Combination therapy for small cell lung cancer

Abstract

The present disclosure provides a method of treating small cell lung cancer (SCLC) in a subject comprising administering to the subject a bispecific T cell engager molecule (TCE) in combination with an anti-B7-H3 antibody drug conjugate (ADC), and in some cases, an anti-PD-L1 antibody. The bispecific TCE comprises a human DLL3-binding domain and a human CD3-binding domain. The anti-B7-H3 ADC comprises an anti-B7-H3 monoclonal antibody conjugated to a topoisomerase I inhibitor.

Description

Amgen Ref. No. 10954-W001-SECCOMBINATION THERAPY FOR SMALL CELL LUNG CANCER BACKGROUND

[0001] Small cell lung cancer (SCLC) is an aggressive form of lung cancer characterized by rapid growth, early metastasis, and a distinct natural history. SCLC displays a high growth fraction and rapid doubling time. While 30% of patients present with disease confined to one hemithorax (limited stage disease), the majority have extensive stage disease (ES-SCLC) not encompassed by one radiotherapy field. SCLC is initially highly sensitive to first-line chemotherapy, with response rates of approximately 60% to 70%. However, patients often develop subsequent resistance to second-line and later therapies (Gustafsson et al, 2008; Byers and Rudin, 2015). Patients with ES-SCLC typically develop drug resistance and succumb to disease at a median time of 10 to 12 months from diagnosis (Rudin et al, 2015).

[0002] For patients with ES-SCLC, first-line treatment typically involves platinum-based chemotherapy. In the United States, most patients receive platinum-etoposide chemotherapy (with either carboplatin or cisplatin) plus a PD-L1 inhibitor (atezolizumab or durvalumab). The addition of PD-L1 inhibitors to platinum chemotherapy plus etoposide has shown modest improvements in overall survival (see, e.g., Hom et al, 2018; and Paz-Ares et al, 2019).

[0003] Beyond the first-line setting, treatment options are limited. Topotecan is approved for SCLC relapses occurring after 45 days from the completion of chemotherapy, but has shown disappointing response rates (Byers and Rudin, 2015). Lurbinectedin received accelerated approval based on results from a phase 2 study in patients with SCLC after failure of first-line therapy (Trigo et al, 2020). While nivolumab and pembrolizumab were initially granted accelerated approval for treatment of metastatic SCLC with progression after platinum-based chemotherapy and at least one other line of therapy, these approvals were subsequently withdrawn after confirmatory studies did not meet their primary endpoint of overall survival (Merck, 2021; Bristol Myers Squibb, 2020).Amgen Ref. No. 10954-W001-SEC

[0004] Given the limitations of existing treatment modalities, there remains a need for novel therapeutic strategies that can improve outcomes for patients with previously treated SCLC.SUMMARY

[0005] Based on the disclosure provided herein, those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments described herein. Such equivalents are intended to be encompassed by the following embodiments (E).

[0006] El . The presently disclosed subject matter is directed to a method of treating small cell lung cancer (SCLC) in a subject. The method comprises administering to the subject once every three weeks (Q3W) each of (a) 15 mg-30 mg of a bispecific T cell engager molecule (TCE) and (b) 0.5 mg / kg - 2.5 mg / kg of an antibody-drug conjugate (ADC). The bispecific TCE comprises (i) a human DLL3-binding domain comprising SEQ ID NOs: 5-10 and (ii) a human CD3-binding domain comprising SEQ ID NOs: 14-19. The ADC is of Formula I:Formula Iwherein Ab is an anti-B7-H3 monoclonal antibody comprising SEQ ID NOs: 25-30, SEQ ID NOs: 31-36, or SEQ ID NOs: 37-42; and q is 6 to 8.

[0007] E2. In some embodiments of El, the bispecific TCE and the ADC are administered to the subject in multiple 21 -day cycles.Amgen Ref. No. 10954-W001-SEC

[0008] E3. In some embodiments of El or E2, the bispecific TCE and the ADC are administered on day 1 of each of the multiple 21 -day cycles.

[0009] E4. In some embodiments of any one of E1-E3, the method further comprises administering 0.5 mg-2.0 mg of the bispecific TCE prior to administering 15 mg-30 mg of the bispecific TCE in the first cycle the bispecific TCE is administered.

[0010] E5. In some embodiments of any one of E1-E4, the method comprises administering to the subject: (a) 0.5 mg-2.0 mg of the bi specific TCE and 0.5 mg / kg-2.5 mg / kg of the ADC on day 1; (b) 15 mg-30 mg of the bispecific TCE on day 8, and (c) 15 mg-30 mg of the bispecific TCE and 0.5 mg / kg- 2.5 mg / kg of the ADC starting on day 22 and once every three weeks (Q3W) thereafter.

[0011] E6. In some embodiments of E5, the method comprises administering to the subject: (a) 1 mg of the bi specific TCE and 0.8 mg / kg, 1.6 mg / kg, 2.0 mg / kg, or 2.4 mg / kg of the ADC on day 1; (b) 20 mg of the bispecific TCE on day 8; and (c) 20 mg of the bispecific TCE and 0.8 mg / kg, 1.6 mg / kg, 2.0 mg / kg, or 2.4 mg / kg of the ADC on day 22 and once every three weeks (Q3W) thereafter.

[0012] E7. In some embodiments of E6, the method comprises administering 0.8 mg / kg of the ADC to the subject on days 1 and 22 and Q3W thereafter.

[0013] E8. In some embodiments of E6, the method comprises administering 1.6 mg / kg of the ADC to the subject on days 1 and 22 and Q3W thereafter.

[0014] E9. In some embodiments of E6, the method comprises administering 2.0 mg / kg of the ADC to the subject on days 1 and 22 and Q3W thereafter.

[0015] E10. In some embodiments of E6, the method comprises administering 2.4 mg / kg of the ADC to the subject on days 1 and 22 and Q3W thereafter.Amgen Ref. No. 10954-W001-SEC

[0016] El 1. In some embodiments of any one of E1-E10, the bispecific TCE and the ADC are administered to the subject via intravenous (IV) injection.

[0017] E12. The presently disclosed subject matter is directed to a method of treating small cell lung cancer (SCLC) in a subject comprising administering to the subject once every three weeks (Q3W) each of: (a) a bispecific T cell engager molecule (TCE) comprising (i) a DLL3-binding domain comprising SEQ ID NOs: 5-10 and (ii) a CD3 -binding domain comprising SEQ ID NOs: 14-19; (b) an anti-PD-Ll antibody; and (c) an antibody-drug conjugate (ADC) of Formula I;Formula Iwherein Ab is an anti-B7-H3 monoclonal antibody comprising SEQ ID NOs: 25-30, SEQ ID NOs: 31-36, or SEQ ID NOs: 37-42; and q is 6 to 8.

[0018] E13. In some embodiments of E12, the bispecific TCE, the ADC, and the anti-PD-Ll antibody are administered to the subject in multiple 21 -day cycles.

[0019] E14. In some embodiments of E13, the bispecific TCE, the ADC, and the anti-PD-Ll antibody are administered on day 1 of each of the multiple 21 -day cycles.

[0020] E15. In some embodiments of any one of E12-E14, the method comprises administering to the subject: (a) 0.5 mg-2.0 mg of the bispecific TCE, 0.5 mg / kg-2.5 mg / kg of the ADC, and 1000 mg-2000 mg of the anti-PD-Ll antibody on day 1; (b) 15 mg-30 mg of the bispecific TCE on day 8; (c) 15 mg-30 mg of the bispecific TCE, 0.5 mg / kg-2.5 mg / kg of theAmgen Ref. No. 10954-W001-SECADC, and 1000 mg-2000 mg of the anti-PD-Ll antibody on days 22, 43, and 64; and (d) 15 mg-30 mg of the bispecific TCE and 1000 mg-2000 mg of the anti-PD-Ll antibody starting on day 85 and once every three weeks (Q3W) thereafter.

[0021] E16. In some embodiments of E15, the method comprises administering to the subject (a) 1 mg of the bispecific TCE, 0.8 mg / kg, 1.6 mg / kg, 2.0 mg / kg, or 2.4 mg / kg of the ADC, and 1000 mg-2000 mg of the anti-PD-Ll antibody on day 1; (b) 20 mg of the bispecific TCE on day 8; and (c) 20 mg of the bispecific TCE, 0.8 mg / kg, 1.6 mg / kg, 2.0 mg / kg, or 2.4 mg / kg of the ADC and 1000 mg-2000 mg of the anti-PD-Ll antibody on days 22, 43, and 64; and (d) 20 mg of the bispecific TCE and 1000 mg-2000 mg of the anti-PD-L l antibody starting on day 85 and once every three weeks (Q3W) thereafter.

[0022] E17. Tn some embodiments of E16, the method comprises administering 0.8 mg / kg of the ADC to the subject on days 1, 22, 43, and 64.

[0023] E18. In some embodiments of E16, the method comprises administering 1.6 mg / kg of the ADC to the subject on days 1, 22, 43, and 64.

[0024] E19. In some embodiments of E16, the method comprises administering 2.0 mg / kg of the ADC to the subject on days 1, 22, 43, and 64.

[0025] E20. In some embodiments of E16, the method comprises administering 2.4 mg / kg of the ADC to the subject on days 1, 22, 43, and 64.

[0026] E21. In some embodiments of any one of E12-E20, the bispecific TCE and the ADC are administered to the subject via intravenous (IV) injection.

[0027] E22. In some embodiments of any one of E12-E21, the anti-PD-Ll antibody is durvalumab or atezolizumab.

[0028] E23. In some embodiments of E22, the method comprises administering 1500 mg durvalumab intravenously (IV) to the subject on days 1, 22, 43, 64, 85 and Q3W thereafter.Amgen Ref. No. 10954-W001-SEC

[0029] E24. In some embodiments of E22, the method comprises administering 1200 mg atezolizumab IV to the subject on days 1, 22, 43, 64, 85 and Q3W thereafter.

[0030] E25. In some embodiments of any one of E1-E24, the bispecific TCE comprises the amino acid sequence of SEQ ID NO: 13.

[0031] E26. In some embodiments of any one of E1-E25, the bispecific TCE comprises the amino acid sequence of SEQ ID NO: 22.

[0032] E27. In some embodiments of any one of E1-E26, the bispecific TCE comprises the amino acid sequence of SEQ ID NO: 24.

[0033] E28. In some embodiments of any one of E1-E27, the anti-B7-H3 monoclonal antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 45 and a light chain sequence of SEQ ID NO: 46.

[0034] E29. In some embodiments of any one of E1-E28, the small cell lung cancer is extensive stage small cell lung cancer (ES-SCLC).

[0035] E30. In some embodiments of any one of E1-E29, the small cell lung cancer is refractory SCLC or relapsed SCLC.

[0036] E31. In some embodiments of any one ofEl-E30, the small cell lung cancer expresses DLL3 as determined by immunohistochemistry.

[0037] E32. In some embodiments of any one of E1-E31, the SCLC has progressed or relapsed following at least one previous treatment.

[0038] E33. In some embodiments of E32, the at least one previous treatment comprises platinum-based chemotherapy, etoposide, a PD-L1 inhibitor, or combinations thereof.

[0039] E34. In some embodiments of E33, the platinum-based chemotherapy comprises carboplatin or cisplatin.Amgen Ref. No. 10954-W001-SEC

[0040] E35. In some embodiments of any one of E1-E34, the method further comprises administering at least one additional therapeutic agent to the subject.

[0041] E36. In some embodiments of E35, the at least one additional therapeutic agent comprises dexamethasone, an anti-emetic agent, granulocyte colony-stimulating factor (G-CSF), and / or saline.

[0042] E37. The presently disclosed subject matter is directed to a method of treating small cell lung cancer (SCLC) in a subject comprising administering to the subject: (a) 0.5 mg-2.0 mg tarlatamab and 0.5 mg / kg-2.5 mg / kg of an antibody-drug conjugate (ADC) on day 1; (b) 15 mg-30 mg tarlatamab on day 8; (c) 15 mg-30 mg tarlatamab and 0.5 mg / kg-2.5 mg / kg of the ADC starting on day 22 and once every three weeks (Q3W) thereafter; wherein the ADC is of Formula i;Formula Iwherein Ab is an anti-B7-H3 monoclonal antibody comprising a heavy chain amino acid sequence of SEQ ID NO: 45 and a light chain sequence of SEQ ID NO: 46, and q is 6 to 8.

[0043] E38. In some embodiments of E37, the method comprises administering to the subject (a) 1 mg tarlatamab and 0.8 mg / kg, 1.6 mg / kg, 2.0 mg / kg, or 2.4 mg / kg of the ADC on day 1; (b) 20 mg tarlatamab on day 8; and (c) 20 mg tarlatamab and 0.8 mg / kg, 1.6 mg / kg, 2.0 mg / kg, or 2.4 mg / kg of the ADC on day 22; and once every three weeks (Q3W) thereafter.Amgen Ref. No. 10954-W001-SEC

[0044] E39. In some embodiments of E37 or E38, the method comprises administering 0.8 mg / kg of the ADC to the subject on days 1 and 22 and Q3W thereafter.

[0045] E40. In some embodiments of E37 or E38, the method comprises administering 1.6 mg / kg of the ADC to the subject on days 1 and 22 and Q3W thereafter.

[0046] E41. In some embodiments of E37 or E38, the method comprises administering 2.0 mg / kg of the ADC to the subject on days 1 and 22 and Q3W thereafter.

[0047] E42. In some embodiments of E37 or E38, the method comprises administering 2.4 mg / kg of the ADC to the subject on days 1 and 22 and Q3W thereafter.

[0048] E43. The presently disclosed subject matter is directed to a method of treating small cell lung cancer (SCLC) in a subject comprising administering to the subject: (a) 0.5 mg-2.0 mg tarlatamab and 0.5 mg / kg-2.5 mg / kg tambotatug pelitecan on day 1; (b) 15 mg-30 mg tarlatamab on day 8; (c) 15 mg-30 mg tarlatamab and 0.5 mg / kg-2.5 mg / kg tambotatug pelitecan starting on day 22 and once every three weeks (Q3W) thereafter.

[0049] E44. In some embodiments of E43, the method comprises administering to the subject: (a) 1 mg tarlatamab and 0.8 mg / kg, 1.6 mg / kg, 2.0 mg / kg, or 2.4 mg / kg tambotatug pelitecan on day 1; (b) 20 mg tarlatamab on day 8; and (c) 20 mg tarlatamab and 0.8 mg / kg, 1.6 mg / kg, 2.0 mg / kg, or 2.4 mg / kg tambotatug pelitecan on day 22; and once every three weeks (Q3W) thereafter.

[0050] E45. In some embodiments of any one of E37-E44, the small cell lung cancer is extensive stage small cell lung cancer (ES-SCLC).

[0051] E46. In some embodiments of any one of E37-E45, the small cell lung cancer is refractory SCLC or relapsed SCLC.

[0052] E47. In some embodiments of any one of E37-E46, the SCLC has progressed or relapsed following at least one previous treatment.Amgen Ref. No. 10954-W001-SEC

[0053] E48. In some embodiments of E47, the at least one previous treatment comprises platinum-based chemotherapy, etoposide, aPD-Ll inhibitor, or combinations thereof.

[0054] E49. In some embodiments of E48, the platinum-based chemotherapy comprises carboplatin or cisplatin.

[0055] E50. The presently disclosed subject matter is directed to a method of treating small cell lung cancer (SCLC) in a subject comprising administering to the subject: (a) 0.5 mg-2.0 mg of tarlatamab, 0.5 mg / kg-2.5 mg / kg of an antibody-drug conjugate (ADC), and 1000 mg-2000 mg of an anti-PD-Ll antibody on day 1; (b) 15 mg-30 mg of tarlatamab on day 8; (c) 15 mg-30 mg of tarlatamab, 0.5 mg / kg-2.5 mg / kg of the ADC, and 1000 mg-2000 mg of the anti-PD-Ll antibody on each of days 22, 43, and 64; and (d) 15 mg-30 mg of tarlatamab and 1000 mg-2000 mg of the anti-PD-Ll antibody starting on day 85 and once every three weeks (Q3W) thereafter; wherein the ADC is of Formula I;Formula Iwherein Ab is an anti-B7-H3 monoclonal antibody comprising a heavy chain amino acid sequence of SEQ ID NO: 45 and a light chain amino acid sequence of SEQ ID NO: 46, and q is 8.

[0056] E51. In some embodiments of E50, the method comprises administering to the subject: (a) 1 mg tarlatamab, 0.8 mg / kg, 1.6 mg / kg, 2.0 mg / kg, or 2.4 mg / kg of the ADC, andAmgen Ref. No. 10954-W001-SEC1000 mg-2000 mg of the anti-PD-Ll antibody on day 1; (b) 20 mg tarlatamab on day 8; and (c) 20 mg tarlatamab, 0.8 mg / kg, 1.6 mg / kg, 2.0 mg / kg, or 2.4 mg / kg of the ADC and 1000 mg-2000 mg of the anti-PD-Ll antibody on days 22, 43, and 64; and (d) 20 mg tarlatamab and 1000 mg-2000 mg of the anti-PD-Ll antibody starting on day 85 and once every three weeks (Q3W) thereafter.

[0057] E52. In some embodiments of E51, the method comprises administering 0.8 mg / kg of the ADC to the subject on days 1, 22, 43, and 64.

[0058] E53. In some embodiments of E51, the method comprises administering 1.6 mg / kg of the ADC to the subject on days 1, 22, 43, and 64.

[0059] E54. In some embodiments of E51, the method comprises administering 2.0 mg / kg of the ADC to the subject on days 1, 22, 43, and 64.

[0060] E55. In some embodiments of E51, the method comprises administering 2.4 mg / kg of the ADC to the subject on days 1, 22, 43, and 64.

[0061] E56. The presently disclosed subject matter is directed to a method of treating small cell lung cancer (SCLC) in a subject comprising administering to the subject: (a) 0.5 mg-2.0 mg of tarlatamab, 0.5 mg / kg-2.5 mg / kg tambotatug pelitecan, and 1000 mg-2000 mg of an anti-PD-Ll antibody on day 1; (b) 15 mg-30 mg of tarlatamab on day 8; (c) 15 mg-30 mg of tarlatamab, 0.5 mg / kg-2.5 mg / kg tambotatug pelitecan, and 1000 mg-2000 mg of the anti-PD-Ll antibody on each of days 22, 43, and 64; and (d) 15 mg-30 mg of tarlatamab and 1000 mg-2000 mg of the anti-PD-Ll antibody starting on day 85 and once every three weeks (Q3W) thereafter.

[0062] E57. In some embodiments of E56, the method comprises administering to the subject: (a) 1 mg tarlatamab, 0.8 mg / kg, 1.6 mg / kg, 2.0 mg / kg, or 2.4 mg / kg tambotatug pelitecan, and 1000 mg-2000 mg of the anti-PD-Ll antibody on day 1; (b) 20 mg tarlatamab on day 8; and (c) 20 mg tarlatamab, 0.8 mg / kg, 1.6 mg / kg, 2.0 mg / kg, or 2.4 mg / kg tambotatug pelitecan and 1000 mg-2000 mg of the anti-PD-Ll antibody on days 22, 43, and 64; and (d) 20Amgen Ref. No. 10954-W001-SECmg tarlatamab and 1000 mg-2000 mg of the anti-PD-Ll antibody starting on day 85 and once every three weeks (Q3W) thereafter.

[0063] E58. In some embodiments of any one of E50-E57, the small cell lung cancer is extensive stage small cell lung cancer (ES-SCLC).

