8 mg IV (or equivalent dose of other corticosteroid) is administered within 1 hour of all first-cycle doses of tarlatamab. Prophylactic IV hydration (e.g., 500-1000 mL saline administered over approximately 4-5 hours) is also administered after all cycle 1 doses of tarlatamab.

[0190] The study consists of 9 parts, including dose escalation (Parts 1, 2, 3, and 5) and dose expansion (Parts 4, 6, 7, 8, and 9).

[0191] Part 1 (induction tarlatamab D1 / D8 and maintenance tarlatamab Q2W): Tarlatamab is stepped-dose initiated in cycle 1 in combination with atezolizumab, carboplatin, and etoposide, followed by tarlatamab D1 / D8 in combination with atezolizumab, carboplatin, and etoposide in cycles 2 and 3. From cycle 4 onwards, subjects receive maintenance cycles of tarlatamab Q2W + atezolizumab every 4 weeks (Q4W).

[0192] The treatment regimens for Part 1 are listed below.

[0193] Induction: Cycle 1 (21-day cycle): Atezolizumab 1200 mg IV followed by carboplatin to an area under the concentration-time curve (AUC) of 5 IV, then etoposide 100 mg / m on day 1. 2 IV. Tarlatamab is administered after completion of chemotherapy. Tarlatamab D1 / D8 is initiated by a single step of tarlatamab 1 mg IV on day 1 of cycle 1. Etoposide 100 mg / m on days 2 and 3. 2 will be administered intravenously. Tarlatamab D1 / D8 target doses will be administered on days 8 and 15 of cycle 1.

[0194] Cycles 2 and 3 (21-day cycle): Atezolizumab 1200 mg IV followed by carboplatin AUC5 IV on day 1 and etoposide 100 mg / m 2 IV. Tarlatamab target dose will be administered after completion of chemotherapy on day 1. Etoposide 100 mg / m on days 2 and 3. 2 An IV dose will also be administered. The target dose of talutamab will also be administered on day 8.

[0195] Maintenance: Cycle 4+ (28 day cycle): Tarlatamab Q2W at target dose IV on days 1 and 15. Atezolizumab 1680 mg IV Q4W on day 1.

[0196] Part 1 includes a fixed dose of atezolizumab and one or more of the following dose levels of tarlatamab (Table 10-1) in combination with carboplatin and etoposide administered according to standard of care:

[0197] [Table 10-1]

[0198] Part 2 (induction tarlatamab Q3W and maintenance tarlatamab Q3W): Tarlatamab begins with step-up dosing in cycle 1 in combination with atezolizumab, carboplatin, and etoposide, followed by tarlatamab Q3W in combination with atezolizumab, carboplatin, and etoposide in cycles 2 and 3. From cycle 4 onwards, subjects receive maintenance cycles of tarlatamab Q3W + atezolizumab Q3W.

[0199] The treatment regimens for Part 2 are listed below.

[0200] Induction: Cycle 1 (21-day cycle): Atezolizumab 1200 mg IV followed by carboplatin AUC5 IV on day 1 and then etoposide 100 mg / m 2 IV will be matched. Tarlatamab will be administered after completion of chemotherapy. Tarlatamab Q3W will be initiated on day 1 of cycle 1 with the first step dose of tarlatamab (1 mg). Etoposide 100 mg / m 2 IV is administered intravenously on days 2 and 3 of cycle 1. Tarlatamab Q3W target dose is administered on day 8 of cycle 1 and day 15 of cycle 1 (see Table 10-2). Alternatively, tarlatamab Q3W target dose is administered on day 8 of cycle 1 with no treatment on day 15 of cycle 1 (see Table 10-2).

[0201] Cycles 2 and 3 (21-day cycle): Atezolizumab 1200 mg IV followed by carboplatin AUC5 on day 1 and then etoposide 100 mg / m 2IV. Tarlatamab Q3W target dose will be administered after completion of chemotherapy on day 1. Etoposide 100 mg / m on days 2 and 3. 2 An IV is also administered.

[0202] Maintenance: Cycle 4+ (21-day cycle): Atezolizumab 1200 mg IV on day 1 followed by tarlatamab Q3W on day 1 of every 21-day cycle as target dose.