[0064] E59. In some embodiments of any one of E50-E58, the subject has not received prior treatment for SCLC other than one cycle of platinum -based chemotherapy, anti-PD-Ll antibody, and etoposide.

[0065] E60. The presently disclosed subject matter is directed to use of a bispecific T cell engager molecule (TCE) and an antibody-drug conjugate (ADC) in the manufacture of a medicament for the treatment of small cell lung cancer (SCLC) in a subject, wherein the bispecific TCE comprises the amino acid sequence of SEQ ID NO: 13 and the ADC is of Formula I;Formula Iwherein Ab is an anti-B7-H3 monoclonal antibody comprising SEQ ID NOs: 25-30, SEQ ID NOs: 31-36, or SEQ ID NOs: 37-42; and q is 6 to 8, and wherein the treatment comprises administering to the subject: (a) 0.5 mg-2.0 mg of the bispecific TCE and 0.5 mg / kg-2.5 mg / kg of the ADC on day 1; (b) 15 mg-30 mg of the bispecific TCE on day 8, and (c) 15 mg-30 mg of the bispecific TCE and 0.5 mg / kg- 2.5 mg / kg of the ADC starting on day 22 and once every three weeks (Q3W) thereafter.Amgen Ref. No. 10954-W001-SEC

[0066] E61. The presently disclosed subject matter is directed to use of a bispecific T cell engager molecule (TCE), an antibody-drug conjugate (ADC), and an anti-PD-Ll antibody in the manufacture of a medicament for the treatment of small cell lung cancer (SCLC) in a subject, wherein the bispecific TCE comprises the amino acid sequence of SEQ ID NO: 13 and the ADC is of Formula I;Formula Iwherein Ab is an anti-B7-H3 monoclonal antibody comprising SEQ ID NOs: 25-30, SEQ ID NOs: 31-36, or SEQ ID NOs: 37-42; and q is 6 to 8, and wherein the treatment comprises administering to the subject: (a) 0.5 mg-2.0 mg of the bispecific TCE, 0.5 mg / kg-2.5 mg / kg of the ADC, and 1000 mg-2000 mg of the anti-PD-Ll antibody on day 1; (b) 15 mg-30 mg of the bispecific TCE on day 8; (c) 15 mg-30 mg of the bispecific TCE, 0.5 mg / kg-2.5 mg / kg of the ADC, and 1000 mg-2000 mg of the anti-PD-Ll antibody on days 22, 43, and 64; and (d) 15 mg-30 mg of the bispecific TCE and 1000 mg-2000 mg of the anti-PD-Ll antibody starting on day 85 and once every three weeks (Q3W) thereafter.

[0067] E62. In some embodiments of E60 or E61, the bispecific TCE is tarlatamab and the ADC is tambotatug pelitecan.

[0068] E63. The presently disclosed subject matter is directed to a medicament comprising a bispecific T cell engager molecule (TCE) and an antibody-drug conjugate (ADC) for use in a method for treating small cell lung cancer (SCLC) in a subject, wherein the bispecific TCE comprises the amino acid sequence of SEQ ID NO: 13 and the ADC is of Formula I:Amgen Ref. No. 10954-W001-SECFormula Iwherein Ab is an anti-B7-H3 monoclonal antibody comprising SEQ ID NOs: 25-30, SEQ ID NOs: 31-36, or SEQ ID NOs: 37-42; and q is 6 to 8, the method comprising administering to the subject: (a) 0.5 mg-2.0 mg of the bispecific TCE and 0.5 mg / kg-2.5 mg / kg of the ADC on day 1; (b) 15 mg-30 mg of the bispecific TCE on day 8, and (c) 15 mg-30 mg of the bispecific TCE and 0.5 mg / kg- 2.5 mg / kg of the ADC starting on day 22 and once every three weeks (Q3W) thereafter.

[0069] E64. The presently disclosed subject matter is directed to a medicament comprising a bispecific T cell engager molecule (TCE), an antibody-drug conjugate ADC, and an anti-PD-Ll antibody for use in a method of treating small cell lung cancer (SCLC) in a subject, wherein the bispecific TCE comprises the amino acid sequence of SEQ ID NO: 13 and the ADC is of Formula 1;Amgen Ref. No. 10954-W001-SECwherein Ab is an anti-B7-H3 monoclonal antibody comprising SEQ ID NOs: 25-30, SEQ ID NOs: 31-36, or SEQ ID NOs: 37-42; and q is 6 to 8, the method comprising administering to the subject: (a) 0.5 mg-2.0 mg of the bispecific TCE, 0.5 mg / kg-2.5 mg / kg of the ADC, and 1000 mg-2000 mg of the anti-PD-Ll antibody on day 1; (b) 15 mg-30 mg of the bispecific TCE on day 8; (c) 15 mg-30 mg of the bispecific TCE, 0.5 mg / kg-2.5 mg / kg of the ADC, and 1000 mg-2000 mg of the anti-PD-Ll antibody on days 22, 43, and 64; and (d) 15 mg-30 mg of the bispecific TCE and 1000 mg-2000 mg of the anti-PD-Ll antibody starting on day 85 and once every three weeks (Q3W) thereafter.

[0070] E65. In some embodiments of E63 or E64, the bispecific TCE is tarlatamab and the ADC is tambotatug pelitecan.

[0071] E66. The presently disclosed subject matter is directed to (a) 15 mg-30 mg of a bispecific T cell engager molecule (TCE) and (b) 0.5 mg / kg - 2.5 mg / kg of an antibody-drug conjugate (ADC) for use in treating small cell lung cancer (SCLC) in a subject. The bispecific TCE and the ADC are administered to the subject once every three weeks (Q3W), wherein the bispecific TCE comprises (i) a human DLL3-binding domain comprising SEQ ID NOs: 5-10 and (ii) a human CD3-binding domain comprising SEQ ID NOs: 14-19, and the ADC is of Formula I;Formula Iwherein Ab is an anti-B7-H3 monoclonal antibody comprising SEQ ID NOs: 25-30, SEQ ID NOs: 31-36, or SEQ ID NOs: 37-42; and q is 6 to 8.Amgen Ref. No. 10954-W001-SEC

[0072] E67. In some embodiments of E66, the bispecific TCE and the ADC are administered to the subject in multiple 21 -day cycles.

[0073] E68. In some embodiments of E66 or E67, the bispecific TCE and the ADC are administered on day 1 of each of the multiple 21 -day cycles.

[0074] E69. In some embodiments of any one of E66-E68, the treatment comprises administering to the subject: (a) 0.5 mg-2.0 mg of the bispecific TCE and 0.5 mg / kg-2.5 mg / kg of the ADC on day 1 ; (b) 15 mg-30 mg of the bispecific TCE on day 8; and (c) 15 mg-30 mg of the bispecific TCE and 0.5 mg / kg-2.5 mg / kg of the ADC starting on day 22 and once every three weeks (Q3W) thereafter.

[0075] E70. In some embodiments of E69, the treatment comprises administering to the subject: (a) 1 mg of the bispecific TCE and 0.8 mg / kg, 1.6 mg / kg, 2.0 mg / kg, or 2.4 mg / kg of the ADC on day 1; (b) 20 mg of the bispecific TCE on day 8; and (c) 20 mg of the bispecific TCE and 0.8 mg / kg, 1.6 mg / kg, 2.0 mg / kg, or 2.4 mg / kg of the ADC on day 22 and once every three weeks (Q3W) thereafter.

[0076] E71. In some embodiments of E70, the treatment comprises administering 0.8 mg / kg of the ADC to the subject on days 1 and 22 and Q3W thereafter.

[0077] E72. In some embodiments of E70, the treatment comprises administering 1.6 mg / kg of the ADC to the subject on days 1 and 22 and Q3W thereafter.

[0078] E73. In some embodiments of E70, the treatment comprises administering 2.0 mg / kg of the ADC to the subject on days 1 and 22 and Q3W thereafter.

[0079] E74. In some embodiments of E70, the treatment comprises administering 2.4 mg / kg of the ADC to the subject on days 1 and 22 and Q3W thereafter.

[0080] E75. In some embodiments of any one of E66-E74, the bi specific TCE and the ADC are administered to the subject via intravenous (IV) injection.Amgen Ref. No. 10954-W001-SEC

[0081] E76. The presently disclosed subject matter is directed to (a) a bispecific T cell engager molecule (TCE) comprising (i) a DLL3-binding domain comprising SEQ ID NOs: 5-10 and (ii) a CD3 -binding domain comprising SEQ ID NOs: 14-19; (b) an anti-PD-Ll antibody; and (c) an antibody-drug conjugate (ADC) of Formula I for use in treating small cell lung cancer (SCLC) in a subject.Formula IThe bispecific TCE, the anti-PD-Ll antibody, and the ADC are administered to the subject once every three weeks (Q3W); wherein Ab is an anti-B7-H3 monoclonal antibody comprising SEQ ID NOs: 25-30, SEQ ID NOs: 31-36, or SEQ ID NOs: 37-42; and q is 6 to 8.

[0082] E77. In some embodiments of E76, the bispecific TCE, the ADC, and the anti-PD-Ll antibody are administered to the subject in multiple 21-day cycles.

[0083] E78. In some embodiments of E77, the bispecific TCE, the ADC, and the anti-PD-Ll antibody are administered on day 1 of each of the multiple 21-day cycles.

[0084] E79. In some embodiments of any one of E76-E78, the treatment comprises administering to the subject: (a) 0.5 mg-2.0 mg of the bispecific TCE, 0.5 mg / kg-2.5 mg / kg of the ADC, and 1000 mg-2000 mg of the anti-PD-Ll antibody on day 1; (b) 15 mg-30 mg of the bispecific TCE on day 8; (c) 15 mg-30 mg of the bispecific TCE, 0.5 mg / kg-2.5 mg / kg of the ADC, and 1000 mg-2000 mg of the anti-PD-Ll antibody on days 22, 43, and 64; and (d) 15 mg-Amgen Ref. No. 10954-W001-SEC30 mg of the bispecific TCE and 1000 mg-2000 mg of the anti-PD-Ll antibody starting on day 85 and once every three weeks (Q3W) thereafter.

[0085] E80. In some embodiments of E79, the treatment comprises administering to the subject: (a) 1 mg of the bispecific TCE, 0.8 mg / kg, 1.6 mg / kg, 2.0 mg / kg, or 2.4 mg / kg of the ADC, and 1000 mg-2000 mg of the anti-PD-Ll antibody on day 1; (b) 20 mg of the bispecific TCE on day 8; (c) 20 mg of the bispecific TCE, 0.8 mg / kg, 1.6 mg / kg, 2.0 mg / kg, or 2.4 mg / kg of the ADC and 1000 mg-2000 mg of the anti-PD-Ll antibody on days 22, 43, and 64; and (d) 20 mg of the bispecific TCE and 1000 mg-2000 mg of the anti-PD-Ll antibody starting on day 85 and once every three weeks (Q3W) thereafter.

[0086] E81. In some embodiments of E80, the treatment comprises administering 0.8 mg / kg of the ADC to the subject on days 1, 22, 43, and 64.

[0087] E82. In some embodiments of E80, the treatment comprises administering 1.6 mg / kg of the ADC to the subject on days 1, 22, 43, and 64.

[0088] E83. In some embodiments of E80, the treatment comprises administering 2.0 mg / kg of the ADC to the subject on days 1, 22, 43, and 64.

[0089] E84. In some embodiments of E80, the treatment comprises administering 2.4 mg / kg of the ADC to the subject on days 1, 22, 43, and 64.

[0090] E85. In some embodiments of any one of E76-E84, the bispecific TCE and the ADC are administered to the subject via intravenous (IV) injection.

[0091] E86. In some embodiments of any one of E76-E85, the anti-PD-Ll antibody is durvalumab or atezolizumab.

[0092] E87. In some embodiments of E86, the treatment comprises administering 1500 mg durvalumab intravenously (IV) to the subject on days 1, 22, 43, 64, 85 and Q3W thereafter.Amgen Ref. No. 10954-W001-SEC

[0093] E88. In some embodiments of E86, the treatment comprises administering 1200 mg atezolizumab IV to the subject on days 1, 22, 43, 64, 85 and Q3W thereafter.

[0094] E89. In some embodiments of any one of E66-E88, the bispecific TCE comprises the amino acid sequence of SEQ ID NO: 13.

[0095] E90. In some embodiments of any one of E66-E89, the bispecific TCE comprises the amino acid sequence of SEQ ID NO: 22.

[0096] E91. In some embodiments of any one of E66-E90, the bispecific TCE comprises the amino acid sequence of SEQ ID NO: 24.

[0097] E92. In some embodiments of any one of E66-E91, the anti-B7-H3 monoclonal antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 45 and a light chain amino acid sequence of SEQ ID NO: 46.

[0098] E93. In some embodiments of any one of E66-E92, the small cell lung cancer is extensive stage small cell lung cancer (ES-SCLC).

[0099] E94. In some embodiments of any one of E66-E93, the small cell lung cancer is refractory SCLC or relapsed SCLC.

[0100] E95. In some embodiments of any one of E66-E94, the small cell lung cancer expresses DLL3 as determined by immunohistochemistry.

[0101] E96. In some embodiments of any one of E66-E95, the SCLC has progressed or relapsed following at least one previous treatment.

[0102] E97. In some embodiments of E96, the at least one previous treatment comprises platinum-based chemotherapy, etoposide, a PD-L1 inhibitor, or combinations thereof.

[0103] E98. In some embodiments of E97, the platinum-based chemotherapy comprises carboplatin or cisplatin.Amgen Ref. No. 10954-W001-SEC

[0104] E99. In some embodiments of any one of E66-E98, the treatment further comprises administering at least one additional therapeutic agent to the subject.

[0105] El 00. In some embodiments of E99, the at least one additional therapeutic agent comprises dexamethasone, an anti-emetic agent, granulocyte colony-stimulating factor (G-CSF), and / or saline.

[0106] E101. The presently disclosed subject matter is directed to tarlatamab and an antibody-drug conjugate (ADC) for use in treating small cell lung cancer (SCLC) in a subject. The treatment comprises administering to the subject: (a) 0.5 mg-2.0 mg tarlatamab and 0.5 mg / kg-2.5 mg / kg of the ADC on day 1; (b) 15 mg-30 mg tarlatamab on day 8; (c) 15 mg-30 mg tarlatamab and 0.5 mg / kg-2.5 mg / kg of the ADC starting on day 22 and once every three weeks (Q3W) thereafter; wherein the ADC is of Formula I;Formula Iwherein Ab is an anti-B7-H3 monoclonal antibody comprising a heavy chain amino acid sequence of SEQ ID NO: 45 and a light chain sequence of SEQ ID NO: 46, and q is 6 to 8.

[0107] E102. In some embodiments of E101, the treatment comprises administering to the subject: (a) 1 mg tarlatamab and 0.8 mg / kg, 1.6 mg / kg, 2.0 mg / kg, or 2.4 mg / kg of the ADC on day 1; (b) 20 mg tarlatamab on day 8; and (c) 20 mg tarlatamab and 0.8 mg / kg, 1.6 mg / kg, 2.0 mg / kg, or 2.4 mg / kg of the ADC on day 22 and once every three weeks (Q3W) thereafter.Amgen Ref. No. 10954-W001-SEC

[0108] E103. In some embodiments of E101 or E102, the treatment comprises administering 0.8 mg / kg of the ADC to the subject on days 1 and 22 and Q3W thereafter.

[0109] E104. In some embodiments of E101 or E102, the treatment comprises administering 1.6 mg / kg of the ADC to the subject on days 1 and 22 and Q3W thereafter.

[0110] E105. In some embodiments of E101 or E102, the treatment comprises administering 2.0 mg / kg of the ADC to the subject on days 1 and 22 and Q3W thereafter.[OHl] E106. In some embodiments ofElOl or E102, the treatment comprises administering 2.4 mg / kg of the ADC to the subject on days 1 and 22 and Q3W thereafter.

[0112] E107. The presently disclosed subject matter is directed to tarlatamab and tambotatug pelitecan for use in treating small cell lung cancer (SCLC) in a subject. The treatment comprises administering to the subject: (a) 0.5 mg-2.0 mg tarlatamab and 0.5 mg / kg-2.5 mg / kg tambotatug pelitecan on day 1; (b) 15 mg-30 mg tarlatamab on day 8; (c) 15 mg-30 mg tarlatamab and 0.5 mg / kg-2.5 mg / kg tambotatug pelitecan starting on day 22 and once every three weeks (Q3W) thereafter.

[0113] E108. In some embodiments of E107, the treatment comprises administering to the subject: (a) 1 mg tarlatamab and 0.8 mg / kg, 1.6 mg / kg, 2.0 mg / kg, or 2.4 mg / kgtambotatug pelitecan on day 1; (b) 20 mg tarlatamab on day 8; and (c) 20 mg tarlatamab and 0.8 mg / kg, 1.6 mg / kg, 2.0 mg / kg, or 2.4 mg / kg tambotatug pelitecan on day 22 and once every three weeks (Q3W) thereafter.

[0114] E109. In some embodiments of any one of E101-E108, the small cell lung cancer is extensive stage small cell lung cancer (ES-SCLC).

[0115] E110. In some embodiments of any one of E101-E109, the small cell lung cancer is refractory SCLC or relapsed SCLC.Amgen Ref. No. 10954-W001-SEC

[0116] El 11. In some embodiments of any one of E101-E110, the SCLC has progressed or relapsed following at least one previous treatment.

[0117] El 12. In some embodiments of El 11, the at least one previous treatment comprises platinum-based chemotherapy, etoposide, aPD-Ll inhibitor, or combinations thereof.

[0118] El 13. In some embodiments of El 12, the platinum-based chemotherapy comprises carboplatin or cisplatin.

[0119] El 14. The presently disclosed subject matter is directed to tarlatamab, an antibodydrug conjugate (ADC), and an anti-PD-Ll antibody for use in treating small cell lung cancer (SCLC) in a subject. The treatment comprises administering to the subject: (a) 0.5 mg-2.0 mg of tarlatamab, 0.5 mg / kg-2.5 mg / kg of the ADC, and 1000 mg-2000 mg of the anti-PD-Ll antibody on day 1; (b) 15 mg-30 mg of tarlatamab on day 8; (c) 15 mg-30 mg of tarlatamab, 0.5 mg / kg-2.5 mg / kg of the ADC, and 1000 mg-2000 mg of the anti-PD-Ll antibody on each of days 22, 43, and 64; and (d) 15 mg-30 mg of tarlatamab and 1000 mg-2000 mg of the anti-PD-Ll antibody starting on day 85 and once every three weeks (Q3W) thereafter; wherein the ADC is of Formula I;Formula Iwherein Ab is an anti-B7-H3 monoclonal antibody comprising a heavy chain amino acid sequence of SEQ ID NO: 45 and a light chain amino acid sequence of SEQ ID NO: 46, and q is 8.Amgen Ref. No. 10954-W001-SEC

[0120] El 15. In some embodiments of El 14, the treatment comprises administering to the subject: (a) 1 mg tarlatamab, 0.8 mg / kg, 1.6 mg / kg, 2.0 mg / kg, or 2.4 mg / kg of the ADC, and 1000 mg-2000 mg of the anti-PD-Ll antibody on day 1; (b) 20 mg tarlatamab on day 8; (c) 20 mg tarlatamab, 0.8 mg / kg, 1.6 mg / kg, 2.0 mg / kg, or 2.4 mg / kg of the ADC and 1000 mg-2000 mg of the anti-PD-Ll antibody on days 22, 43, and 64; and (d) 20 mg tarlatamab and 1000 mg-2000 mg of the anti-PD-Ll antibody starting on day 85 and once every three weeks (Q3W) thereafter.

[0121] El 16. In some embodiments of El 15, the treatment comprises administering 0.8 mg / kg of the ADC to the subject on days 1, 22, 43, and 64.

[0122] El 17. In some embodiments of El 15, the treatment comprises administering 1.6 mg / kg of the ADC to the subject on days 1, 22, 43, and 64.

[0123] El 18. In some embodiments of El 15, the treatment comprises administering 2.0 mg / kg of the ADC to the subject on days 1, 22, 43, and 64.

[0124] El 19. In some embodiments of El 15, the treatment comprises administering 2.4 mg / kg of the ADC to the subject on days 1, 22, 43, and 64.

[0125] E120. The presently disclosed subject matter is directed to tarlatamab, tambotatug pelitecan, and an anti-PD-Ll antibody for use in treating small cell lung cancer (SCLC) in a subject. The treatment comprises administering to the subject: (a) 0.5 mg-2.0 mg of tarlatamab, 0.5 mg / kg-2.5 mg / kg tambotatug pelitecan, and 1000 mg-2000 mg of the anti-PD-Ll antibody on day 1; (b) 15 mg-30 mg of tarlatamab on day 8; (c) 15 mg-30 mg of tarlatamab, 0.5 mg / kg-2.5 mg / kg tambotatug pelitecan, and 1000 mg-2000 mg of the anti-PD-Ll antibody on each of days 22, 43, and 64; and (d) 15 mg-30 mg of tarlatamab and 1000 mg-2000 mg of the anti-PD-Ll antibody starting on day 85 and once every three weeks (Q3W) thereafter.

[0126] E121. In some embodiments of E120, the treatment comprises administering to the subject: (a) 1 mg tarlatamab, 0.8 mg / kg, 1.6 mg / kg, 2.0 mg / kg, or 2.4 mg / kgAmgen Ref. No. 10954-W001-SECtambotatug pelitecan, and 1000 mg-2000 mg of the anti-PD-Ll antibody on day 1; (b) 20 mg tarlatamab on day 8; (c) 20 mg tarlatamab, 0.8 mg / kg, 1.6 mg / kg, 2.0 mg / kg, or 2.4 mg / kg tambotatug pelitecan and 1000 mg-2000 mg of the anti-PD-Ll antibody on days 22, 43, and 64; and (d) 20 mg tarlatamab and 1000 mg-2000 mg of the anti-PD-Ll antibody starting on day 85 and once every three weeks (Q3W) thereafter.

[0127] E122. In some embodiments of any one of El 14-E121, the small cell lung cancer is extensive stage small cell lung cancer (ES-SCLC).

[0128] E123. In some embodiments of any one of El 14-E122, the subject has not received prior treatment for SCLC other than one cycle of platinum -based chemotherapy, anti-PD-Ll antibody, and etoposide.BRIEF DESCRIPTION OF THE FIGURES

[0129] FIGS. 1A-1C illustrates cytotoxicity of tarlatamab / AMG 757 with varying concentrations YL201 (EC20 = 24.8nM, EC50 = 166.6 nM, and EC90 = 3404.8nM) in DMS53 target cells co-cultured with human effector T cells as described in Example 1. Cytotoxicity was assessed at effector to target cell ratios (E:T ratio) of 10:1 E:T (FIG. 1 A.), 1 : 1 E:T (FIG. IB), and 1:3 (FIG. 1C) Tarlatamab / AMG 757 concentration is shown on the x-axis.

[0130] FIG. 2A shows average volumes of DMS53 xenograft tumors in NSG mice treated with (1) control EGFRvIII-HLE BiTE® molecule, (2) tarlatamab / AMG 757, (3) Isotype Control, (4) YL201, (5) EGFRvIII-HLE BiTE® molecule + Isotype Control, (6) EGFRvIII-HLE BiTE® molecule + YL201, (7) tarlatamab / AMG 757 + Isotype Control, and (8) tarlatamab / AMG 757 + YL201. FIG. 2B shows average body weight change of NSG mice treated with the abovereferenced molecules.

[0131] FIG. 3 is a diagram illustrating Parts 1-3 of the clinical study described in Example 3.

[0132] FIG. 4 is a diagram illustrating Parts 1 and 2 of the clinical study described in Example 3.Amgen Ref. No. 10954-W001-SEC

[0133] FIG. 5 is a diagram illustrating Part 3 of the clinical study described in Example 3.DETAILED DESCRIPTION

[0134] The present disclosure relates to a method for treating small cell lung cancer (SCLC) which combines multiple therapeutic approaches: a bispecific T cell engager (TCE) molecule targeting DLL3 and CD3 and an antibody-drug conjugate (ADC) targeting B7-H3. In some embodiments, the method includes the administration of an anti-PD-Ll antibody in combination with the bispecific TCE and ADC.

[0135] The dual -targeting mechanism of the bispecific TCE and ADC provides enhanced efficacy against SCLC compared to single-agent treatments. By engaging both the immune system and directly targeting cancer cells, this approach may overcome treatment resistance that is often observed in SCLC patients.

[0136] In some cases, the combination therapy may be particularly effective for treating extensive stage small cell lung cancer (ES-SCLC), including SCLC that has progressed or relapsed following previous treatments, such as platinum-based chemotherapy, etoposide, PD-L1 inhibitors, or combinations thereof.

[0137] In certain aspects, the bispecific TCE is tarlatamab and the ADC is YL201 (INN tambotatug pelitecan). Supported by preclinical studies showing increased T-cell infiltration and cytotoxic activity when tarlatamab is combined with cytotoxic chemotherapy (You R et al, 2023) as well as promising anti-tumor efficacy of ADCs plus T-cell engagers (TCEs) in other tumor types (Dickinson et al, 2023; Olszewski et al, 2022), YL201 offers an orthogonal mechanism of action to tarlatamab, potentially increasing benefit to patients. Notably, pre-clinical studies in mice described herein show that the combination of tarlatamab and tambotatug pelitecan induce a strong and sustained synergistic anti -tumor effect.Amgen Ref. No. 10954-W001-SECAnti-DLL3 Bispecific T Cell Engagers

[0138] In some aspects, the disclosed method comprises administering to a subject in need thereof a bispecific T cell engager molecule (also referred to herein as “TCE”) that binds to DLL3. The term “bi specific T cell engager” molecule refers to a recombinant protein construct made from two flexibly linked binding domains; each domain derived from antibodies. Antigenbinding domains retain the ability to specifically bind to an antigen (preferably with substantially the same binding affinity). Examples of an antigen-binding domains include (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CHI domains; (ii) a F(ab’)2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fd fragment consisting of the VH and CHI domains; (iv) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody; and (v) a dAb fragment (Ward et al., Nature 341 :544-546 (1989)), which consists of a VH domain. Furthermore, although the two domains of the Fv fragment, VL and VH, are coded for by separate genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as single chain Fv (scFv); see e.g., Bird et al. Science 242: 423-426 (1988) and Huston et al., Proc. Natl. Acad. Sci. USA 85: 5879-5883 (1988). One binding domain of the bispecific TCE is specific for a tumor-associated surface antigen (such as DLL3); the second binding domain is specific for CD3, a subunit of the T cell receptor complex on T cells. A variety of bispecific TCE formats are known in the art, including, but not limited to, BiTE® molecules. By their design, bispecific TCEs, such as BiTE® molecules, are uniquely suited to transiently connect T cells with target cells and, at the same time, potently activate the inherent cytolytic potential of T cells against target cells. See e.g., International Patent Publication Nos. WO 99 / 54440, WO 2005 / 040220, and WO 2008 / 119567, each of which is incorporated by reference in its entirety.

[0139] As used herein, the term “antibody” refers to an immunoglobulin of any isotype with specific binding to the target antigen; an antibody may be a polyclonal or monoclonal antibody, aAmgen Ref. No. 10954-W001-SECchimeric antibody, a humanized antibody, a human antibody, etc. In a native antibody, a heavy chain comprises a variable region, VH, and three constant regions, CHI, CH2, and CH3. The VH domain is at the amino-terminus of the heavy chain, and the CH3 domain is at the carboxyterminus. In a native antibody, a light chain comprises a variable region, VL, and a constant region, CL. The variable region of the light chain is at the amino-terminus of the light chain. In a native antibody, the variable regions of each light / heavy chain pair typically form the antigenbinding site. The constant regions are typically responsible for effector function. A native antibody is a tetramer of two full-length heavy chains and two full-length light chains.

[0140] In a human antibody, CHI means a region having the amino acid sequence at positions 118 to 215 of the EU index or EU numbering system, which is based on the sequential numbering of the first human IgGl sequenced (i.e., the “EU antibody”) (Edelman et al., Proc Natl Acad Sci USA, 63(1): 78-85 (1969)). A highly flexible amino acid region called a “hinge region” exists between CHI and CH2. CH2 represents a region having the amino acid sequence at positions 231 to 340 of the EU index, and CH3 represents a region having the amino acid sequence at positions 341 to 446 of the EU index.

[0141] “CL” represents a constant region of a light chain. In the case of a kappa (K) chain of a human antibody, CL represents a region having the amino acid sequence at positions 108 to 214 of the EU index. In a lambda (X) chain, CL represents a region having the amino acid sequence at positions 108 to 215.

[0142] In a native antibody, the variable regions typically exhibit the same general structure in which relatively conserved framework regions (FRs) are joined by three hypervariable complementarity determining regions (CDRs). The CDRs from the two chains of each pair typically are aligned by the framework regions, which may enable binding to a specific epitope. From N-terminus to C-terminus, both light and heavy chain variable regions typically comprise the domains FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4. Typically, CDR3 is the greatest source of molecular diversity within the antigen binding site. The assignment of amino acids toAmgen Ref. No. 10954-W001-SECeach domain is typically in accordance with the definitions of Kabat et al. (1991) Sequences of Proteins of Immunological Interest (National Institutes of Health, Publication No. 91-3242, vols.1-3, Bethesda, Md.); or Chothia, C., andLesk, A. M. (1987) J. Mol. Biol., 196: 901-917. In some embodiments, the CDRs of an antigen-binding protein are defined according to the definition of Kabat or Chothia. In the present application, the term “CDR” refers to a CDR from either the light or heavy chain, unless otherwise specified.

[0143] In some aspects of the method, the bispecific TCE comprises a binding domain that binds to human DLL3 on the surface of a target cell (a “DLL3 -binding domain”) and a binding domain that binds to human CD3 (a “CD3-binding domain”) on the surface of a T cell. The human DLL3 protein consists of 619 amino acids and an extracellular region comprising several domains: a signal peptide, an N-terminus domain, a Del ta / Serrate / L AG-2 (DSL) domain, six epidermal growth factor (EGF)-like repeats (i.e., EGF-1, EGF-2, EGF-3, EGF-4, EGF-5, and EGF-6), and a membrane proximal domain. The DLL3 C-terminus comprises the transmembrane domain. Alternative splicing of the gene encoding DLL3 produces two isoforms of the protein, which differ at the C-terminus but are identical in the extracellular region. The canonical DLL3 isoform is the 619 amino acid protein, the sequence of which is provided herein as SEQ ID NO: 1 and is disclosed in UniProt Q9NYJ7 and NCBI Reference Sequence: NP 058637.1. The amino acid sequence of the human DLL3 extracellular region comprises SEQ ID NO: 2, and the specific domains of the extracellular region may be defined by the amino acid positions shown in Table 1.Table 1Amgen Ref. No. 10954-W001-SEC

[0144] The bispecific TCE described herein may bind to any domain of the extracellular region defined herein. In some aspects, the first domain of the bispecific TCE binds to an epitope of DLL3 comprised within the amino acid sequence of SEQ ID NO: 2. In other aspects, the first domain of the bi specific TCE binds to an epitope of DLL3 comprised within the amino acid sequence of SEQ ID NO: 3. For example, the first domain of the bispecific TCE binds to an epitope of DLL3 comprised within the amino acid sequence of SEQ ID NO: 4.

[0145] The term “epitope” refers to any polypeptide determinant capable of specifically binding to an immunoglobulin, a T cell or B cell receptor, or any interacting protein, such as a surface protein. In certain embodiments, an epitope is a region of an antigen that is specifically bound by an antibody. In certain embodiments, an epitope may include chemically active surface groupings of molecules such as amino acids, sugar side chains, phosphoryl, or sulfonyl groups. In certain embodiments, an epitope may have specific three-dimensional structural characteristics (e.g., a “conformational” epitope) and / or specific charge characteristics.Conversely, the term “paratope,” as used herein, refers to the region of an antibody that recognizes and binds to an epitope of an antigen. Paratopes primarily, but not exclusively, areAmgen Ref. No. 10954-W001-SEClocated in the CDRs (Kunik et al., PLoS Comput Biol 8(2): el002388 (2012). doi.org / 10.1371 / journal.pcbi.1002388).

[0146] The CDRs of exemplary DLL3 -binding domains and CD3 -binding domains are provided in Table 6. The CDRs can be defined according to Kabat, Chothia, the accumulation of both Kabat and Chothia, AbM, contact, North, and / or conformational definitions or any method of CDR determination well known in the art. See, e.g., 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 in a particular antibody that make up a CDR can be determined using methods known in the art.

[0147] In certain embodiments, the DLL3-binding domain of the bispecific TCE comprises (a) a heavy chain variable region (VH) that comprises (i) a VH complementarity determining region one (CDR-H1) comprising the amino acid sequence of SEQ ID NO: 5, (ii) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 6, and (iii) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 7; and (b) a light chain variable region (VL) that comprises (i) a VL complementarity determining region one (CDR-L1) comprising the amino acid sequence of SEQ ID NO: 8, (ii) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 9, and (iii) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 10.

[0148] In certain embodiments, the DLL3-binding domain comprises a VH that comprises the amino acid sequence of SEQ ID NO: 11, and a VL that comprises the amino acid sequence of SEQ ID NO: 12. In some embodiments, the VH and VL are joined by a linker to form a single chain Fv (scFv). Linkers are known in the art and further described in, e.g., WO2017 / 021349, hereby incorporated by reference in its entirety. In certain embodiments, the DLL3 binding domain comprises the amino acid sequence of SEQ ID NO: 13Amgen Ref. No. 10954-W001-SEC

[0149] In various aspects, the CD3-binding domain of the bispecific TCE comprises (a) a VH that comprises (i) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 14, (ii) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 15, and (iii) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 16; and a VL that comprises (i) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 17, (ii) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 18, and (iii) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 19.

[0150] In certain embodiments, the CD3-binding domain comprises a VH that comprises the amino acid sequence of SEQ ID NO: 20, and a VL that comprises the amino acid sequence of SEQ ID NO: 21. In some embodiments, the VH and VL are joined by a linker to form a single chain Fv (scFv). In some embodiments, the linker is a peptide linker. In certain embodiments, the CD3-binding domain comprises the amino acid sequence of SEQ ID NO: 22. In some aspects, the bispecific TCE described herein comprises the amino acid sequence of SEQ ID NO: 23.

[0151] In certain aspects, in addition to the DLL3 -binding domain and the CD3 -binding domain, the bispecific TCE described herein comprises a third domain which comprises an Fc domain (or 2 Fc domains). Preferably, the Fc domain amino acid sequence(s) are positioned C-terminal of the first and second binding domains, through other arrangements (for example, Fc domain(s) sequences that are not C-terminal to the first binding domain and second binding domain) are also contemplated. For example, in certain embodiments, the third domain comprises two polypeptide monomers, each comprising a hinge, a CH2 domain, and a CH3 domain, wherein said two polypeptide monomers are fused to each other via a peptide linker. Preferably, the third domain comprises in an N- to C-terminal order: hinge-CH2-CH3-linker-hinge-CH2-CH3. It is appreciated that common C-terminal variants such as C-terminal lysine clipping may be present in constructs comprising Fc domains.

[0152] In various aspects, the bispecific TCE is tarlatamab. Tarlatamab has been approved by the U.S. Food and Drug Administration (FDA) under the brand name IMDELLTRA® for theAmgen Ref. No. 10954-W001-SECtreatment of adults with extensive-stage small cell lung cancer (ES-SCLC) with disease progression on or after platinum-based chemotherapy. The activity of tarlatamab requires the simultaneous binding to both target cells (DLL3+ cells) and T cells. The pharmacological effect of tarlatamab is mediated by specific redirection of previously primed cytotoxic CD8+ or CD4+ T lymphocytes to kill DLL3+ cells. Clinical evaluations of tarlatamab in earlier lines of SCLC (monotherapy and combination therapy) and neuroendocrine prostate cancer are ongoing (see, e.g., ClinicalTrials.gov Identifiers NCT03319940 and NCT04702737 and Owonikoko et al., Journal of Clinical Oncology 39:15_suppl, 8510-8510 (2021)). Tarlatamab is described in detail in, for example, WO 2017 / 021349 and WO 2021 / 092134. Tarlatamab comprises the amino acid sequence of SEQ ID NO: 24.Antibody-Drug Conjugate

[0153] In other aspects, the method disclosed herein comprises administering to the subject an antibody-drug conjugate (ADC) and the bispecific TCE. ADCs combine the specificity of monoclonal antibodies with the cancer-killing ability of chemotherapy, allowing for more precise targeting of cancer cells while minimizing damage to healthy tissue. An ADC typically contains three main components: (1) an antibody or other antigen-binding protein designed to specifically bind to a particular antigen found on the surface of cancer cells; (2) a cytotoxic agent (or “payload”) that is highly potent against cancer cells; and (3) a chemical linker that connects the antibody or antigen-binding protein to the cytotoxic agent. The cytotoxic agent is released from the linker once the ADC enters a cancer cell and / or within tumor tissues. As of 2023, 11 ADC therapeutics have been approved by the FDA for both hematological cancer and solid tumors, and more than 100 ADCs are currently in clinical development (Gogia et al., Cancers (Basel), 15(15): 3886 (2023)).

[0154] In some aspects, the ADC comprises a monoclonal antibody that binds to B7 homolog 3 (B7-H3). B7 homolog 3, also known as CD276, is a type I transmembrane protein with high expression in human SCLC that has been implicated in immune evasion and associatedAmgen Ref. No. 10954-W001-SECwith poor prognosis (Qiu et al, 2021; Zhang et al, 2017). Due to the poor outcomes associated with SCLC and the high unmet need for SCLC treatments, B7-H3 has been considered as an attractive target for SCLC therapy.

[0155] The terms “payload molecule” and “payload” refer to a molecule that exerts a desired therapeutic effect (e.g., cytotoxicity) after internalization of an ADC into target cells and / or in tumor tissues. For example, once an ADC enters the bloodstream and binds to a target receptor on the surface of a target cell, the newly formed ADC-receptor complex is internalized and degraded by lysosomes. The payload molecule is then released to exert its toxic effect, often by disrupting cellular processes such as DNA replication or protein synthesis. Therapeutically effective payload molecules are typically characterized by high potency / toxicity, low immunogenicity, high stability, and the presence of functional groups that can be modified without significantly affecting their potency. Commonly used payload molecules include, but are not limited to, microtubule inhibitors (e.g., auristatin, maytansinoids), DNA damaging agents (e g., calicheamicin, duocarmycins, anthracy clines, pyrrol obenzodiazepine dimers) and DNA transcription inhibitors (e.g., amatoxin and quinoline alkaloid (SN-38)).

[0156] The linker that connects an antibody to a payload molecule should ensure that a payload molecule remains attached until the ADC reaches its target cells. A suitable linker should also enable the payload molecule to be released in the target cell after internalization and / or in tumor tissues, which is often triggered by specific conditions such as low pH, the presence of specific enzymes, or reduction in the intracellular environment.