[0203] [Table 10-2]

[0204] In parts 1 and 2, depending on observed safety data, the following may occur: 1) de-escalation to the next lowest dose cohort level, 2) additional enrollment at the current dose cohort level, or 3) initiation of enrollment in dose escalation or dose expansion to the next highest dose cohort level. Re-escalation to the next higher dose cohort level will be permitted if necessary. If re-escalation occurs, alternative (intermediate) dose cohort levels, including adjustment of the tarlatamab dose or adjustment of tarlatamab dosing days, will be investigated per Dose Level Review Meeting (DLRM) recommendations. If tarlatamab monotherapy doses of 100 mg D1 / D8 and 200 mg Q3W are deemed safe, Part 1 dose level 1.3 and Part 2 dose level 2.3 will be investigated.

[0205] Part 3 (induction tarlatamab D1 / D8 and maintenance tarlatamab Q3W): Tarlatamab is stepped-dose starting in cycle 1 in combination with atezolizumab, carboplatin, and etoposide, followed by tarlatamab D1 / D8 in combination with atezolizumab, carboplatin, and etoposide in cycles 2 and 3. From cycle 4 onwards, subjects receive maintenance cycles of tarlatamab Q3W + atezolizumab Q3W.

[0206] Part 3 treatment regimens are listed below.

[0207] Induction: Cycle 1 (21-day cycle): Atezolizumab 1200 mg IV followed by carboplatin AUC5 IV on day 1 and then etoposide 100 mg / m 2 IV. Tarlatamab is administered after completion of chemotherapy. The most safe and tolerated dose of tarlatamab D1 / D8 is 1 mg escalation starting on day 1 of cycle 1. Etoposide 100 mg / m 2 will be administered on days 2 and 3. Tarlatamab will be administered on days 8 and 15 of cycle 1.

[0208] Cycles 2 and 3 (21-day cycle): Atezolizumab 1200 mg IV followed by carboplatin AUC5 IV on day 1 and then etoposide 100 mg / m 2 IV. Tarlatamab D1 / D8 target dose will be administered after completion of chemotherapy on day 1. Etoposide 100 mg / m on days 2 and 3. 2 An IV dose will also be administered. The target dose of talutamab will also be administered on day 8.

[0209] Maintenance: Cycle 4+ (21 day cycles): Atezolizumab 1200 mg IV on day 1 followed by tarlatamab Q3W target dose on day 1 of each 21 day cycle.

[0210] [Table 10-3]

[0211] Part 4 (an extension of Part 1, Part 2, or Part 3)

[0212] Part 5 (maintenance tarlatamab Q2W + atezolizumab): Tarlatamab will be administered in combination with atezolizumab starting at stepwise dosing in cycle 1. From cycle 2 onwards, subjects will receive tarlatamab Q2W + atezolizumab Q4W.

[0213] Part 5 begins with tarlatamab dose level 5.1 (Table 10-4). If lower dose level combinations are declared safe in Parts 1 or 2, enrollment may begin at dose levels 5.2 or 5.3.

[0214] Part 5 treatment regimens are listed below.

[0215] Cycle 1 (28-day cycle): Atezolizumab 1680 mg IV on day 1, followed by tarlatamab. Tarlatamab was initiated in cycle 1, escalated with 1 mg tarlatamab IV on day 1 of cycle 1, followed by tarlatamab Q2W target dose IV on days 8 and 15.

[0216] Cycle 2+ (28-day cycle): Atezolizumab 1680 mg IV Q4W on day 1, followed by the target dose of tarlatamab on days 1 and 15 of cycle 2 and beyond.

[0217] [Table 10-4]

[0218] Part 6 (Expanded version of Part 5)

[0219] Part 7: Expansion of selected combination doses for expansion from Parts 1, 2, or 3 using durvalumab as the PD-L1 inhibitor. Durvalumab is administered at a dose of 1500 mg IV every 4 weeks or 1500 mg every 3 weeks.

[0220] Part 8: Expansion of combination dose cohorts selected for expansion from Part 5 using durvalumab as the PD-L1 inhibitor. Durvalumab will be administered at a dose of 1500 mg IV once every 4 weeks.

[0221] Part 9: Expansion cohort of maintenance tarlatamab + durvalumab, each administered every 3 weeks. The tarlatamab Q3W dose will be selected from one of the dose levels in Table 10-2. Durvalumab will be administered at a dose of 1500 mg every 3 weeks.