[0157] The ADC may comprise any suitable linker. In general, ADCs are generated using linkers that are classified as cleavable or non-cleavable. Cleavable linkers release payload molecules in response to enzymes, changes in pH, changes in temperature, or under reducing or oxidizing conditions. Exemplary cleavable linkers include, but are not limited to, acid cleavable linkers (e.g., hydrazone or carbonate linkers), reducible disulfide linkers (e.g., glutathione (GSH)), Fe(II) cleavable linkers (e.g., 1, 2, 4-tri oxolane), photo-responsive cleavable linkers (e.g.,Amgen Ref. No. 10954-W001-SECheptamethine cyanine fluorophore, O-Nitrobenzyl, and PC4AP), and enzyme-cleavable linkers (e.g., valine-vitrulline (Val-Cit), dipeptide linkers (e.g., alanine-alanine), triglycyl peptide linker, and glycine-phenylalanine-leucine-glycine (GFLG) linkers.) Other cleavable linkers are known in the art (see, e.g., Bargh et al., Chem. Soc. Rev.: 48, 4361-4374 (2019); Su et al., Acta Pharm SinB., 1 l(12):3889-3907 (2021); and Khongorzul et al., Mol Cancer Res, 18: 3-19 (2020)). Non-cleavable linkers are designed to retain the payload attached to the antibody until the entire ADC is internalized and degraded within the target cell. The payload is then released as an active metabolite, which includes the payload and a portion of the linker, ensuring precise delivery and minimal systemic release. In some aspects, non-cleavable linkers are substantially resistant to acid-induced cleavage, light-induced cleavage, peptidase-induced cleavage, esterase-induced cleavage, and disulfide bond cleavage. In general, non-cleavable linkers may be classified as a thioether linker or a maleimidocaproyl (MC) linker. Exemplary non-cleavable linkers include linkers having an N-succinimidyl ester, N-sulfosuccinimidyl ester moiety, or maleimido- or haloacetyl-based moieties for reaction with a payload molecule or an antibody. Non-cleavable linkers comprising a maleimido-based moiety include, but are not limited to, N-succinimidyl 4-(maleimidomethyl)cyclohexanecarboxylate (SMCC), N-succinimidyl-4-(N-maleimidomethyl)-cyclohexane-l-carboxy-(6-amidocaproate), which is a “long chain” analog of SMCC (LC-SMCC), K-maleimidoundecanoic acid N-succinimidyl ester (KMUA), y-maleimidobutyric acid N-succinimidyl ester (GMBS), e-maleimidocaproic acid N-hydroxysuccinimide ester (EMCS), m-maleimidobenzoyl-N-hydroxysuccinimide ester (MBS), N-(a-maleimidoacetoxy)-succinimide ester (AMAS), succinimidyl-6-(P-maleimidopropionamido)hexanoate (SMPH), N-succinimidyl 4-(p-maleimidophenyl)-butyrate (SMPB), and N-(p-maleimidophenyl)isocyanate (PMPI). Non-cleavable linkers comprising a haloacetyl-based moiety include, but are not limited to, N-succinimidyl-4-(iodoacetyl)-aminobenzoate (SIAB), N-succinimidyl iodoacetate (SIA), N-succinimidyl bromoacetate (SBA), and N-succinimidyl 3-(bromoacetamido)propionate (SBAP). Other non-cleavable linkers are known in the art (see, e.g., Su et al., Acta Pharm Sin B.,Amgen Ref. No. 10954-W001-SEC11 ( 12): 3889-3907 (2021) and Jain et al., Pharm Res., 32: 3526-3540 (2015); and Nolting, B. (2013). Linker Technologies for Antibody-Drug Conjugates. In: Ducry, L. (eds) Antibody-Drug Conjugates. Methods in Molecular Biology, vol 1045. Humana Press, Totowa, NJ).

[0158] The number of payload molecules attached to an antibody, referred to as the drug-to-antibody ratio or “DAR,” refers to the number of drug molecules attached to an antibody molecule in an ADC. The term DAR may be used to refer to the number of drug molecules attached to a single antibody, or alternatively, to refer to the average or mean DAR of a group of ADCs. DAR affects the properties and pharmacokinetics of an ADC. In this regard, a low DAR may result in low potency of the ADC, while increasing the number of payload molecules could lead to higher concentrations of the drug at the target sites. On the other hand, a DAR that is too high may adversely affect affinity of the ADC toward the target antigen and may also result in aggregation and precipitation of the antibody, potentially leading to a decrease in ADC stability and faster clearance of the ADC. The DAR of an ADC can range from 1 to 16, but depends on the number of attachment sites in the antibody, thus higher loads (e.g., 20) are also possible. The DAR of an ADC may be measured by methods known in the art, including ultraviolet-visible (UV / Vis) spectroscopy, hydrophobic interaction chromatography (HIC), reverse-phase high-performance liquid chromatography (RP-HPLC), and mass spectrometry (MS). In certain embodiments, DAR of an ADC is measured by mass spectrometry.

[0159] Exemplary B7-H3 ADCs that may be used in the disclosed methods include, but are not limited to ifinatamab deruxtecan, GSK5764227 / HS-20093, and YL201 (INNtambotatug pelitecan). Ifinatamab deruxtecan (LDXd) is an is an investigational ADC comprising a humanized monoclonal antibody that targets B7-H3 conjugated to the cytotoxic agent deruxtecan. I-DXd is being is being jointly developed by Daiichi Sankyo and Merck for the treatment of a variety of solid tumors, including SCLC (see, e.g., ClinicalTrials.gov IDs, NCT06330064, NCT06362252, and NCT06780137). GSK5764227, also known as HS-20093, is another investigational B7-H3 -targeted ADC composed of a fully human anti-B7-H3 monoclonalAmgen Ref. No. 10954-W001-SECantibody covalently linked to a topoisomerase inhibitor payload. GSK5764227 is being developed by Hansoh Pharma in China and GlaxoSmithKline in the U.S. for the treatment of lung cancer, sarcoma, head and neck cancers and other solid tumors (see, e.g., ClinicalTrials.gov ID NCT05276609). GSK5764227 was granted Breakthrough Therapy Designation by the U.S. FDA for the treatment of patients with relapsed or refractory extensive-stage small-cell lung cancer disease progression on or after platinum-based chemotherapy (relapsed or refractory) and for the treatment of patients with relapsed or refractory osteosarcoma who have progressed on at least two prior lines of therapy. B7-H3 -targeting ADCs are described in further detail in, for example, U.S. Patents 9,808,537 and 10,195,288; and U.S. Patent Application Publication No.2021 / 0347894.

[0160] In various aspects of the disclosed method, the ADC is YL201. YL201 is a B7-H3-targeting ADC comprised of an anti-B7-H3 human monoclonal antibody conjugated to a topoisomerase 1 inhibitor via a protease-cleavable linker. YL201 is being developed by Medilink for the treatment of various solid tumors including SCLC (see e.g., NCT06057922, NCT06612151). The anti-B7-H3 monoclonal antibody of YL201 comprises a VH that comprises (i) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 25, (ii) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 26, and (iii) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 27; and a VL that comprises (i) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 28, (ii) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 29, and (iii) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 30. The VH of the YL201 anti-B7-H3 monoclonal antibody comprises the amino acid sequence SEQ ID NO: 43, and the VL comprises the amino acid sequence of SEQ ID NO: 44. The YL201 anti-B7-H3 monoclonal antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 45, and a light chain amino acid sequence of SEQ ID NO: 46.

[0161] The structure of YL201 is described in in U.S. Patent Application Publication No.2024 / 0108745, which is hereby incorporated by reference herein. YL201 comprises an anti-B7-Amgen Ref. No. 10954-W001-SECH3 monoclonal antibody conjugated to the payload (S)-7-ethyl-7-hydroxy-14-(3-hydroxypropyl)-10,13-dihydro-HH-[l,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[l,2-b]quinolin-8, 1 l(7H)-dione, which is a topoisomerase I inhibitor. The linker-payload molecule of YL201 is referred to as N-((l 1S,14S)-1 l-(4-(di-n-propylamino)butyl)-l-((S)-7-ethyl-7-hydroxy-8,1 l-dioxo-7,8,1 l,13-tetrahydro-10H-[l,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[l,2-b]quinolin-14-yl)-15-methyl-7,10,13-trioxo-4-oxa-6,9,12-triazahexadecan-14-yl)-6-(2-(methanesulfonyl)pyrimidin-5-yl)hex-5-ynamid. The YL201 linker has high in vivo systemic circulation stability and high chemical stability and drives ADC enrichment in the tumor microenvironment through the linker’s physicochemical properties, such as basicity and lipophilicity. The linker-payload of YL201 exhibits extracellular cleavage ability and tumor microenvironment enrichment ability. Such an ADC has high in vivo anti-tumor activity.

[0162] The structure of YL201 is shown in Formula I; wherein Ab is an anti-B7-H3 monoclonal antibody comprising SEQ ID NOs: 25-30, SEQ ID NOs: 31-36, SEQ ID NOs: 37- 42, SEQ ID NOs: 43 and 44, or SEQ ID NOs: 45 and 46; and the drug to antibody ratio (g) is 6Amgen Ref. No. 10954-W001-SEC

[0163] Formula 1A illustrates the YL201 structure indicating the linker and payload (toxin) molecules.Formula 1A

[0164] As discussed above, in certain aspects the DAR (represented as q in Formula I) can indicate the number of cytotoxic payload molecules conjugated to a single antibody or the average DAR for a group of ADCs. For example, the anti-B7-H3 ADC may comprise a DAR value of 6 to 8, inclusive of all values in between, including but not limited to 6.0, 6.1, 6.5, 7.7, 7.97, and 8. YL201 maybe prepared using the methods disclosed in U.S. Patent Application Publication No. 2024 / 0108745.Anti-PD-Ll Antibody

[0165] In some aspects of the disclosed method, the bispecific TCE and ADC are administered in combination with an antagonist of the PD-1 / PD-L1 signaling pathway.Programmed Cell Death protein 1 (PD-1), also known as CD279, SLEB2, and hSLEl, is a transmembrane protein expressed on activated T, natural killer (NK) and B lymphocytes, macrophages, dendritic cells (DCs) and monocytes. Notably, PD-1 is highly expressed on tumorspecific 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 referred to as CD279 and B7-H1) and PD-1Amgen Ref. No. 10954-W001-SECLigand 2 (also known as PD-L2, 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 DC and macrophages (Xing et al., Oncoimmunology 7(3): el356144 (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 the suppression of T cell immune responses in cancer. Antagonists of this pathway have been clinically validated across a number of solid tumor indications. Anti-PD-1 antibodies, e.g., nivolumab, pembrolizumab, tislelizumab, and cemiplimab, and anti-PD-Ll antibodies, e.g., atezolizumab, avelumab, and durvalumab, target the PD-1 / PD-L1 pathway, and each has been approved by the U.S. Food and Drug Administration (FDA) and / or other regulatory agencies for the treatment of various cancers.

[0166] In some aspects, the methods described herein further comprise administering an ani-PD-L1 antibody to the subject. Exemplary anti-PD-Ll antibodies include, but are not limited to, atezolizumab (e.g., TECENTRIQ®), avelumab (e.g., BAVENCIO®), and durvalumab (e.g., IMFINZI®). In various aspects of the disclosure, the method comprises administering to the subject durvalumab or atezolizumab.Method of Treating Cancer

[0167] Provided herein is a method of treating a small cell lung cancer (SCLC) in a subject, which comprises administering to the subject an effective amount (or dose) of each of the DLL3-binding bispecific TCE and the B7-H3-binding ADC described herein once every three weeks (Q3W), and in some aspects, an anti-PD-Ll antibody. As used herein, Q3W means 21-day cycles. Thus, the method comprises administering the DLL3-binding bispecific TCE, the B7-H3-binding ADC, and in some aspects, the anti-PD-Ll antibody described herein in one or more 21-day cycles. As used herein, an “effective amount” means an amount that will elicit the biological or medical response or desired therapeutic effect on a tissue, system, animal, mammal, or human that is being sought by the researcher, medical doctor, or other clinician. An effective amount of the bispecific TCE, ADC, and anti-PD-Ll antibody may vary according to factors such as theAmgen Ref. No. 10954-W001-SECdisease state, age, sex, and weight of the individual, and the ability of the bispecific TCE, ADC, and anti-PD-Ll antibody to elicit a desired response in the individual. An effective amount is also one in which any toxic or detrimental effect of any of the bispecific TCE, ADC, and anti-PD-Ll antibody is outweighed by the therapeutically beneficial effects. Such benefit includes improving signs or symptoms of a disease state. An effective amount of each of the bi specific TCE, ADC, and anti-PD-Ll antibody described herein may be administered in a single dose or in multiple doses. In determining the effective amount for a patient, a number of factors are considered by the attending medical practitioner, including, but not limited to: the patient’s size (e.g., weight or mass), body surface area, age, and general health; the specific disease or disorder involved; the severity of the disease or disorder; the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances known to medical practitioners.

[0168] In some aspects, the subject suffers from a small cell lung cancer (SCLC), examples of which include relapsed / refractory SCLC (RR SCLC), extensive stage SCLC (ES SCLC) (which may be relapsed or refractory), and limited-stage SCLC (LS-SCLC) (which may be relapsed or refractory). LS-SCLC often refers to SCLC cancers found only on one side of the chest (e.g., only in one lung), enabling treatment with a single radiation field. In various aspects of the disclosure, LS-SCLC has not progressed in the subject following concurrent chemoradiation therapy. ES-SCLC includes cancers that have spread more widely throughout the lung and / or to the other lung, and often to other locations within the body. Relapsed SCLC include cancers which, e.g., reemerge within three months of a first line of treatment (e.g., chemotherapy and / or radiation). In certain aspects, the subject is suffering from ES-SCLC.

[0169] In other aspects, the disclosed methods may be used to treat DLL3 -expressing cancers other than SCLC. Examples of such cancers include, but are not limited to, glioma, glioblastoma, melanoma, prostate cancer such as neuroendocrine prostate cancer, neuroendocrineAmgen Ref. No. 10954-W001-SECpancreatic cancer, hepatoblastoma, large cell pulmonary neuroendocrine cancer, pancreatic neuroendocrine cancer, bladder neuroendocrine cancer, gastric neuroendocrine cancer, adrenal exocrine tumors, Merkel cell carcinoma, neuroblastoma, head and neck carcinoid or neuroendocrine cancer, head and neck paraganglioma, and cervical small cell neuroendocrine cancer.

[0170] In some aspects, the method provided herein comprises administering about 0.5 mg to about 30 mg of the bispecific TCE to a subject once every three weeks (Q3W). For example, in some aspects, the method provided herein comprises administering a bispecific TCE comprising a DLL3-binding domain comprising the amino acid sequences of SEQ ID NOs: 5-10 and a CD3-binding domain comprising the amino acid sequences of SEQ ID NOs: 14-19. In various aspects, the bispecific TCE comprises a DLL3-binding domain comprising the amino acid sequence of SEQ ID NO: 13 and a CD3-binding domain comprising the amino acid sequence of SEQ ID NO: 22. In other aspects, the bispecific TCE is tarlatamab, which comprises the amino acid sequence of SEQ ID NO: 24.

[0171] In some aspects, the method comprises administering the bispecific TCE in an amount ranging from about 0.5 mg to about 30 mg, about 0.5 mg to about 20 mg, about 0.5 mg to about 10 mg, about 0.5 mg to about 5 mg, about 10 mg to about 30 mg, about 10 mg to about 20 mg, about 10 mg to about 15 mg, about 15 mg to about 30 mg, about 15 mg to about 25 mg, about 15 mg to about 20 mg, about 20 mg to about 30 mg, about 20 mg to about 25 mg, or about 25 mg to about 30 mg. In exemplary aspects, the method comprises administering about 15 mg to about 25 mg (e.g., 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, or 20 mg) of the bispecific TCE once every 3 weeks. For example, the method may comprise administering about 20 mg of the bispecific TCE to the subject once every 3 weeks (Q3W).

[0172] In some aspects, the method comprises administering a “step dose” of the bispecific TCE, which refers to an initial quantity of the bispecific TCE that is lower than the ultimate target quantity or dose of the bispecific TCE. A “step-up” dosing regimen may include one orAmgen Ref. No. 10954-W001-SECmore quantities of the bispecific TCE that increase to reach a target dose. It is believed that incrementally increasing the dose of T cell engager molecules administered to a patient before reaching the target dose level allows for priming of a subject’s immune system in a more gradual manner, thereby modulating the balance between T cell activation and expansion, and cytokine-mediated efficacy and toxicity. The term “dose” refers to a measured quantity of a therapeutic agent that is given to a subject at one time. In certain aspects, a step dose is administered in the initial or first cycle where the bispecific TCE is administered.

[0173] In various aspects, the method provided herein comprises a first administration or step dose of the bispecific TCE of about 0.5 mg to about 2.0 mg, such as about 0.8 mg to 1.5 mg, on day 1 of an initial 21 -day cycle prior to administration of a target dose of the bispecific TCE in the same cycle. For example, the method may comprise administering about 0.5 mg, 0.8 mg, 1 mg, 1.5 mg, or 2 mg, of the bispecific TCE on day 1 of an initial 21-day cycle. In some aspects, the method comprises administering to the subject about 1 mg of the bispecific TCE on day 1 of an initial 21-day cycle. The terms “first administration,” “second administration,” “third administration,” and “subsequent administration(s)” may be used to refer to the individual amount of each of the bispecific TCE, the ADC, and the anti-PD-Ll antibody that is administered at a given point in time. In certain aspects, the method further comprises subsequent administrations of the bispecific TCE that contain a target quantity of the bispecific TCE. A “target” quantity, dose, or administration of an bispecific TCE refers to a quantity that achieves a desired effect (e.g., ameliorating or reducing the severity of SCLC). In certain aspects, the subsequent administrations of the bispecific TCE (e.g., tarlatamab) are the same (with respect to each other) and greater in quantity than the first administration. For example, each subsequent administration of the bispecific TCE are the same with respect to each other and at least 1.5-fold, at least 2-fold, at least 3 -fold, at least 4-fold, at least 5 -fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, at least 10-fold, at least 20-fold, at least 25- fold, at least 30-fold, at least 35-fold, at least 40-fold, at least 45-fold, or at least 50-foldhigher than the first administration. InAmgen Ref. No. 10954-W001-SECcertain aspects, each subsequent administration of the bispecific TCE may be 2-fold, 5-fold, 10-fold, or 20-fold greater than the first administration.

[0174] In further aspects, the method comprises administering to the subject about 0.5 mg / kg to about 2.5 mg / kg of the ADC. For example, in some aspects, the method comprises administering about 0.5 mg / kg to about 2.5 mg / kg of an ADC of Formula I below, wherein Ab is an anti-B7-H3 monoclonal antibody comprising SEQ ID NOs: 25-30, SEQ ID NOs: 31-36, or SEQ ID NOs: 37-42; and q is 6 to 8:Formula I.In some aspects, Ab is an anti-B7-H3 monoclonal antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 43 and a light chain variable region comprising SEQ ID NO: 44. In other aspects, Ab is an anti-B7-H3 monoclonal antibody comprising a heavy chain amino acid sequence of SEQ ID NO: 45 and a light chain amino acid sequence of SEQ ID NO: 46.

[0175] The method comprises administering the ADC in an amount ranging from about 0.5 mg / kg to about 1.0 mg / kg, about 1.0 mg / kg to about 1.5 mg / kg, about 1.5 mg / kg to about 2.0 mg / kg, or about 2.0 mg / kg to about 2.5 mg / kg, inclusive of all values therebetween. InAmgen Ref. No. 10954-W001-SECexemplary aspects, the method comprises administering about 0.5 mg / kg, 0.8 mg / kg, 1.0 mg / kg, 1.5 mg / kg, 1.6 mg / kg, 1.8 mg / kg, 2.0 mg / kg, 2.4 mg / kg, or 2.5 mg / kg of the ADC once every 3 weeks. For example, the method may comprise administering about 0.8 mg / kg, 1.6 mg / kg, 2.0 mg / kg, or 2.4 mg / kg of the ADC to the subject every 3 weeks.

[0176] In some aspects, the method provided herein comprises administering to the subject an anti-PD-Ll antibody in addition to the bispecific TCE and ADC. Any suitable anti-PD-Ll antibody may be administered to the subject, such as those disclosed herein. In exemplary aspects, the anti-PD-Ll antibody is atezolizumab, durvalumab, or avelumab. Anti-PD-Ll antibodies are typically administered intravenously on a fixed dosing schedule, such as every 2, 3, or 4 weeks. The dosing regimens may vary depending on the specific antibody and indication. For example, atezolizumab may be administered at 840 mg every 2 weeks, 1200 mg every 3 weeks, or 1680 mg every 4 weeks, while durvalumab may be administered at 10 mg / kg, 15 mg / kg, or 20 mg / kg every 2-4 weeks or 1500 mg every 4 weeks for certain indications.Avelumab is usually given at 800 mg every 2 weeks. In exemplary aspects, the method comprises administering 1000 mg-2000 mg of the anti-PD-Ll antibody. In some aspects, the method comprises administering the anti-PD-Ll antibody in an amount ranging from about 1200 mg to about 1400 mg, about 1400 mg to about 1600 mg, about 1600 mg to about 1800 mg, about 1800 mg to about 2000 mg, about 1000 mg to about 1100 mg, about 1100 mg to about 1300 mg, about 1300 mg to about 1500 mg, about 1500 mg to about 1700 mg, about 1700 mg to about 1900 mg, or about 1900 mg to about 2000 mg. In exemplary aspects, the method comprises administering about 1500 mg durvalumab intravenously (IV) to the subject or administering about 1200 mg atezolizumab IV to the subject once every three weeks. Further details regarding the dosing of durvalumab, atezolizumab, and avelumab can be found in the prescribing information for IMFINZI®, TECENTRIQ®, and BAVENCIO®, respectively.

[0177] Both flat dosing and weight-based dosing are acceptable approaches for administering the therapeutic agents described herein. It will be appreciated that flat dosingAmgen Ref. No. 10954-W001-SECprovides a standardized dosage regardless of patient weight, simplifying administration and ensuring consistent drug exposure across a broad population. Conversely, weight-based dosing allows for individualized drug administration based on patient body weight, optimizing therapeutic effects and minimizing potential adverse reactions. The choice between these dosing strategies may depend on factors such as a therapeutic agent’s pharmacokinetic properties, therapeutic index, target patient population, and other clinical considerations.

[0178] Each of the bispecific TCE, the ADC, and the anti-PD-Ll antibody may be administered to the subject in accordance with a treatment regimen that involves cycles of periodic administration to the subject. A cycle may comprise any appropriate period of time, and multiple cycles may be employed which entail different frequency of administration and / or different quantities administered. In some aspects, one cycle in the course of treatment comprises administering the bispecific TCE, the ADC, and optionally the anti-PD-Ll antibody once every three weeks (or “Q3W” or 21 -day treatment cycles); however, other cycles with different dosing regimens may be part of the overall course of treatment. In certain aspects, the bispecific TCE, the ADC, and in some aspects the anti-PD-Ll antibody, are repeatedly administered over the course of one or multiple 21-day cycles. For example, the bispecific TCE and the ADC may be administered to the subject on day 1 of each of the multiple 21-day cycles. For 21-day (Q3W) treatment cycles, “day 1” refers to cycle 1, day 1; “day 8” refers to cycle 1, day 8; “day 22” refers to cycle 2, day 1; “day 43” refers to cycle 3, day 1; “day 64” refers to cycle 4, day 1; and “day 85” refers to cycle 5, day 1.

[0179] In certain aspects, each of the bispecific TCE, the ADC, and the anti-PD-Ll antibody may be administered individually or in any combination on a single day of a particular treatment cycle. For example, in some aspects, each of the bispecific TCE, the ADC, and the anti-PD-Ll antibody are administered on the same day(s) of a particular treatment cycle. Alternatively, the bispecific TCE may be administered on a particular day without administration of the ADC and the anti-PD-Ll antibody. In other aspects, the ADC may be administered on a particular dayAmgen Ref. No. 10954-W001-SECwithout administration of the bispecific TCE and the anti-PD-Ll antibody, or the anti-PD-Ll antibody may be administered on a particular day without administration of the bispecific TCE and the ADC.

[0180] In one aspect, the method comprises administering the bispecific TCE and ADC to a subject with SCLC as follows: (a) 0.5 mg-2.0 mg of the bi specific TCE and 0.5 mg / kg-2.5 mg / kg of the ADC on day 1; (b) 15 mg-30 mg of the bispecific TCE on day 8, and (c) 15 mg-30 mg of the bispecific TCE and 0.5 mg / kg- 2.5 mg / kg of the ADC starting on day 22 and once every three weeks (Q3W) thereafter. For example, the method may comprise administering to the subject: (a) 1 mg of the bispecific TCE and 0.8 mg / kg, 1.6 mg / kg, 2.0 mg / kg, or 2.4 mg / kg of the ADC on day 1; (b) 20 mg of the bispecific TCE on day 8; and (c) 20 mg of the bispecific TCE and 0.8 mg / kg, 1.6 mg / kg, 2.0 mg / kg, or 2.4 mg / kg of the ADC on day 22 and once every three weeks (Q3W) thereafter. In certain aspects, the method comprises administering 0.8 mg / kg of the ADC to the subject on days 1 and 22 and Q3W thereafter. In other aspects, the method comprises administering 1.6 mg / kg of the ADC to the subject on days 1 and 22 and Q3W thereafter. In further aspects, the method comprises administering 2.0 mg / kg of the ADC to the subject on days 1 and 22 and Q3W thereafter. In various aspects, the method comprises administering 2.4 mg / kg of the ADC to the subject on days 1 and 22 and Q3W thereafter.

[0181] In another aspect, the method comprises administering the bispecific TCE, the ADC, and the anti-PD-Ll antibody to a subject with SCLC as follows: (a) 0.5 mg-2.0 mg of the bispecific TCE, 0.5 mg / kg-2.5 mg / kg of the ADC, and 1000 mg-2000 mg of the anti-PD-Ll antibody on day 1; (b) 15 mg-30 mg of the bispecific TCE on day 8; (c) 15 mg-30 mg of the bispecific TCE, 0.5 mg / kg-2.5 mg / kg of the ADC, and 1000 mg-2000 mg of the anti-PD-Ll antibody on days 22, 43, and 64; and (d) 15 mg-30 mg of the bispecific TCE and 1000 mg-2000 mg of the anti-PD-Ll antibody starting on day 85 and once every three weeks (Q3W) thereafter. For example, the method may comprise administering to the subject: (a) 1 mg of the bispecific TCE, 0.8 mg / kg, 1.6 mg / kg, 2.0 mg / kg, or 2.4 mg / kg of the ADC, and 1000 mg-2000 mg of theAmgen Ref. No. 10954-W001-SECanti-PD-Ll antibody on day 1; (b) 20 mg of the bispecific TCE on day 8; and (c) 20 mg of the bi specific TCE, 0.8 mg / kg, E6 mg / kg, 2.0 mg / kg, or 2.4 mg / kg of the ADC and 1000 mg-2000 mg of the anti-PD-Ll antibody on days 22, 43, and 64; and (d) 20 mg of the bispecific TCE and 1000 mg-2000 mg of the anti-PD-Ll antibody starting on day 85 and once every three weeks (Q3W) thereafter. In certain aspects, the method comprises administering 0.8 mg / kg of the ADC to the subject on days 1, 22, 43, and 64. In other aspects, the method comprises administering 1.6 mg / kg of the ADC to the subject on days 1, 22, 43, and 64. In further aspects, the method comprises administering 2.0 mg / kg of the ADC to the subject on days 1, 22, 43, and 64. In various aspects, the method comprises administering 2.4 mg / kg of the ADC to the subject on days 1, 22, 43, and 64.

[0182] As merely an example, the disclosure provides a method of treating small cell lung cancer (SCLC) in a subject comprising administering to the subject: (a) 0.5 mg-2.0 mg tarlatamab and 0.5 mg / kg-2.5 mg / kg of an antibody-drug conjugate (ADC) on day 1; (b) 15 mg-30 mg tarlatamab on day 8; (c) 15 mg-30 mg tarlatamab and 0.5 mg / kg-2.5 mg / kg of the ADC starting on day 22 and once every three weeks (Q3W) thereafter; wherein the ADC is of FormulaAmgen Ref. No. 10954-W001-SECwherein Ab is an anti-B7-H3 monoclonal antibody comprising a heavy chain amino acid sequence of SEQ ID NO: 45 and a light chain sequence of SEQ ID NO: 46, and q is 6 to 8. In a further exemplary aspect, the method comprises administering to the subject: (a) 1 mg tarlatamab and 0.8 mg / kg, 1.6 mg / kg, 2.0 mg / kg, or 2.4 mg / kg of the ADC on day 1; (b) 20 mg tarlatamab on day 8; and (c) 20 mg tarlatamab and 0.8 mg / kg, 1.6 mg / kg, 2.0 mg / kg, or 2.4 mg / kg of the ADC on day 22; and once every three weeks (Q3W) thereafter. In certain aspects, the method comprises administering 0.8 mg / kg of the ADC to the subject on days 1 and 22 and Q3W thereafter. In other aspects, the method comprises administering 1.6 mg / kg of the ADC to the subject on days 1 and 22 and Q3W thereafter. In further aspects, the method comprises administering 2.0 mg / kg of the ADC to the subject on days 1 and 22 and Q3W thereafter. In various aspects, the method comprises administering 2.4 mg / kg of the ADC to the subject on days 1 and 22 and Q3W thereafter.

[0183] In another example, the disclosure provides a method of treating small cell lung cancer (SCLC) in a subject comprising administering to the subject: (a) 0.5 mg-2.0 mg of tarlatamab, 0.5 mg / kg-2.5 mg / kg of an antibody-drug conjugate (ADC), and 1000 mg-2000 mg of an anti-PD-Ll antibody on day 1; (b) 15 mg-30 mg of tarlatamab on day 8; (c) 15 mg-30 mg of tarlatamab, 0.5 mg / kg-2.5 mg / kg of the ADC, and 1000 mg-2000 mg of the anti-PD-Ll antibody on each of days 22, 43, and 64; and (d) 15 mg-30 mg of tarlatamab and 1000 mg-2000 mg of the anti-PD-Ll antibody starting on day 85 and once every three weeks (Q3W) thereafter; wherein the ADC is of Formula I;Amgen Ref. No. 10954-W001-SECFormula Iwherein Ab is an anti-B7-H3 monoclonal antibody comprising a heavy chain amino acid sequence of SEQ ID NO: 45 and a light chain amino acid sequence of SEQ ID NO: 46, and q is 8. In a further exemplary aspect, the method comprises administering to the subject: (a) 1 mg tarlatamab, 0.8 mg / kg, 1.6 mg / kg, 2.0 mg / kg, or 2.4 mg / kg of the ADC, and 1000 mg-2000 mg of the anti-PD-Ll antibody on day 1; (b) 20 mg tarlatamab on day 8; and (c) 20 mg tarlatamab, 0.8 mg / kg, 1.6 mg / kg, 2.0 mg / kg, or 2.4 mg / kg of the ADC and 1000 mg-2000 mg of the anti-PD-Ll antibody on days 22, 43, and 64; and (d) 20 mg tarlatamab and 1000 mg-2000 mg of the anti-PD-Ll antibody starting on day 85 and once every three weeks (Q3W) thereafter. In certain aspects, the method comprises administering 0.8 mg / kg of the ADC to the subject on days 1, 22, 43, and 64. In other aspects, the method comprises administering 1.6 mg / kg of the ADC to the subject on days 1, 22, 43, and 64. In further aspects, the method comprises administering 2.0 mg / kg of the ADC to the subject on days 1, 22, 43, and 64. In various aspects, the method comprises administering 2.4 mg / kg of the ADC to the subject on days 1, 22, 43, and 64.

[0184] In various aspects of the method, the bispecific TCE, the ADC, and the anti-PD-Ll antibody are each delivered to a subject via a parenteral administration route. For example, in some aspects, each of the bispecific TCE, the ADC, and the anti-PD-Ll antibody is administered to a subject via intravenous (IV) administration, such as IV injection. Intravenous administrationAmgen Ref. No. 10954-W001-SECinvolves injecting therapeutic agents directly into the systemic venous circulation. Intravenous injection can occur within a few seconds or over time, i.e., an IV bolus versus an IV infusion. When the duration of injection lasts more than 1-2 minutes, the delivery is considered to be an infusion. In exemplary aspects, each of the bispecific TCE, the ADC, and the anti-PD-Ll antibody is administered via intravenous infusion over a period of at least about 15 minutes, but no more than about 2 hours (e.g., about 30 minutes to about 2 hours). For example, in some aspects, each of the bispecific TCE, the ADC, and the anti-PD-Ll antibody is administered via intravenous infusion over a period of about 15-90 minutes, about 15-60 minutes, about 15-50 minutes, about 15-40 minutes, or about 15-30 minutes. In other aspects, each of the bi specific TCE, the ADC, and the anti-PD-Ll antibody is administered via intravenous infusion over a period of about 30 minutes to about 2 hours, about 30-90 minutes, about 30-60 minutes, or about 30-45 minutes. In certain aspects, each of the bispecific TCE, the ADC, and the anti-PD-Ll antibody is administered via intravenous infusion over a period of about 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75 or 80 minutes. In certain aspects, the first administration of the anti-PD-Ll antibody may be a 60 minute intravenous infusion followed by 30 minute IV infusions for all subsequent administrations. For example, in some aspects, the bispecific TCE is administered via intravenous infusion over a period of about 60 minutes, the ADC is administered via IV infusion over a period of about 60 minutes, and atezolizumab is administered via IV infusion over a period of 60 minutes. If the first infusion is tolerated, all subsequent infusions may be delivered over 30 minutes. In another exemplary aspect, the bispecific TCE is administered via intravenous infusion over a period of about 60 minutes, the ADC is administered via IV infusion over a period of about 60 minutes, and durvalumab is administered via IV infusion over a period of 60 minutes.

[0185] In various aspects, the subject suffering from SCLC has not received any prior line of cancer treatment. By “prior line of treatment” is meant a previous treatment with another anticancer therapeutic, e.g., a first- or second-line cancer therapy or standard of care therapy,Amgen Ref. No. 10954-W001-SECbefore administration of the bispecific TCE. In other words, the methods described herein may be the first-line treatment (i.e., initial or primary treatment) a subject receives for SCLC. In other aspects, the subject suffers from SCLC which has not progressed or relapsed after one or more prior lines of treatment. In some aspects, for example, the subject has received a first-line cancer therapy, after which the subject’s disease has not progressed (defined as ongoing response or stable disease per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)). In other aspects, the subject suffers from SCLC which has progressed or relapsed after one or more prior lines of treatment in the subject, such as a SCLC relapse after two or more prior lines of treatment in the subject. For example, the subject has, in various aspects, received at least one, two, three, four, five, or six prior lines of treatment for the SCLC. In various aspects, at least one of the prior lines of treatment is a platinum-based chemotherapeutic, such as, for example, carboplatin or cisplatin. Alternatively or in addition, at least one of the prior lines of treatment is etoposide, anti-PDl antibody, anti-PD-Ll antibody therapy, or combinations thereof. In various aspects of the disclosed method, a subject with SCLC (e.g., ES-SCLC) has received no prior systemic treatment for SCLC other than one cycle of platinum-based chemotherapy, etoposide, and PD-L1 inhibitor in a first-line setting. Where the subject has undergone prior lines of treatment, administration of the bispecific TCE, the ADC, and optionally the anti-PD-Ll antibody may occur at any timepoint following completion of the prior lines of treatment. For instance, the bispecific TCE, the ADC, and the anti-PD-Ll antibody may be administered at least 28 days (e.g., at least 60 days or at least 90 days) after the completion of any prior lines of treatment for SCLC.

[0186] Due to the risk of CRS and immune effector cell-associated neurotoxicity syndrome (ICANS), in various embodiments, the method comprises hospitalizing and monitoring the subject for up to about 10 hours (e.g., about 9 hours, about 8 hours, about 7 hours, about 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, or 1 hour) after the administration of the bispecific TCE on day 1 and day 8 of cycle 1 (i.e., C1D1 and C1D8) and day 1 of cycle 2 (i.e., C2D1 or dayAmgen Ref. No. 10954-W001-SEC22). For example, in some aspects, the method comprises monitoring the subject for about 1-2 hours (e.g., about 1 hour, about 90 minutes, or about two hours) or for about 6-8 hours (e.g., about 6, 6.5, 7, 7.5, or 8 hours). The subject may be monitored for CRS symptoms, including, for example, fever at the onset, hypotension, capillary leak (hypoxia), and end organ dysfunction. The onset of ICANS may be determined using criteria established in Lee et al. (2019), and / or by clinical signs and symptoms. ICANS symptoms include, but are not limited to, apraxia, confusion, depressed level of consciousness, dysgraphia, dysphasia, elevated ICP / cerebral edema, encephalopathy, headache, impaired attention, increased tone, motor weakness / findings, myoclonus, seizure, and tremor. In certain embodiments, the method may comprise measuring the level of one or more cytokines in the subject’s blood or serum, such as IL-6, IL-8, IL- 10, TNF-a, and IFN-g, after the administration of the bispecific TCE (e g., tarlatamab) in cycle 1 and hospitalizing and monitoring the subject for up to about 48 hours (e.g., about 24 hours, 12 hours, 8 hours, 7 hours, 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, or 1 hour) if any of the level of any of the cytokines is above a normal reference level. The cytokines can be measured or tested using methods known in the art.Additional Therapeutic Agents

[0187] In some embodiments, the method provided herein further comprises the administration of one or more additional therapeutic agents to the subject. For example, in certain aspects, the method may comprise administration of the bispecific TCE, the ADC, optionally the anti-PD-Ll antibody, and at least one additional therapeutic agent to achieve a desired biological effect in a subject (i.e., as part of a “combination therapy”). In other aspects, one or more additional therapeutic agents may be administered to prevent, reduce, or mitigate the risk of adverse effects associated with the administration of the bispecific TCE, the ADC, and the anti-PD-Ll antibody.

[0188] A major adverse effect associated with the use of the bispecific TCE is cytokine release syndrome (CRS). Therapeutic agents useful for preventing, reducing, or mitigating theAmgen Ref. No. 10954-W001-SECrisk of CRS include, but are not limited to, corticosteroids (e.g., dexamethasone), fluid (e.g., saline), etanercept (e.g., ENBREL®), and an anti-IL6 antibody (e.g., tocilizumab or siltuximab). In some aspects of the method, dexamethasone is administered (oral or IV) prior to administration of the bispecific TCE on day 1 and day 8 of the first 21 -day cycle. An exemplary dose of dexamethasone comprises about 3 mg to about 10 mg (e.g., about 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, or 10 mg) per administration, not exceeding about 24 mg / day. An anti-IL6 antibody (e.g., tocilizumab or siltuximab) may be administered as needed. An exemplary dose of tocilizumab comprises about 4-8 mg / kg, which can be repeated for an additional three administrations with an at least 8-hour interval between doses. As symptoms of CRS include fever, nausea, fatigue, headache, myalgias, malaise, therapeutic agents useful for treating such these symptoms (e.g., paracetamol / acetaminophen for fever) may also be used.