[0222] Dose escalation / deescalation recommendations were guided by the modified Toxicity Probability Interval-2 (mTPI-2) model (Guo et al., 2017), with a target toxicity probability of 30%, an equivalent toxicity interval of (25%, 35%), and a probability of overdose of 95% using beta(1,1) as the prior distribution.

[0223] result As of January 3, 2023, a total of 15 patients have been enrolled (5 patients in part 2 cohort 2.1, 2 subjects in cohort-2.1, and 8 patients in cohort 5.1). Fourteen patients received tarlatamab in dose-finding parts 2 and 5 of the study (5 patients in part 2 cohort 2.1, 1 patient in part 2 cohort-2.1, and 8 patients in part 5 cohort 5.1). Stepwise dosing was utilized in both parts. Specifically, in part 2 cohort 2.1, patients received 1 mg (induction dose) on day 1, cycle 1, followed by 20 mg (target dose) on days 8 and 15 of cycle 1, followed by 20 mg Q3W. For part 2 cohort-2.1, patients were administered 1 mg (induction dose) on day 8 of cycle 1, followed by 20 mg (target dose) on day 15 of cycle 1, then 20 mg Q3W. One subject in cohort-2.1 received chemotherapy and atezolizumab on day 1 of cycle 1, but did not receive tarlatamab due to an unrelated infection and completed the study. For part 5, patients were administered 1 mg (induction dose) on day 1 of cycle 1, followed by 10 mg (target dose) on days 8 and 15 of the cycle, then 10 mg Q2W. Atezolizumab and chemotherapy were administered as above.

[0224] In part 2, of the 5 subjects who received tarlatamab in cohort 2.1, 5 subjects underwent imaging assessment for response. 2 patients had a confirmed partial response (PR), 1 subject had an unconfirmed PR, and 2 patients had stable disease (SD). 1 subject who received tarlatamab in cohort-2.1 had an unconfirmed PR. Overall responses for part 2 were 2 / 6 confirmed PR (33%), 2 / 6 unconfirmed PR (33%), and 2 SD (33%).

[0225] In part 5, of 8 subjects who received tarlatamab, 5 subjects had imaging assessment for response. Of these 5 subjects, 3 subjects had SD (60%) and 2 subjects had disease progression (40%). 3 subjects had not yet had imaging assessment.

[0226] Due to the known high response rates to initial standard of care, the primary response assessment for tarlatamab in combination with chemotherapy and PD-L1 inhibitors was 6 months progression-free survival and overall survival, and it is too early to assess these measures. Overall, responses to date are encouraging for the tarlatamab combination regimen.

[0227] Of the 15 patients enrolled, treatment-emergent adverse events were observed in 14 (93.3%) patients. Grade 2 or higher treatment-related emergent adverse events were observed in 13 (86.7%) patients. In part 2 cohort 2.1, two subjects discontinued treatment due to treatment-related adverse events. One subject experienced a grade 3 ICANS event of seizures and one subject experienced grade 4 thrombocytopenia related to chemotherapy. Cytokine release syndrome occurred in 7 (46.7%) of 15 subjects. Six subjects experienced grade 1 CRS and one subject experienced grade 2 CRS.

[0228] Table 11 below lists the sequences referenced in this application.

[0229] This specification is best understood in light of the teachings of the references cited herein. The embodiments within the specification provide an explanation of the embodiments of the invention and should not be construed as limiting the scope of the invention. Those skilled in the art will readily recognize that many other embodiments are encompassed by the present invention. All publications, patents, and sequences cited in this disclosure are incorporated by reference in their entirety. To the extent that any material incorporated by reference contradicts or is inconsistent with this specification, the present specification takes precedence over any such material. The citation of any reference herein is not an admission that such reference is prior art to the present invention.

[0230] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the embodiments described above.

[0231] [Table 11-1]

[0232] [Table 11-2]

[0233] [Table 11-3]

[0234] [Table 11-4]

[0235] [Table 11-5]

[0236] [Table 11-6]

[0237]

Table 11-7

[0238]

Table 11-8

Claims

1. 1. A composition for treating DLL3-positive cancer, comprising an anti-DLL3 agent comprising the amino acid sequences of SEQ ID NOs: 13 and 23, wherein the composition is administered to a subject in need thereof, and the anti-DLL3 agent is administered at a dose of 10 mg to 100 mg twice every three weeks.

2. 10. The composition of claim 1, wherein the anti-DLL3 agent is administered at a dose of 10 mg, 30 mg, or 100 mg twice every three weeks.