[0189] In some aspects, an anti-emetic agent may be provided prior to infusion of the ADC.Exemplary anti-emetic agents include, but are not limited to, olanzapine, NK1 receptor antagonist, 5-HT3 receptor antagonist, and dexamethasone. When dexamethasone is provided as an anti-emetic prior to ADC administration, it may not be necessary to administer additional dexamethasone prior to administration of the bispecific TCE for CRS prophylaxis.

[0190] As discussed herein, YL201 is an exemplary ADC that may be employed in the disclosed method. Adverse events associated with YL201 include, for example, hematologic toxi cities with neutropenia. An exemplary therapeutic agent useful for preventing, reducing, or mitigating the risk of such toxicities is granulocyte colony-stimulating factor (G-CSF). Thus, in some aspects of the method, G-CSF is administered during the first four cycles of ADC administration, such as YL201. Short-acting or long-acting forms of G-CSF may be administered. For example, short-acting G-CSF may be initiated 1 day after or up to 3 to 4 days after YL201 infusion, followed by daily administration following YL201 infusion until absolute neutrophil count (ANC) recovers to normal or near normal levels as determined by laboratory standards. Alternatively, long-acting G-CSF may be administered 24 to 72 hours after YL201Amgen Ref. No. 10954-W001-SECinfusion, with at least 12 days separating the dose of long-acting G-CSF and the next YL201 administration. As disclosed herein,, YL201 comprises Formula I:Formula IDLL3 Expression

[0191] For any of the methods of treating SCLC described herein, the cancer cells may express DLL3 on the cell surface. In other embodiments, the cancer cells may express DLL3 on the cell surface and in the cytoplasm. In some aspects, cell surface expression and intercellular expression of DLL3 protein may be determined by immunohistochemistry (THC) or positron emission tomography (PET). Any suitable IHC assay for determining DLL3 protein expression may be used in connection with the present disclosure. Desirably, the IHC assay is approved by a regulatory agency, such as the U.S. FDA or an agency that has CE-IVD registration authority. DLL3-specific IHC assays, and components thereof, are known in the art and commercially available from a variety of sources. For example, DLL3 expression in cancer or tumor cells may be detected using the VENTANA® DLL3 (SP347) Assay (Roche Diagnostics, GmbH, Mannheim, Germany). Other anti-DLL3 antibodies that may be used to detect DLL3 expression in an IHC assay include, but are not limited to, NBP2-24669 (Novus Biological, Littleton, CO); PA5-26336 (Thermo Fisher Scientific, Waltham, MA); and ab229902 (Abeam, Cambridge, MA).Amgen Ref. No. 10954-W001-SEC

[0192] In other embodiments, DLL3 gene expression in cancer cells may be determined. Methods for detecting and quantifying gene expression (e.g., mRNA levels) are known in the art and can be used in the context of the present disclosure. Such methods include, for example, flow cytometry-based methods polymerase chain reaction (PCR) analysis, sequencing analysis (e.g., RNA sequencing), electrophoretic analysis, restriction fragment length polymorphism (RFLP) analysis, Northern blot analysis, quantitative PCR, reverse-transcriptase-PCR analysis (RT-PCR), and the like.Therapeutic Response

[0193] The efficacy of the disclosed methods for treating cancer SCLC may be assessed by a variety of clinical outcomes, endpoints, and / or measures. In this regard, clinical outcomes that may be assessed include, but are not limited to, Progression Free Survival (PFS), Overall Survival (OS), Partial Response (PR), Complete Response (CR), Objective Response (OR), Disease Control (DC), Duration of Response (DOR), Time to Response (TTR), time to progression, and time to subsequent therapy. The term “progression free survival (PFS)” refers to the time from the first dose of investigational product to the first documentation of disease progression or death due to any cause, whichever occurs first. The term “overall survival (OS)” refers to the time from the first dose of investigational product to death due to any cause. A “partial response (PR)” is indicated by at least a 30% decrease in the sum of the diameters of target lesions as compared to the baseline sum of diameters prior to treatment. The term “complete response (CR)” refers to the disappearance of all target non-nodal lesions (target lymph node must have reduction in short axis to < 10 mm, not total disappearance). The term “objective response (OR)” is a measure of the best overall response of complete response (CR) or partial response (PR). The term “duration of response (DoR)” refers to the time from the first documentation of CR or PR (subsequently confirmed) to disease progression or death due to any cause, whichever occurs first. Duration of response may be calculated only for subjects who achieve a best overall response of CR or PR. The term “disease control (DC),” as used herein,Amgen Ref. No. 10954-W001-SECdescribes the percentage of patients with advanced cancer whose therapeutic intervention has led to a complete response, partial response, or stable disease. The term “time to response” (TTR) refers to the time from the first dose of investigational product to the first documented CR or PR that is subsequently confirmed per RECIST 1.1. Time to response may be calculated only for confirmed responders. “Time to progression” refers to the time from the first dose of investigational product until the first documentation of disease progression. “Time to subsequent therapy” refers to the time from first dose of investigational product to the initiation of subsequent therapy. Clinical endpoints with respect to cancer therapies are further described in, e.g., Delgado A. and Guddati, A.K., et al., Am J Cancer Res 2021 ;11(4): 1121-1131.

[0194] In some aspects, the disclosed methods desirably result in an objective response (OR), partial response (PR), or complete response (CR). The terms “treatment,” “treating,” and “treat” refer to all processes wherein there may be a slowing, interrupting, arresting, controlling, stopping, or reversing of the progression of the small cell lung cancer, but does not necessarily indicate a total elimination of all cancer symptoms. Thus, in some aspects of the methods disclosed herein, treatment includes: (a) inhibiting further progression of SCLC ; and (b) relieving the SCLC, i.e., causing regression of the cancer or alleviating symptoms or complications thereof. In such cases, administration of the bispecific TCE, ADC, and anti-PD-Ll antibody may be paused or ceased entirely. In other aspects, administration of the bispecific TCE, ADC, and anti-PD-Ll antibody in accordance with the disclosed methods may be paused or ceased if there is evidence of disease progression or if the subject experiences unacceptable toxicity.Kits

[0195] The present disclosure additionally provides kits comprising the bispecific TCE, the ADC, and optionally the anti-PD-Ll of the present disclosure, or compositions separately comprising each of the bispecific TCE, the ADC, and the anti-PD-Ll antibody. In some embodiments, the components of the kit are packaged with instructions for administration to aAmgen Ref. No. 10954-W001-SECpatient. In some embodiments, the kit comprises one or more devices for administration to a patient, e.g., a needle and syringe, and the like. In some aspects, each of the bispecific TCE, the ADC, and the anti-PD-Ll antibody, or compositions comprising each of the foregoing separately, is / are pre-packaged in a ready to use form, e.g., a syringe, an intravenous bag, etc. In exemplary aspects, the ready to use form is for a single use. In exemplary aspects, the kit comprises multiple single use, ready to use forms of the bi specific TCE, the ADC, and optionally the anti-PD-Ll antibody of the present disclosure or compositions comprising each of the foregoing separately. In some aspects, the kit further comprises other therapeutic or diagnostic agents or pharmaceutically acceptable carriers (e.g., solvents, buffers, diluents, etc.), including any of those described herein.

[0196] The following examples further illustrate the invention but, of course, should not be construed as in any way limiting its scope.EXAMPLE 1

[0197] This example demonstrates in vitro activity of tarlatamab in combination with the YL201 ADC.

[0198] In vitro cytotoxicity of tarlatamab / AMG 757 and the B7-H3 -targeting YL201 ADC (MediLink Therapeutics) as monotherapies was assessed using a CELLTITER-GLO® (Promega Corp.) viability assay. Human T cells were co-cultured with DLL3- and B7-H3 -positive DMS53 target cells at a 10:1 effector-to-target (E:T) ratio and incubated with increasing concentrations of tarlatamab / AMG 757 or YL201. Cell viability was assessed on day 6. Tarlatamab / AMG 757 demonstrated potent T-cell-dependent cytotoxicity with an EC50 of 0.035 nM in DMS53 cells. Dose-response analyses from these studies were used to determine the EC20, EC50, EC90 concentrations for each molecule. Tarlatamab and YL201 were then combined at these concentrations to treat DMS53 cells at E:T ratios of 10:1, 1:1, and 1 :3. Across multiple conditions, the combination of tarlatamab / AMG 757 with graded doses of YL201, and viceAmgen Ref. No. 10954-W001-SECversa, demonstrated increased cytotoxicity relative to monotherapy treatment, as shown in FIGs.1A-1C.EXAMPLE 2

[0199] This example demonstrates anti-tumor effects of tarlatamab in combination with the YL201 ADC in a small-cell lung carcinoma xenograft model.

[0200] The anti-tumor activity of tarlatamab / AMG 757 was evaluated in combination with the YL201 ADC in a human SCLC xenograft model using the DLL3- and B7-H3 -positive DMS53 cell line. Seven-week old female NSG mice (JAX 005557) were subcutaneously implanted on Day 0 with 8 x 106DMS53 cells (DLL3 and B7-H3 -positive by flow cytometry) in a 1:1 mixture of Matrigel (Corning 354234) and PBS Mg7CF. On Day 18 post-implantation, all mice received a single intraperitoneal injection of 2 x 107in iv / z' -activated human CD3+T cells. Twenty -four hours later (Day 19), tarlatamab / AMG 757 or a control BiTE® molecule (EGFRvIII-HLE) was administered intravenously at a dose of 0.03 mg / kg. Five hours after tarlatamab / AMG 757 treatment, YL201 or isotype control was administered intravenously at 1.0 mg / kg. Monotherapy doses were optimized and selected from internal data. The data reported represent a single dose of each agent.

[0201] Treatment groups (n = 8) were as follows: 1) EGFRvIII-HLE BiTE® molecule (control), (2) AMG 757, (3) Isotype Control, (4) YL201, (5) EGFRvIII-HLE BiTE® molecule + Isotype Control, (6) EGFRvIII-HLE BiTE® molecule + YL201, (7) tarlatamab + Isotype Control, and (8) tarlatamab + YL201.

[0202] Tumor volumes were measured twice weekly by digital caliper. Tumor growth inhibition (TGI %) was calculated with the following equation, using EGFRvIIL BiTE® molecule-treated mice as reference:%TGI = 100Amgen Ref. No. 10954-W001-SEC

[0203] %TGI across treatment days is summarized in Table 2 below, and further shown in FIG. 2A. The average body weight change of treated mice is shown in FIG. 2B.Table 2. %TGI values of each treatment vs EGFRvIII-BiTE®Regression observed and reported)

[0204] The combination of tarlatamab / AMG 757 and YL201 demonstrated a strong and sustained synergistic anti-tumor effect in vivo. Monotherapy with either tarlatamab / AMG 757 or YL201 produced moderate tumor growth inhibition, while the combination resulted in marked enhancement of efficacy, with %TGI values exceeding 100% and evidence of tumor regression observed at later timepoints. Analysis using the Bliss independence model (S = Eobserved- (EA+confirmed that the observed combination effects were greater than the predicted additive outcomes, with positive synergy scores at all measured intervals and a peak at Day 29 (TxlO), as shown in Table 3. This persistent synergistic interaction indicates that tarlatamab / AMG 757 and YL201 act cooperatively to enhance tumor growth suppression beyond independent activity, supporting a complementary mechanism of action that yields a superior therapeutic benefit relative to single-agent or control treatments.Amgen Ref. No. 10954-W001-SECTable 3. Bliss synergy (S) scores of tarlatamab and YL201 treated tumor bearing mice

[0205] At four days post-treatment, antibody-drug conjugate (ADC)-mediated bystander toxicity toward T cells was evaluated in tumors co-treated with YL201 and tarlatamab. Flow cytometric analysis did not indicate any appreciable toxicity within the CD8+or CD4+T-cell compartments.EXAMPLE 3

[0206] This example describes a phase lb open-label, multicenter study evaluating the safety, tolerability, pharmacokinetics, and efficacy of tarlatamab in combination with an antibody-drug conjugate with or without an anti-PD-Ll antibody in subjects with extensive stage small cell lung cancer (ES-SCLC).Study Rationale

[0207] Tn a first-in-human phase 1 study (DeLLphi-300, NCTO3319940), tarlatamab (IMDELLTRA® INN; AMG 757) demonstrated a manageable safety profile with durable antitumor activity in previously treated SCLC including an objective response rate (ORR) of 23.4% (2 complete responses and 23 partial responses) and a median duration of response of 12.3 months (Paz-Ares et al, 2023). The subsequent phase 2 study of tarlatamab in third-line or later ES-SCLC (DeLLphi-301, NCT05060016) identified no new safety concerns and reported a higher ORR of 40.0% in patients treated at a target dose of 10 mg (Ahn et al, 2023). On the basis of these studies, the FDA granted accelerated approval in May 2024 for tarlatamab at a dose ofAmgen Ref. No. 10954-W001-SEC10 mg IV every 2 weeks (Q2W) for the treatment of adult patients with ES-SCLC with disease progression on or after platinum-based chemotherapy.

[0208] As discussed herein, YL201 (INN tambotatug pelitecan) is a B7-H3-targeting ADC comprised of an anti-B7-H3 human monoclonal antibody conjugated to a topoisomerase 1 inhibitor (YL0010014) via a protease-cleavable linker. In phase 1 studies, YL201 has been studied with doses ranging from 0.8 mg / kg to 3.0 mg / kg and has demonstrated a manageable safety profile and encouraging efficacy in subjects with previously treated SCLC. The adverse event profile of YL201 monotherapy was tolerable and most notable for hematologic toxi cities, and neutropenia improved with the addition of prophylactic granulocyte colony-stimulating factor (G-CSF).

[0209] While both tarlatamab and YL201 have demonstrated promising single-agent activity in previously treated SCLC, there are still opportunities to improve the efficacy with either agent in monotherapy. Preclinical studies have shown increased T-cell infiltration and cytotoxic activity when tarlatamab is combined with cytotoxic chemotherapy (carboplatin and etoposide) in a SCLC xenograft mouse model (You et al, 2023). While this data supports combination of tarlatamab with standard of care chemotherapy, the profile may be improved by replacing chemotherapy with an ADC that binds tumor-specific antigens to allow targeted delivery of the potent cytotoxic agent with reduced off-target toxicity.

[0210] In addition to studying the safety, tolerability, and preliminary anti-tumor activity of tarlatamab in combination with YL201, this study will further explore tarlatamab in combination with YL201 and an anti-PD-Ll antibody (hereafter referred to as the triplet combination).Overall Design

[0211] The study is a phase lb, multi-center, open-label study in subjects with ES-SCLC.Safety and efficacy of tarlatamab in combination with YL201 will be explored in Parts 1 and 2 asAmgen Ref. No. 10954-W001-SECwell as that of the triplet combination with tarlatamab in combination with YL201 and anti-PD-L1 therapy in Part 3.

[0212] The study includes a 21 -day screening period, treatment period, a safety follow-up (SFU) visit, and a long-term follow-up (LTFU) period. The study will consist of 3 parts: dose exploration (Part 1), dose expansion (Part 2), and triplet combination (Part 3).

[0213] Dose Exploration (Part 1): Multiple dose levels of YL201 will be explored in combination with tarlatamab administered at a fixed dose of 20 mg intravenous (IV) every 3 weeks (Q3W) using one-step dosing. Part 1 will be conducted in subjects with ES-SCLC that has progressed or recurred following at least 1 platinum -based anti-cancer treatment. Cohort 1-1 will be the first cohort in dose exploration and will test tarlatamab in combination with YL201 at 0.8 mg / kg IV Q3W, which represents 2 doses lower than the lowest dose studied in the YL201 first-in-human dose expansion study (NCT06057922). Dose level review meeting decisions will occur after at least 3 subjects are evaluable for dose limiting toxicities (DLTs). If cohort 1-1 is deemed to be safe and tolerable by the dose level review team (DLRT), cohort 1-2 will study tarlatamab in combination with YL201 at 1.6 mg / kg IV Q3W. If cohort 1-2 is deemed to be safe and tolerable by the DLRT, cohort 1-3 will study tarlatamab in combination with YL201 at 2.0 mg / kg IV Q3W. If cohort 1-3 is deemed to be safe and tolerable by the DLRT, cohort 1-4 will study tarlatamab in combination with YL201 at 2.4 mg / kg IV Q3W, which represents the higher of the 2 doses studied in the YL201 first-in-human dose expansion study. The Part 1 dosing cohort is shown Table 4. In all dosing cohorts, the maximum YL201 dose that may be administered is 200 mg.Amgen Ref. No. 10954-W001-SECTable 4. Dosing by Cohort

[0214] Dose level review meeting (DLRM) decisions will occur after at least 3 subjects are evaluable for DLTs. Dose escalation / de-escalation recommendations will be guided by Bayesian Optimal Interval (BOIN) design with target toxicity probability of 0.25 and overdose control probability cutoff of 0.95 (Yuan, et al, 2016). Dose exploration cohorts will enroll up to 20 subjects (including backfill) per cohort.

[0215] YL201 and tarlatamab will both be initiated on cycle 1 day 1. YL201 will be administered IV Q3W. Tarlatamab will be administered IV starting with a 1 mg step dose on cycle 1 day 1 followed by a 20 mg target dose on cycle 1 day 8, cycle 2 day 1 (also referred to herein as day 22) and then Q3W thereafter. The cycle length is 21 days. The study DLT period is 21 days starting with cycle 1 day 1.Amgen Ref. No. 10954-W001-SEC

[0216] In Part 1, treatment with YL201 and tarlatamab will be continued until the subject meets criteria for discontinuation of study treatment or meets rules for withholding or permanent discontinuation of investigational product.

[0217] Dose Expansion (Part 2): Following selection of MTCD or RP2D in dose exploration (Part 1), enrollment will commence in the dose expansion phase (Part 2) to confirm the safety and tolerability as well as further evaluate anti-tumor activity of the combination of tarlatamab and YL201. The YL201 + tarlatamab dose expansion cohort (cohort 2-1) will enroll up to 40 subjects as shown in Table 4.

[0218] In Part 2, treatment with YL201 and tarlatamab will be continued until the subject meets criteria for discontinuation of study treatment or meets rules for withholding or permanent discontinuation of investigational product.

[0219] Triplet Combination (Part 3): Part 3 will explore the safety and tolerability of the triplet combination of tarlatamab, YL201, and an anti-PD-Ll antibody (atezolizumab or durvalumab) in subjects with ES-SCLC with no prior systemic treatment for ES-SCLC other than 1 cycle of platinum-based chemotherapy, etoposide, and PD-(L)1 inhibitor in the first-line setting. Subjects in Part 3 will be treated with 4 cycles of YL201 in combination with tarlatamab and an anti-PD-Ll antibody followed by ongoing tarlatamab and anti-PD-Ll until progression. Part 3 will follow Part 1 and run in parallel with Part 2. In cohort 3-1, atezolizumab 1200 mg IV Q3W will be administered on day 1 of each 21 -day cycle (also referred to herein as days 1, 22, 43, 64, and 85). In cohort 3-2, durvalumab 1500 mg IV Q3W will be administered on day 1 of each 21-day cycle (also referred to herein as days 1, 22, 43, 64, and 85). Following a safety run-in wherein a DLRM will be held when at least 3 subjects are DLT-evaluable, up to 40 subjects may be enrolled in each of the 2 triplet combination cohorts (cohorts 3-1 and 3-2) as shown in Table 4. Dose-limiting toxicity period for the safety run-in will be 21 days starting from cycle 1 day 1.Amgen Ref. No. 10954-W001-SEC

[0220] In Part 3, treatment with YL201 will be continued for 4 cycles, unless the subject meets rules for withholding or permanent discontinuation of YL201 prior to completion of 4 cycles. Tarlatamab and anti-PD-Ll will be continued until the subject meets criteria for discontinuation of study treatment or meets rules for withholding or permanent discontinuation of investigational product.

[0221] Up to a total of 200 subjects will be enrolled in Parts 1, 2, and 3.

[0222] The study design for Parts 1, 2, and 3, is shown schematically in FIG. 3. The study design for Parts 1 and 2 are further illustrated in FIG. 4, and the study design for Part 3 is further illustrated in FIG. 5. The objectives and endpoints of the study are summarized in Table 5.Table 5Amgen Ref. No. 10954-W001-SECHospitalization and Monitoring

[0223] All subjects will be monitored for 6 to 8 hours following the end of tarlatamab infusion on cycle 1 day 1, cycle 1 day 8, and cycle 2 day 1 (day 22). Subjects will be required to stay within 1 hour of a hospital and have a cohabitant caregiver for 24 hours post tarlatamabAmgen Ref. No. 10954-W001-SECinfusion on cycle 1 day 1, cycle 1 day 8, and cycle 2 day 1 (day 22). Counseling will be provided to the subject and caregiver on signs and symptoms of CRS and ICANS by a health care provider prior to discharge. Subjects will return to site on cycle 1 day 2, cycle 1 day 9 and cycle 2 day 2 for vital signs, physical examination and research laboratory tests.

[0224] Starting with cycle 3, monitoring post-infusion may be at investigator’s discretion, with the exception of monitoring per cycle 1 guidelines if a subject experiences grade > 2 CRS, any grade ICANS, or any neurological toxicity after the immediate prior treatment. Subjects may otherwise be discharged if there are no signs and symptoms of CRS or other acute toxicities according to the discretion of the treating physician.Justification for DoseTarlatamab

[0225] The planned tarlatamab dose to be evaluated in this study is 20 mg IV Q3W with one-step dosing in cycle 1 (1 mg on cycle 1 day 1). The selection of this dosing regimen is supported by the observed PK, safety, and tolerability data from the ongoing phase lb study in subjects with ES-SCLC who were administered the tarlatamab 20 mg Q3W regimen in the first-line setting in combination with carboplatin + etoposide + anti-PD-Ll with a manageable safety profile. The selection of the 20 mg Q3W regimen is also supported by the totality of safety and efficacy data from phase 1 (Study 20160323, DeLLphi-300) and phase 2 (Study 20200491, DeLLphi-301) studies in subjects with previously treated SCLC.

[0226] Briefly, in the first-in-human, phase 1 DeLLphi-300 clinical trial in subjects with previously treated SCLC, tarlatamab administered IV demonstrated manageable toxicities and encouraging response durability (Paz-Ares et al, 2023). In the subsequent phase 2 DeLLphi-301 clinical trial of tarlatamab in third-line or later ES-SCLC, dose comparison between 10 mg and 100 mg resulted in selection of the 10 mg target dose administered IV Q2W with 1 mg step dose on treatment initiation (Ahn et al, 2023) as the dosing regimen to be further evaluated in clinicalAmgen Ref. No. 10954-W001-SECtrials. The phase 2 trial was designed to compare 2 active doses, which is consistent with the FDA Project Optimus initiative aimed at dose optimization in the development of oncologic drugs. As reported in Ahn et al, 2023, among subjects treated with tarlatamab 10 mg IV Q2W (n = 100), ORR was 40% with median PFS of 4.9 months and 9-month OS estimate of 68%. The most common adverse event was CRS in 51% of patients treated with tarlatamab 10 mg IV Q2W. Most CRS events were grade 1 or 2 in severity with only 1% of subjects with grade 3 CRS.

[0227] The exposure range to be evaluated in this study will be within the range of exposures that have been deemed safe and tolerable in prior IV tarlatamab studies.YL201

[0228] Cohort 1-1 will be the first cohort in dose exploration and will test tarlatamab in combination with YL201 at 0.8 mg / kg IV Q3W, which represents 2 dose levels lower than the lowest of the 2 doses studied in the YL201 first-in-human dose expansion study (NCT06057922). Dose escalation can continue to cohort 1-2 (YL201 dosed at 1.6 mg / kg), cohort 1-3 (YL201 dosed at 2.0 mg / kg), and then cohort 1-4 (YL201 dosed at 2.4 mg / kg) if the previous dosing cohort is deemed to be safe and tolerable by the DLRT. Cohorts 1-3 and 1-4 dose YL201 at the doses studied in the YL201 first-inhuman dose expansion study. Part 1 dosing by cohort is provided in Table 4.Atezolizumab

[0229] Atezolizumab, in combination with carboplatin and etoposide, is approved for first-line treatment of adult subjects with ES-SCLC. Atezolizumab is approved as 840 mg IV Q2W, 1200 mg IV Q3W, or 1680 mg IV Q4W (TECENTRIQ® prescribing information). In this study, atezolizumab will be administered in the first-line setting and dosed at the approved 1200 mg IV Q3W dose, however atezolizumab will be dosed with YL201 and tarlatamab instead of carboplatin and etoposide.Amgen Ref. No. 10954-W001-SECDurvalumab

[0230] Durvalumab, in combination with etoposide and either carboplatin or cisplatin, is approved for first-line treatment of subjects with ES-SCLC. When administered with etoposide and either carboplatin or cisplatin, durvalumab is approved as 1500 mg Q3W prior to chemotherapy. When administered as a single agent after completion of chemotherapy, durvalumab is approved as 1500 mg Q4W (IMFINZI® prescribing information). An exception to 1500 mg fixed dosing is made for subjects with low body weight (below 30 kg). Subjects with a body weight of less than 30 kg must receive weight-based dosing, equivalent to 20 mg / kg, until weight increases to 30 kg or greater.

[0231] In this study, durvalumab will be administered in the first-line setting and dosed at 1500 mg Q3W; however, durvalumab will be administered in combination with YL201 and tarlatamab instead of platinum based chemotherapy + etoposide.Summary of Subject Eligibility Criteria

[0232] Key Inclusion Criteria• Subjects > 18 years of age (or > legal adult age within country) at time of signing informed consent.• Subjects with histologically or cytologically confirmed ES-SCLCo For Parts 1 and 2, subject must have ES-SCLC that has progressed or recurred following at least 1 line of platinum-based anti-cancer therapy.o For Part 3, subjects must have ES-SCLC and no prior systemic treatment for ES- SCLC other than 1 cycle of platinum-based chemotherapy, etoposide, and PD- (L) 1 inhibitor in the first-line setting.• At least 1 measurable lesion as defined by RECIST 1.1 within 21-day screening period, not previously irradiated.Amgen Ref. No. 10954-W001-SEC• Subjects must have adequate organ function (cardiac, pulmonary, kidney, bone marrow, and liver)

[0233] Key Exclusion Criteria• Prior DLL3 or B7-H3 targeting therapy.• Prior exposure to topoisomerase I inhibitors or ADC with topoisomerase I inhibitor payload• Symptomatic central nervous system (CNS) metastaseso Note: Subjects with asymptomatic brain metastases are eligible provided the subject has received definitive treatment or brain metastasis does not require local therapy per investigator’s judgement.• History of (non-infectious) interstitial lung disease (ILD) / pneumonitis that required corticosteroids, current ILD / pneumonitis, or suspected ILD / pneumonitis that cannot be ruled out by imaging at screening.• Baseline requirement of supplemental oxygenEfficacy Assessments

[0234] The extent of disease will be evaluated by contrast-enhanced CT / MRI according to RECIST 1.1. In order to reduce radiation exposure for subjects, low dose CT should be utilized whenever possible.

[0235] Screening scans will be performed within 21 days prior to enrollment. If there are multiple screening scans, the one closest to the enrollment will be used as baseline. Radiological assessment will include CT / MRI of the chest, abdomen and pelvis, as well as assessment of all other known sites of disease.

[0236] All subjects will have screening MRI of the brain performed. Subjects with a history of brain metastases will have MRI / CT of the brain performed with radiologic imaging for tumorAmgen Ref. No. 10954-W001-SECassessments and as clinically indicated per standard of care. All brain scans are required to be MRI unless MRI is contraindicated, and then CT with contrast is acceptable. Brain imaging (MRI or CT) of the brain should be performed if signs or symptoms suggestive of central nervous system metastases are present.

[0237] All subsequent scans should be performed in the same manner (e.g., with the same contrast, MRI field strength) as at screening preferably on the same scanner. If the imaging modality is altered (e.g., unscheduled assessment) consultation with a medical monitor is recommended.

[0238] During treatment and follow-up, radiological imaging of the chest, abdomen, pelvis, as well as all other known sites of disease, will be performed independent of treatment cycle. Imaging may also be performed more frequently if clinically necessitated at the discretion of the managing physician. Confirmed radiographic response (complete response, partial response) requires confirmation by a repeat scan at least 4 weeks after the first documentation of response, but may be performed later at the next scheduled scan.

[0239] Radiologic imaging and tumor assessment will be performed until start of new anticancer therapy, disease progression, death, withdrawal of consent, or end of study, whichever occurs first.Safety Assessments

[0240] Safety assessments that will be evaluated include vital signs (e.g., systolic / diastolic blood pressure, heart rate, respiratory rate, pulse oximetry and temperature), electrocardiograms, and various clinical laboratory assessments. Subjects also will be monitored for cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and neutropenia as described herein.Amgen Ref. No. 10954-W001-SECEnd of Study

[0241] An individual subject is considered to have completed the study if they have completed the last visit or a final scheduled procedure. The total anticipated study duration for an individual subject is approximately 3.5 years. The study duration will consist of up to 21 days for screening, a variable period on treatment, a SFU visit approximately 60 (± 5) days after the last dose of investigational product for subjects treated in Parts 1 and 2 (tarlatamab and YL201), 90 (+5) days after the last dose of investigational product for subjects treated in Part 3 cohort 3-2 (tarlatamab, YL201, and durvalumab), 150 (+ 5) days after the last dose of investigational product for subjects treated in Part 3 cohort 3-1 (tarlatamab, YL201, and atezolizumab), and LTFU. Long-term follow-up will be conducted every 3 months (± 2 weeks) up to 3 years from the last dose of investigational product for all subjects who have not withdrawn consent. The actual duration for individual subjects will vary depending upon tolerability of study treatment, evidence of clinical and / or radiological disease progression, and willingness to participate in the study.

[0242] The end of study date for the entire study is defined as the date when the last subject across all sites is assessed or receives an intervention for evaluation in the study (i.e., last subject last visit), including any additional parts in the study (e.g., LTFU, antibody testing), as applicable.Preliminary Data

[0243] As of February 2026, a total of 25 participants have enrolled in this study, including four participants in cohort 1-1 (tarlatamab 20 mg IV Q3W + YL201 0.8 mg / kg Q3W), 15 participants in cohort 1-2 (tarlatamab 20 mg IV Q3W + YL201 1.6 mg / kg Q3W), and 6 participants in cohort 1-3 (tarlatamab 20 mg IV Q3W + YL201 2 mg / kg Q3W). The cumulative safety data from cohort 1-1 and cohort 1-2 were reviewed and these combination doses were deemed safe and tolerable. Safety evaluation of cohort 1-3 is ongoing.Amgen Ref. No. 10954-W001-SEC

[0244] An interim efficacy assessment in 11 participants with more than 13 weeks of follow-up showed a best overall response of partial response in 67% (2 of 3 participants) for cohort 1-1, 100% (4 of 4 participants) for cohort 1-2, and 25% (1 of 4 participants) for cohort 1-3. For all 11 patients, the study overall response rate was 64% with a disease control rate of 91%. Response data remain immature and additional enrollment is needed to better characterize efficacy. Nonetheless, the overall response rate observed in cohort 1-2 is encouraging and exceeds expectations for the 2L+ SCLC treatment setting. In summary, the preliminary safety and efficacy data shows encouraging results, comparing favorably with single-agent studies of YL201 (Ma Y et al., Nature Medicine, 31 : 1949-1957 (2025)) and tarlatamab (Mountzios G et al., NEJM, 393: 349-361 (2025)).

[0245] It should be understood that when describing a range of values, the characteristic being described could be an individual value found within the range. For example, “a dose from about 3 mg to about 100 mg,” could be, but is not limited to, 5 mg, 10 mg, 25 mg, 50 mg, etc. and any value in between such values. In any of the ranges described herein, the endpoints of the range are included in the range. However, the description also contemplates the same ranges in which the lower and / or the higher endpoint is excluded.

[0246] “About” or “approximately,” when used in connection with a measurable numerical variable, refers to the indicated value of the variable and to all values of the variable that are within the experimental error of the indicated value (e.g., within the 95% confidence interval for the mean) or ±10% of the indicated value, whichever is greater.

[0247] Additional features and variations of the disclosure will be apparent to those skilled in the art from the entirety of this application, including the drawings, detailed description, and appended claims, and all such features are intended as aspects of the disclosure. Likewise, features of the disclosure described herein can be re-combined into additional embodiments thatAmgen Ref. No. 10954-W001-SECalso are intended as aspects of the disclosure, irrespective of whether the combination of features is specifically mentioned above as an aspect or embodiment of the disclosure. The disclosure also includes all aspects narrower in scope in any way than the variations specifically mentioned. Also, only such limitations which are described herein as critical to the invention should be viewed as such.Amgen Ref. No. 10954-W001-SECTable 6. Amino Acid SequencesAmgen Ref. No. 10954-W001-SECAmgen Ref. No. 10954-W001-SECAmgen Ref. No. 10954-W001-SECAmgen Ref. No. 10954-W001-SECReferences

[0248] All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein.1. Aggarwal, C., Prawira, A., Antonia, S., et al. “Dual checkpoint targeting of B7-H3 and PD-1 with enoblituzumab and pembrolizumab in advanced solid tumors: interim results from a multicenter phase l / II trial.” J Immunother Cancer. 2022 Apr;10(4):e004424.2. Ahn, M.J., Cho, B.C., Felip, E., et al. “Tarlatamab for Patients with Previously Treated Small-Cell Lung Cancer.” N Engl J Med. 2023 Nov 30;389(22):2063-2075. doi:10.1056 / NEJMoa2307980.3. Belmontes, B , Sawant, D.V., Zhong, W., et al. “Immunotherapy combinations overcome resistance to bispecific T cell engager treatment in T cell-cold solid tumors.” Sci Transl Med. 2021 Aug 25;13(608):eabdl524. doi: 10.1126 / scitranslmed.abdl524.4. Brahmer, J., et al. “Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline.” J Clin Oncol. 2018;36( 17): 1714- 1768. doi: 10.1200 / JC0.2017.77.6385. 5. Bristol Myers Squibb. “Bristol Myers Squibb Statement on Opdivo (nivolumab) Small Cell Lung Cancer U.S. Indication.” 2020. Available at news.bms.com.6. Brookmeyer, R., Crowley, J. “A confidence interval for the median survival time.” Biometrics. 1982;38(1): 29-41. doi: 10.2307 / 2530286.7. Byers, L.A., Rudin, C.M. “Small cell lung cancer: where do we go from here?” Cancer.2015;121:664-672. doi: 10.1002 / cncr.29098.8. Clopper, C .J., Pearson, E.S. “The use of confidence or fiducial limits illustrated in the case of the binomial.” Biometrika. 1934;26(4):404-413. doi: 10.1093 / biomet / 26.4.404.9. Coiffier, B., Altman, A., Pui, C.H., Younes, A., Cairo, M.S. “Guidelines for the management of pediatric and adult tumor lysis syndrome: an evidence-based review.” J Clin Oncol. 2008;26:2767-2778. doi: 10.1200 / JC0.2007.15.0177.Amgen Ref. No. 10954-W001-SEC10. Dickinson, M., Viardot, A., Marks, R., et al. “Glofitamab + Pola-R-CHP in patients with previously untreated diffuse large B-cell lymphoma (DLBCL): Results from a phase lb study.” ASCO. Jun. 2023. doi: 10.1200 / JC0.2023.41.16 suppl.75.11. Eisenhauer, E.A., Therasse, P., Bogaerts, J., et al. “New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1).” Eur J Cancer. 2009;45(2):228-247. doi: 10.1016 / j.ejca.2008.10.026.12. Friberg, G., Reese, D. “Blinatumomab (Blincyto): lessons learned from the bispecific T-cell engager (BiTE) in acute lymphocytic leukemia (ALL) .” Ann Oncol. 2017 Aug l;28(8):2009-2012. doi: 10.1093 / annonc / mdxl50.13. Goldstraw, P., Chansky, K., Crowley, J., et al. “The IASLC Lung Cancer Staging Project: Proposals for Revision of the TNM Stage Groupings in the Forthcoming (Eighth) Edition of the TNM Classification for Lung Cancer.” J Thorac Oncol. 2016; 11(1):39-51. doi:10.1016 / j.jtho.2015.09.009.14. Gonzalez-Rodriguez, E., Rodriguez-Abreu, D. “Immune Checkpoint Inhibitors: Review and Management of Endocrine Adverse Events.” Oncologist. 2016;21(7):804-816. doi:10.1634 / theoncologist.2015-0509.15. Horn, L., Mansfield, A.S., Szczesna, A., et al. “First-Line Atezolizumab plus Chemotherapy in Extensive-Stage Small-Cell Lung Cancer.” N Engl J Med. 2018;379(23):2220-2229. doi: 10.1056 / NEJMoal809064.16. Imfinzi® (durvalumab) [prescribing information], Wilmington, DE: AstraZeneca Pharmaceutical LP; June 2024. Available at: azpicentral.com.17. Keytruda® (pembrolizumab) [prescribing information], Rahway, NJ: Merck Sharp & Dohme LLC; November 2023. Available at: merck.com.18. Opdivo® (nivolumab) [prescribing information], Princeton, NJ: Bristol-Myers Squibb Company; October 2023. Available at: packageinserts.bms.com.19. Tecentriq® (atezolizumab) [prescribing information], San Francisco, CA: Genentech, Inc; April 2024. Available at: gene.com.20. United States Food and Drug Administration. “Guidance for Industry Drug-Induced Liver Injury: Premarketing Clinical Evaluation.” July 2009.Amgen Ref. No. 10954-W001-SEC21. Yuan, Y., Hess, K.R., Hilsenbeck, S.G., Gilbert, M R. “Bayesian Optimal Interval Design: A Simple and Well-Performing Design for Phase I Oncology Trials.” Clin Cancer Res.2016;22(17):4291-4301. doi: 10.1158 / 1078-0432.CCR-16-0592.22. Zhang, X., Fang, C., Zhang, G., et al. “Prognostic value of B7-H3 expression in patients with solid tumors: a meta-analysis.” Oncotarget. 2017 Sep 21;8(54):93156-93167. doi:10.18632 / oncotarget.21114.

Claims

Amgen Ref. No. 10954-W001-SECCLAIMS1. A method of treating small cell lung cancer (SCLC) in a subject, the method comprising administering to the subject once every three weeks (Q3W) each of(a) 15 mg-30 mg of a bispecific T cell engager molecule (TCE) and (b) 0.5 mg / kg - 2.5 mg / kg of an antibody-drug conjugate (ADC), wherein the bi specific TCE comprises (i) a human DLL3 -binding domain comprising SEQ ID NOs: 5-10 and (ii) a human CD3-binding domain comprising SEQ ID NOs: 14-19, and the ADC is of Formula I;Formula Iwherein Ab is an anti-B7-H3 monoclonal antibody comprising SEQ ID NOs: 25- 30, SEQ ID NOs: 31-36, or SEQ ID NOs: 37-42; and q is 6 to 8.