3. 10. The method of claim 1, wherein the anti-DLL3 agent is administered on days 1 and 8 of a 21-day cycle.

4. The composition of claim 1, wherein the anti-DLL3 agent is administered once every two weeks at a dose of 10 mg to 100 mg before or after the two administrations every three weeks.

5. The composition of claim 4, wherein the anti-DLL3 agent is administered once every two weeks at a dose of 10 mg, 30 mg, 50 mg, or 100 mg.

6. The composition of claim 4, wherein the anti-DLL3 agent is administered on days 1 and 15 of a 28-day cycle.

7. The composition of claim 1, wherein the anti-DLL3 agent is administered once every three weeks at a dose of 20 mg to 100 mg before or after the two administrations every three weeks.

8. The composition of claim 1, wherein the anti-DLL3 agent is also administered once every three weeks at a dose of 100 mg to 200 mg before or after the two administrations every three weeks.

9. The composition of claim 1, wherein the anti-DLL3 agent is also administered once every three weeks at a dose of 20 mg, 60 mg, 100 mg, or 200 mg before or after the two administrations every three weeks.

10. The method of claim 1, wherein prior to the two three-weekly administrations, the anti-DLL3 agent is administered in a 21-day cycle according to the following regimen: (i) a first dose of 1 mg on day 1 and a second dose of 10 mg to 100 mg on day 8; or (ii) a first dose of 1 mg on day 8 and a second dose of 10 mg to 100 mg on day 15; 2. The composition of claim 1, wherein the 21-day cycle is the first cycle in which the anti-DLL3 agent is administered to the subject.

11. The composition described in claim 10, wherein the second dose in (i) or (ii) is 20 mg.

12. 1. A composition for treating DLL3-positive cancer, comprising an anti-DLL3 agent comprising the amino acid sequences of SEQ ID NOs: 13 and 23, wherein the composition is administered to a subject in need thereof, and the anti-DLL3 agent is administered at a dose of 20 mg to 200 mg once every three weeks.

13. 13. The composition of claim 12, wherein the anti-DLL3 agent is administered at a dose of 20 mg to 100 mg once every three weeks.

14. 13. The composition of claim 12, wherein the anti-DLL3 agent is administered at a dose of 100 mg to 200 mg once every three weeks.

15. 13. The composition of claim 12, wherein the anti-DLL3 agent is administered in a dose of 20 mg, 60 mg, 100 mg, or 200 mg.

16. 13. The composition of claim 12, wherein the anti-DLL3 agent is administered on day 1 of a 21-day cycle.

17. The composition of claim 12, wherein the anti-DLL3 agent is administered once every two weeks at a dose of 10 mg to 100 mg before or after the once every three weeks administration.

18. The composition of claim 17, wherein the anti-DLL3 agent is administered once every two weeks at a dose of 10 mg, 30 mg, 50 mg, or 100 mg.

19. The composition of claim 17, wherein the anti-DLL3 agent is administered on days 1 and 15 of a 28-day cycle.

20. The composition of claim 12, wherein the anti-DLL3 agent is administered once every three weeks at a dose of 20 mg to 100 mg before or after the once every three weeks administration.

21. The composition of claim 12, wherein the anti-DLL3 agent is also administered once every three weeks at a dose of 100 mg to 200 mg before or after the once every three weeks administration.

22. The composition of claim 12, wherein the anti-DLL3 agent is also administered once every three weeks at a dose of 20 mg, 60 mg, 100 mg, or 200 mg before or after the once every three weeks administration.

23. The method of claim 22, wherein prior to the once every three weeks administration, the anti-DLL3 agent is administered in a 21-day cycle according to the following regimen: (i) a first dose of 1 mg on day 1 and a second dose of 10 mg to 100 mg on day 8; or (ii) a first dose of 1 mg on day 8 and a second dose of 10 mg to 100 mg on day 15; 13. The composition of claim 12, wherein the 21-day cycle is the first cycle in which the anti-DLL3 agent is administered to the subject.

24. The composition of claim 23, wherein the second dose in (i) or (ii) is 20 mg.

25. 1. A composition for treating DLL3-positive cancer, comprising an anti-DLL3 agent comprising the amino acid sequence of SEQ ID NOs: 13 and 23, said composition being administered to a subject in need thereof, wherein said anti-DLL3 agent is administered in a regimen of: a) administering the anti-DLL3 agent in a first cycle wherein (i) the anti-DLL3 agent is administered by continuous intravenous infusion over 2 to 7 days at a dose of 1 mg to 200 mg, and (ii) following the continuous intravenous infusion, the anti-DLL3 agent is administered by bolus intravenous infusion on day 8, day 15, or both days 8 and 15; b) The following i) to iii) i) administering said anti-DLL3 agent at a dose of 10 mg to 100 mg starting on day 29 and one or more subsequent doses once every two weeks thereafter; ii) administering said anti-DLL3 agent at a dose of 10 mg to 100 mg starting on day 22, and then every three weeks for two or more subsequent doses; iii) administering one or more subsequent doses of said anti-DLL3 agent at a dose of 20 mg to 200 mg starting on day 22 and once every three weeks thereafter; administering the anti-DLL3 agent according to any one of the following: The composition is administered according to the method of claim 1.

26. 26. The composition of claim 25, wherein a) the anti-DLL3 agent is administered by continuous intravenous infusion over 2, 3, 5 or 7 days at a dose of 30 mg to 100 mg.

27. 26. The composition of claim 25, wherein a) the anti-DLL3 agent is administered by continuous intravenous infusion over 2, 3, 5 or 7 days at a dose of 30 mg, 50 mg or 100 mg.

28. 26. The composition of claim 25, wherein a) the anti-DLL3 agent is administered by continuous intravenous infusion over 3, 5 or 7 days at a dose of 30 mg, 50 mg or 100 mg.

29. 29. The composition of claim 28, wherein a) the anti-DLL3 agent is administered at a dose of 30 mg or 100 mg by continuous intravenous infusion over three days.

30. A combination for treating DLL3-positive cancer, comprising an anti-DLL3 agent comprising the amino acid sequences of SEQ ID NOs: 13 and 23, and an anti-PD-L1 antibody, said combination being administered to a subject in need thereof, wherein the anti-DLL3 agent is selected from the group consisting of the following a) to c): a) administering the anti-DLL3 agent at a dose of 10 mg to 100 mg once every two weeks; b) administering the anti-DLL3 agent at a dose of 10 mg to 100 mg twice every three weeks; c) administering the anti-DLL3 agent at a dose of 20 mg to 200 mg once every three weeks; and A combination, optionally wherein said combination is administered in conjunction with one or more chemotherapeutic agents.

31. 31. The combination of claim 30, wherein the anti-DLL3 agent is administered once every two weeks at a dose of 10 mg to 100 mg.

32. 32. The combination of claim 31 , wherein the anti-DLL3 agent is administered once every two weeks at a dose of 10 mg, 30 mg, 50 mg, or 100 mg.

33. 32. The combination of claim 31 , wherein the anti-DLL3 agent is administered on days 1 and 15 of a 28-day cycle.

34. 31. The combination of claim 30, wherein the anti-DLL3 agent is administered at a dose of 10 mg to 100 mg twice every three weeks.

35. 35. The combination of claim 34, wherein the anti-DLL3 agent is administered at a dose of 10 mg, 30 mg, or 100 mg twice every three weeks.

36. 35. The combination of claim 34, wherein the anti-DLL3 agent is administered on days 1 and 8 of a 21-day cycle.

37. 31. The combination of claim 30, wherein the anti-DLL3 agent is administered once every three weeks at a dose of 20 mg to 100 mg.

38. 31. The combination of claim 30, wherein the anti-DLL3 agent is administered once every three weeks at a dose of 100 mg to 200 mg.

39. 31. The combination of claim 30, wherein the anti-DLL3 agent is administered once every three weeks at a dose of 20 mg, 60 mg, 100 mg, or 200 mg.

40. 38. The combination of claim 37, wherein the anti-DLL3 agent is administered on day 1 of a 21-day cycle.

41. 31. The combination of claim 30, characterized in that prior to any one of a) to c), the anti-DLL3 agent is administered in a 21-day cycle according to the following regimen: a first dose of 0 mg or 1 mg on day 1, a second dose of 1 mg to 100 mg on day 8, and a third dose of 10 mg to 200 mg on day 15.

42. 42. The combination of claim 41, wherein the first dose is 1 mg on day 1, the second dose is 10 mg to 100 mg on day 8, and the third dose is 10 mg to 100 mg on day 15.

43. 42. The combination of claim 41, wherein the first dose is 1 mg on day 1, the second dose is 10-100 mg on day 8, and the third dose is 20-200 mg on day 15.