2. The method of claim 1, wherein the bispecific TCE and the ADC are administered to the subject in multiple 21 -day cycles.

3. The method of claim 1 or 2, wherein the bispecific TCE and the ADC are administered on day 1 of each of the multiple 21 -day cycles.

4. The method of any one of claims 1-3, comprising administering to the subject:(a) 0.5 mg-2.0 mg of the bispecific TCE and 0.5 mg / kg-2.5 mg / kg of the ADC on day 1;(b) 15 mg-30 mg of the bispecific TCE on day 8, andAmgen Ref. No. 10954-W001-SEC(c) 15 mg-30 mg of the bispecific TCE and 0.5 mg / kg- 2.5 mg / kg of the ADC starting on day 22 and once every three weeks (Q3W) thereafter.

5. The method of claim 4, comprising administering to the subject:(a) 1 mg of the bispecific TCE and 0.8 mg / kg, 1.6 mg / kg, 2.0 mg / kg, or 2.4 mg / kg of the ADC on day 1 ;(b) 20 mg of the bispecific TCE on day 8; and(c) 20 mg of the bispecific TCE and 0.8 mg / kg, 1.6 mg / kg, 2.0 mg / kg, or 2.4 mg / kg of the ADC on day 22 and once every three weeks (Q3W) thereafter.

6. The method of claim 5, comprising administering 0.8 mg / kg of the ADC to the subject on days 1 and 22 and Q3W thereafter.

7. The method of claim 5, comprising administering 1.6 mg / kg of the ADC to the subject on days 1 and 22 and Q3W thereafter.

8. The method of claim 5, comprising administering 2.0 mg / kg of the ADC to the subject on days 1 and 22 and Q3W thereafter.

9. The method of claim 5, comprising administering 2.4 mg / kg of the ADC to the subject on days 1 and 22 and Q3W thereafter.

10. The method of any one of claims 1-9, wherein the bispecific TCE and the ADC are administered to the subject via intravenous (IV) injection.

11. A method of treating small cell lung cancer (SCLC) in a subject comprising administering to the subject once every three weeks (Q3W) each of:(a) a bispecific T cell engager molecule (TCE) comprising (i) a DLL3-binding domain comprising SEQ ID NOs: 5-10 and (ii) a CD3-binding domain comprising SEQ IDNOs: 14-19;(b) an anti-PD-Ll antibody; and(c) an antibody-drug conjugate (ADC) of Formula I;Amgen Ref. No. 10954-W001-SECFormula Iwherein Ab is an anti-B7-H3 monoclonal antibody comprising SEQ ID NOs: 25- 30, SEQ ID NOs: 31-36, or SEQ ID NOs: 37-42; and q is 6 to 8.

12. The method of claim 12, wherein the bispecific TCE, the ADC, and the anti-PD-L1 antibody are administered to the subject in multiple 21 -day cycles.

13. The method of claim 13, wherein the bispecific TCE, the ADC, and the anti-PD-L1 antibody are administered on day 1 of each of the multiple 21 -day cycles.

14. The method of any one of claims 11-13, comprising administering to the subject:(a) 0.5 mg-2.0 mg of the bispecific TCE, 0.5 mg / kg-2.5 mg / kg of the ADC, and 1000 mg-2000 mg of the anti-PD-Ll antibody on day 1;(b) 15 mg-30 mg of the bispecific TCE on day 8;(c) 15 mg-30 mg of the bispecific TCE, 0.5 mg / kg-2.5 mg / kg of the ADC, and 1000 mg-2000 mg of the anti-PD-Ll antibody on days 22, 43, and 64; and(d) 15 mg-30 mg of the bispecific TCE and 1000 mg-2000 mg of the anti-PD-Ll antibody starting on day 85 and once every three weeks (Q3W) thereafter.

15. The method of claim 14, comprising administering to the subject:(a) 1 mg of the bispecific TCE, 0.8 mg / kg, 1.6 mg / kg, 2.0 mg / kg, or 2.4 mg / kg of the ADC, and 1000 mg-2000 mg of the anti-PD-Ll antibody on day 1;Amgen Ref. No. 10954-W001-SEC(b) 20 mg of the bispecific TCE on day 8; and(c) 20 mg of the bispecific TCE, 0.8 mg / kg, E6 mg / kg, 2.0 mg / kg, or 2.4 mg / kg of the ADC and 1000 mg-2000 mg of the anti-PD-Ll antibody on days 22, 43, and 64; and(d) 20 mg of the bispecific TCE and 1000 mg-2000 mg of the anti-PD-Ll antibody starting on day 85 and once every three weeks (Q3W) thereafter.

16. The method of claim 15, comprising administering 0.8 mg / kg of the ADC to the subject on days 1, 22, 43, and 64.

17. The method of claim 15, comprising administering 1.6 mg / kg of the ADC to the subject on days 1, 22, 43, and 64.

18. The method of claim 15, comprising administering 2.0 mg / kg of the ADC to the subject on days 1, 22, 43, and 64.

19. The method of claim 15, comprising administering 2.4 mg / kg of the ADC to the subject on days 1, 22, 43, and 64.

20. The method of any one of claims 11-19, wherein the bispecific TCE and the ADC are administered to the subject via intravenous (IV) injection.

21. The method of any one of claims 11-20, wherein the anti-PD-Ll antibody is durvalumab or atezolizumab.

22. The method of claim 21, comprising administering 1500 mg durvalumab intravenously (IV) to the subject on days 1, 22, 43, 64, 85 and Q3W thereafter.

23. The method of claim 21, comprising administering 1200 mg atezolizumab IV to the subject on days 1, 22, 43, 64, 85 and Q3W thereafter.

24. The method of any one of claims 1-23, wherein the bispecific TCE comprises the amino acid sequence of SEQ ID NO: 13.Amgen Ref. No. 10954-W001-SEC25. The method of any one of claims 1-24, wherein the bispecific TCE comprises the amino acid sequence of SEQ ID NO: 22.

26. The method of any one of claims 1-25, wherein the bispecific TCE comprises the amino acid sequence of SEQ ID NO: 24.

27. The method of one of claims 1-26, wherein the anti-B7-H3 monoclonal antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 45 and a light chain amino acid sequence of SEQ ID NO: 46.

28. The method of any one of claims 1-27, wherein the small cell lung cancer is extensive stage small cell lung cancer (ES-SCLC).

29. The method of any one of claims 1-28, wherein the small cell lung cancer is refractory SCLC or relapsed SCLC.

30. The method of any one of claims 1-29, wherein the small cell lung cancer expresses DLL3 as determined by immunohistochemistry.

31. The method of any one of claims 1-30, wherein the SCLC has progressed or relapsed following at least one previous treatment.

32. The method of claim 31, wherein the at least one previous treatment comprises platinum-based chemotherapy, etoposide, aPD-Ll inhibitor, or combinations thereof.

33. The method of claim 32, wherein the platinum-based chemotherapy comprises carboplatin or cisplatin.

34. The method of any one of claims 1-33, further comprising administering at least one additional therapeutic agent to the subject.

35. The method of claim 34, wherein the at least one additional therapeutic agent comprises dexamethasone, an anti-emetic agent, granulocyte colony-stimulating factor (G-CSF), and / or saline.Amgen Ref. No. 10954-W001-SEC36. A method of treating small cell lung cancer (SCLC) in a subject comprising administering to the subject:(a) 0.5 mg-2.0 mg tarlatamab and 0.5 mg / kg-2.5 mg / kg of an antibody-drug conjugate (ADC) on day 1;(b) 15 mg-30 mg tarlatamab on day 8;(c) 15 mg-30 mg tarlatamab and 0.5 mg / kg-2.5 mg / kg of the ADC starting on day 22 and once every three weeks (Q3W) thereafter;wherein the ADC is of Formula I;Formula Iwherein Ab is an anti-B7-H3 monoclonal antibody comprising a heavy chain amino acid sequence of SEQ ID NO: 45 and a light chain sequence of SEQ ID NO: 46, and q is 6 to 8.

37. The method of claim 36, comprising administering to the subject:(a) 1 mg tarlatamab and 0.8 mg / kg, 1.6 mg / kg, 2.0 mg / kg, or 2.4 mg / kg of the ADC on day 1 ;(b) 20 mg tarlatamab on day 8; and(c) 20 mg tarlatamab and 0.8 mg / kg, 1.6 mg / kg, 2.0 mg / kg, or 2.4 mg / kg of the ADC on day 22; and once every three weeks (Q3W) thereafter.Amgen Ref. No. 10954-W001-SEC38. The method of claim 36 or claim 37, comprising administering 0.8 mg / kg of the ADC to the subject on days 1 and 22 and Q3W thereafter.

39. The method of claim 36 or claim 37, comprising administering 1.6 mg / kg of the ADC to the subject on days 1 and 22 and Q3W thereafter.

40. The method of claim 36 or claim 37, comprising administering 2.0 mg / kg of the ADC to the subject on days 1 and 22 and Q3W thereafter.

41. The method of claim 36 or claim 37, comprising administering 2.4 mg / kg of the ADC to the subject on days 1 and 22 and Q3W thereafter.

42. A method of treating small cell lung cancer (SCLC) in a subject comprising administering to the subject:(a) 0.5 mg-2.0 mg tarlatamab and 0.5 mg / kg-2.5 mg / kg tambotatug pelitecan on day 1;(b) 15 mg-30 mg tarlatamab on day 8;(c) 15 mg-30 mg tarlatamab and 0.5 mg / kg-2.5 mg / kg tambotatug pelitecan starting on day 22 and once every three weeks (Q3W) thereafter.

43. The method of claim 42, comprising administering to the subject:(a) 1 mg tarlatamab and 0.8 mg / kg, 1.6 mg / kg, 2.0 mg / kg, or 2.4 mg / kg tambotatug pelitecan on day 1;(b) 20 mg tarlatamab on day 8; and(c) 20 mg tarlatamab and 0.8 mg / kg, 1.6 mg / kg, 2.0 mg / kg, or 2.4 mg / kg tambotatug pelitecan on day 22; and once every three weeks (Q3W) thereafter.

44. The method of any one of claims 36-43, wherein the small cell lung cancer is extensive stage small cell lung cancer (ES-SCLC).

45. The method of any one of claims 36-44, wherein the small cell lung cancer is refractory SCLC or relapsed SCLC.Amgen Ref. No. 10954-W001-SEC46. The method of any one of claims 36-45, wherein the SCLC has progressed or relapsed following at least one previous treatment.

47. The method of claim 46, wherein the at least one previous treatment comprises platinum-based chemotherapy, etoposide, aPD-Ll inhibitor, or combinations thereof.

48. The method of claim 47, wherein the platinum-based chemotherapy comprises carboplatin or cisplatin.

49. A method of treating small cell lung cancer (SCLC) in a subject comprising administering to the subject:(a) 0.5 mg-2.0 mg of tarlatamab, 0.5 mg / kg-2.5 mg / kg of an antibody-drug conjugate (ADC), and 1000 mg-2000 mg of an anti-PD-Ll antibody on day 1;(b) 15 mg-30 mg of tarlatamab on day 8;(c) 15 mg-30 mg of tarlatamab, 0.5 mg / kg-2.5 mg / kg of the ADC, and 1000 mg- 2000 mg of the anti-PD-Ll antibody on each of days 22, 43, and 64; and(d) 15 mg-30 mg of tarlatamab and 1000 mg-2000 mg of the anti-PD-Ll antibody starting on day 85 and once every three weeks (Q3W) thereafter;wherein the ADC is of Formula I;Amgen Ref. No. 10954-W001-SECwherein Ab is an anti-B7-H3 monoclonal antibody comprising a heavy chain amino acid sequence of SEQ ID NO: 45 and a light chain amino acid sequence of SEQ ID NO: 46, and q is 8.

50. The method of claim 49, comprising administering to the subject:(a) 1 mg tarlatamab, 0.8 mg / kg, 1.6 mg / kg, 2.0 mg / kg, or 2.4 mg / kg of the ADC, and 1000 mg-2000 mg of the anti-PD-Ll antibody on day 1;(b) 20 mg tarlatamab on day 8; and(c) 20 mg tarlatamab, 0.8 mg / kg, 1.6 mg / kg, 2.0 mg / kg, or 2.4 mg / kg of the ADC and 1000 mg-2000 mg of the anti-PD-Ll antibody on days 22, 43, and 64; and(d) 20 mg tarlatamab and 1000 mg-2000 mg of the anti-PD-Ll antibody starting on day 85 and once every three weeks (Q3W) thereafter.

51. The method of claim 50, comprising administering 0.8 mg / kg of the ADC to the subject on days 1, 22, 43, and 64.

52. The method of claim 50, comprising administering 1.6 mg / kg of the ADC to the subject on days 1, 22, 43, and 64.

53. The method of claim 50, comprising administering 2.0 mg / kg of the ADC to the subject on days 1, 22, 43, and 64.

54. The method of claim 50, comprising administering 2.4 mg / kg of the ADC to the subject on days 1, 22, 43, and 64.

55. A method of treating small cell lung cancer (SCLC) in a subject comprising administering to the subject:(a) 0.5 mg-2.0 mg of tarlatamab, 0.5 mg / kg-2.5 mg / kg tambotatug pelitecan, and 1000 mg-2000 mg of an anti-PD-Ll antibody on day 1;(b) 15 mg-30 mg of tarlatamab on day 8;(c) 15 mg-30 mg of tarlatamab, 0.5 mg / kg-2.5 mg / kg tambotatug pelitecan, and 1000 mg-2000 mg of the anti-PD-Ll antibody on each of days 22, 43, and 64; and (d) 15 mg-30 mg of tarlatamab and 1000 mg-2000 mg of the anti-PD-Ll antibody starting on day 85 and once every three weeks (Q3W) thereafter.Amgen Ref. No. 10954-W001-SEC56. The method of claim 55, comprising administering to the subject:(a) 1 mg tarlatamab, 0.8 mg / kg, 1.6 mg / kg, 2.0 mg / kg, or 2.4 mg / kg tambotatug pelitecan, and 1000 mg-2000 mg of the anti-PD-Ll antibody on day 1;(b) 20 mg tarlatamab on day 8; and(c) 20 mg tarlatamab, 0.8 mg / kg, 1.6 mg / kg, 2.0 mg / kg, or 2.4 mg / kg tambotatug pelitecan and 1000 mg-2000 mg of the anti-PD-Ll antibody on days 22, 43, and 64; and(d) 20 mg tarlatamab and 1000 mg-2000 mg of the anti-PD-Ll antibody starting on day 85 and once every three weeks (Q3W) thereafter.

57. The method of any one of claims 49-57, wherein the small cell lung cancer is extensive stage small cell lung cancer (ES-SCLC).

58. The method of any one of claims 49-57, wherein the subject has not received prior treatment for SCLC other than one cycle of platinum-based chemotherapy, anti-PD-Ll antibody, and etoposide.

59. Use of a bispecific T cell engager molecule (TCE) and an antibody-drug conjugate (ADC) in the manufacture of a medicament for the treatment of small cell lung cancer (SCLC) in a subject, wherein the bispecific TCE comprises the amino acid sequence of SEQ ID NO: 13 and the ADC is of Formula I;Amgen Ref. No. 10954-W001-SECwherein Ab is an anti-B7-H3 monoclonal antibody comprising SEQ ID NOs: 25- 30, SEQ ID NOs: 31-36, or SEQ ID NOs: 37-42; and q is 6 to 8, and wherein the treatment comprises administering to the subject:(a) 0.5 mg-2.0 mg of the bispecific TCE and 0.5 mg / kg-2.5 mg / kg of the ADC on day 1;(b) 15 mg-30 mg of the bispecific TCE on day 8, and(c) 15 mg-30 mg of the bispecific TCE and 0.5 mg / kg- 2.5 mg / kg of the ADC starting on day 22 and once every three weeks (Q3W) thereafter.

60. Use of a bispecific T cell engager molecule (TCE), an antibody-drug conjugate (ADC), and an anti-PD-Ll antibody in the manufacture of a medicament for the treatment of small cell lung cancer (SCLC) in a subject, wherein the bispecific TCE comprises the amino acid sequence of SEQ ID NO: 13 and the ADC is of Formula I;Formula Iwherein Ab is an anti-B7-H3 monoclonal antibody comprising SEQ ID NOs: 25- 30, SEQ ID NOs: 31-36, or SEQ ID NOs: 37-42; and q is 6 to 8, and wherein the treatment comprises administering to the subject:(a) 0.5 mg-2.0 mg of the bispecific TCE, 0.5 mg / kg-2.5 mg / kg of the ADC, and 1000 mg-2000 mg of the anti-PD-Ll antibody on day 1;(b) 15 mg-30 mg of the bispecific TCE on day 8;Amgen Ref. No. 10954-W001-SEC(c) 15 mg-30 mg of the bispecific TCE, 0.5 mg / kg-2.5 mg / kg of the ADC, and 1000 mg-2000 mg of the anti-PD-Ll antibody on days 22, 43, and 64; and(d) 15 mg-30 mg of the bispecific TCE and 1000 mg-2000 mg of the anti-PD-Ll antibody starting on day 85 and once every three weeks (Q3W) thereafter.

61. The use of claim 59 or 60, wherein the bispecific TCE is tarlatamab and the ADC is tambotatug pelitecan.

62. A medicament comprising a bispecific T cell engager molecule (TCE) and an antibody-drug conjugate (ADC) for use in a method for treating small cell lung cancer (SCLC) in a subject, wherein the bispecific TCE comprises the amino acid sequence of SEQ ID NO: 13 and the ADC is of Formula I;Formula Iwherein Ab is an anti-B7H3 monoclonal antibody comprising SEQ ID NOs: 25- 30, SEQ ID NOs: 31-36, or SEQ ID NOs: 37-42, and q is 6 to 8, the method comprising administering to the subject:(a) 0.5 mg-2.0 mg of the bispecific TCE and 0.5 mg / kg-2.5 mg / kg of the ADC on day 1;(b) 15 mg-30 mg of the bispecific TCE on day 8, and(c) 15 mg-30 mg of the bispecific TCE and 0.5 mg / kg- 2.5 mg / kg of the ADC starting on day 22 and once every three weeks (Q3W) thereafter.Amgen Ref. No. 10954-W001-SEC63. A medicament comprising a bispecific T cell engager molecule (TCE), an antibody-drug conjugate ADC, and an anti-PD-Ll antibody for use in a method of treating small cell lung cancer (SCLC) in a subject, wherein the bispecific TCE comprises the amino acid sequence of SEQ ID NO: 13 and the ADC is of Formula I;Formula Iwherein Ab is an anti-B7-H3 monoclonal antibody comprising SEQ ID NOs: 25- 30, SEQ ID NOs: 31-36, or SEQ ID NOs: 37-42; and q is 6 to 8, the method comprising administering to the subject:(a) 0.5 mg-2.0 mg of the bispecific TCE, 0.5 mg / kg-2.5 mg / kg of the ADC, and 1000 mg-2000 mg of the anti-PD-Ll antibody on day 1;(b) 15 mg-30 mg of the bispecific TCE on day 8;(c) 15 mg-30 mg of the bispecific TCE, 0.5 mg / kg-2.5 mg / kg of the ADC, and 1000 mg-2000 mg of the anti-PD-Ll antibody on days 22, 43, and 64; and(d) 15 mg-30 mg of the bispecific TCE and 1000 mg-2000 mg of the anti-PD-Ll antibody starting on day 85 and once every three weeks (Q3W) thereafter.

64. The medicament of claim 62 or claim 63, wherein the bispecific TCE is tarlatamab and the ADC is tambotatug pelitecan.

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