44. Prior to said once every three weeks administration, said anti-DLL3 agent is administered in a 21-day cycle with one of the following regimens: (i) a first dose of 1 mg on day 1 and a second dose of 10 mg to 100 mg on day 8; or (ii) a first dose of 1 mg on day 8 and a second dose of 10 mg to 100 mg on day 15; 40. The combination of claim 39, wherein the 21-day cycle is the first cycle in which the anti-DLL3 agent is administered to the subject.

45. The combination of claim 44, wherein the second dose of (i) or (ii) is 20 mg.

46. The combination of claim 30, wherein the anti-PD-L1 antibody is a PD-L1 blocking antibody.

47. The combination of claim 46, wherein the anti-PD-L1 antibody is atezolizumab or durvalumab.

48. 31. The combination of claim 30, wherein the one or more chemotherapeutic agents comprises a platinum-based chemotherapeutic agent, etoposide, or both.

49. 49. The combination of claim 48, wherein the platinum-based chemotherapeutic agent is carboplatin or cisplatin.

50. The combination of claim 30, wherein the anti-DLL3 agent is administered after the anti-PD-L1 antibody and the one or more chemotherapeutic agents, if administered on the same day.

51. 1. A combination for treating DLL3-positive cancer, comprising an anti-DLL3 agent comprising the amino acid sequences of SEQ ID NOs: 13 and 23 and an alkylating agent, wherein the combination is administered to a subject in need thereof, and the anti-DLL3 agent is administered to the subject at a dose of 10 mg to 200 mg once every three weeks.

52. 52. The combination of claim 51, wherein the anti-DLL3 agent is administered once every three weeks at a dose of 10 mg to 100 mg.

53. 53. The combination of claim 52, wherein the anti-DLL3 agent is administered once every three weeks at a dose of 100 mg to 200 mg.

54. 52. The combination of claim 51 , wherein the anti-DLL3 agent is administered in a dose of 10 mg, 20 mg, 60 mg, 100 mg, or 200 mg.

55. 52. The combination of claim 51 , wherein the anti-DLL3 agent is administered on day 1 of a 21-day cycle.

56. The combination of claim 51, wherein the alkylating agent is a platinum-based agent.

57. The combination described in claim 56, wherein the platinum-based drug is lurbinectedin.

58. The combination according to claim 57, wherein lurbinectedin is to be administered in an amount of 2.0 mg / m 2 to 3.2 mg / m 2 once every three weeks.

59. The combination of claim 51, wherein the anti-DLL3 agent should be administered after the alkylating agent if administered on the same day.

60. 1. A combination for treating DLL3-positive cancer, comprising an anti-DLL3 agent comprising the amino acid sequences of SEQ ID NOs: 13 and 23 and an alkylating agent, wherein the combination is administered to a subject in need thereof, and the anti-DLL3 agent is administered to the subject according to the following: a first dose of 0 mg or 1 mg on day 1, a second dose of 10 mg to 100 mg on day 8, a third dose of 10 mg to 200 mg on day 15, and one or more subsequent doses of 10 mg to 200 mg starting on day 22 and once every three weeks thereafter.

61. 61. The combination of claim 60, wherein the first dose is 1 mg, the second dose is 10 mg to 100 mg, and the third dose is 10 mg to 200 mg, and the one or more subsequent doses are the same and the same as the third dose.

62. 61. The combination of claim 60, wherein the first dose is 1 mg, the second dose is 20 mg, 60 mg, or 100 mg, the third dose is 20 mg, 60 mg, or 200 mg, and the one or more subsequent doses are the same and are each 20 mg, 60 mg, or 200 mg.

63. 61. The combination of claim 60, wherein the one or more subsequent doses are administered on day 1 of a 21-day cycle.

64. 64. The composition or combination of any one of claims 1 to 63, wherein the anti-DLL3 agent comprises the amino acid sequence of SEQ ID NO: 14, 27 or 32.

65. 64. The composition or combination according to any one of claims 1 to 63, wherein the composition or combination is administered to the subject in combination with one or more additional therapeutic agents.

66. 66. The composition or combination of claim 65, wherein the one or more additional therapeutic agents is a corticosteroid, saline, or an anti-IL6 antibody.

67. 67. The composition or combination of claim 66, wherein the corticosteroid is dexamethasone.

68. 66. The composition or combination of claim 65, wherein the one or more additional therapeutic agents are administered during the first cycle of administering the anti-DLL3 agent.

69. The composition or combination of any one of claims 1 to 63, wherein the cancer is small cell lung cancer (SCLC).

70. 64. The composition or combination of any one of claims 1 to 63, wherein the cancer is relapsed / refractory SCLC (RR SCLC) or extensive stage SCLC (ES SCLC).

71. The composition or combination according to any one of claims 1 to 63, wherein the subject is a human.

72. 72. The composition or combination of claim 71, wherein the subject has undergone at least one prior treatment for the cancer and has experienced a recurrence.

73. 73. The composition or combination of claim 72, wherein said at least one prior treatment for said cancer is platinum chemotherapy, etoposide, and optionally an anti-PD-L1 antibody.

74. 72. The composition or combination of claim 71, wherein the subject has not received previous systemic treatment for the cancer.

75. 64. The composition or combination of any one of claims 1 to 63, wherein the anti-DLL3 agent is tarlatamab.

76. A composition or combination described in any one of claims 1 to 63, wherein the subject is monitored for up to 48 hours after administration of the anti-DLL3 agent.

77. The composition or combination of claim 76, wherein the subject is monitored after cycle 1 and / or cycle 2.

78. A composition for treating DLL3-positive cancer, comprising an anti-DLL3 agent comprising the amino acid sequences of SEQ ID NOs: 13 and 23, said composition being administered to a subject in need thereof in combination with an anti-PD-L1 antibody, wherein the anti-DLL3 agent is one of the following: a) administering the anti-DLL3 agent at a dose of 10 mg to 100 mg once every two weeks; b) administering the anti-DLL3 agent at a dose of 10 mg to 100 mg twice every three weeks; c) administering the anti-DLL3 agent at a dose of 20 mg to 200 mg once every three weeks; and Optionally, said composition is administered in combination with one or more chemotherapeutic agents.

79. A composition for treating DLL3-positive cancer, comprising an anti-PD-L1 antibody, said composition being administered to a subject in need thereof in combination with an anti-DLL3 agent comprising the amino acid sequences of SEQ ID NOs: 13 and 23, wherein the anti-DLL3 agent is one of the following: a) administering the anti-DLL3 agent at a dose of 10 mg to 100 mg once every two weeks; b) administering the anti-DLL3 agent at a dose of 10 mg to 100 mg twice every three weeks; c) administering the anti-DLL3 agent at a dose of 20 mg to 200 mg once every three weeks; and Optionally, said composition is administered in combination with one or more chemotherapeutic agents.

80. A composition for treating DLL3-positive cancer, comprising an anti-DLL3 agent comprising the amino acid sequences of SEQ ID NOs: 13 and 23, said composition being administered to a subject in need thereof in combination with an alkylating agent, wherein the anti-DLL3 agent is administered to the subject at a dose of 10 mg to 200 mg once every three weeks.

81. A composition for treating DLL3-positive cancer, comprising an alkylating agent, said composition being administered to a subject in need thereof in combination with an anti-DLL3 agent comprising the amino acid sequences of SEQ ID NOs: 13 and 23, wherein the anti-DLL3 agent is administered to the subject at a dose of 10 mg to 200 mg once every three weeks.

82. A composition for treating DLL3-positive cancer, comprising an anti-DLL3 agent comprising the amino acid sequences of SEQ ID NOs: 13 and 23, said composition being administered to a subject in need thereof in combination with an alkylating agent, wherein the anti-DLL3 agent is administered to the subject according to the following: a first dose of 0 mg or 1 mg on day 1, a second dose of 10 mg to 100 mg on day 8, a third dose of 10 mg to 200 mg on day 15, and one or more subsequent doses of 10 mg to 200 mg starting on day 22 and once every three weeks thereafter.

83. A composition for treating DLL3-positive cancer, comprising an alkylating agent, said composition being administered to a subject in need thereof in combination with an anti-DLL3 agent comprising the amino acid sequences of SEQ ID NOs: 13 and 23, wherein the anti-DLL3 agent is administered to the subject according to the following: a first dose of 0 mg or 1 mg on day 1, a second dose of 10 mg to 100 mg on day 8, a third dose of 10 mg to 200 mg on day 15, and one or more subsequent doses of 10 mg to 200 mg starting on day 22 and once every three weeks thereafter.

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