The main objective is to compare the efficacy of tarlatamab with standard of care (SOC) on prolonging overall survival (OS).

DRUG: Tarlatamab

Tarlatamab will be administered as an IV infusion.

DRUG: Lurbinectedin

Lurbinectedin will be administered per local SOC.

DRUG: Topotecan

Topotecan will be administered per local SOC.

DRUG: Amrubicin

Amrubicin will be administered per local SOC.

• Overall Survival (OS)

• Participant has provided informed consent prior to initiation of any study specific activities/procedures.
• Age ≥ 18 years (or legal adult age within country, whichever is older) at the time of signing the informed consent.
• Histologically or cytologically confirmed SCLC with demonstrated progression or relapse.
• Participants who progressed or recurred following 1 platinum-based regimen.
• Measurable disease as defined per RECIST 1.1 within the 21-day screening period.
• Eastern Cooperative Oncology Group (ECOG) PS of 0 or 1.
• Minimum life expectancy of 12 weeks.
• Adequate organ function.

• Disease Related

  • Symptomatic central nervous system (CNS) metastases with exceptions defined in the protocol.
  • Diagnosis or evidence of leptomeningeal disease.
  • Prior history of immune checkpoint inhibitors resulting in events defined in the protocol.

• Other Medical Conditions

  • Active autoimmune disease that has required systemic treatment (except replacement therapy) within the past 2 years or any other diseases requiring immunosuppressive therapy.
  • History of solid organ transplantation.
  • History of other malignancy within the past 2 years, with exceptions defined in the protocol.
  • Myocardial infarction and/or symptomatic congestive heart failure (New York Heart Association > class II) within 12 months prior to first dose of study treatment.
  • History of arterial thrombosis (eg, stroke or transient ischemic attack) within 12 months prior to first dose of study treatment.
  • Presence or history of viral infection based on criteria per protocol.
  • Receiving systemic corticosteroid therapy or any other form of immunosuppressive therapy within 7 days prior to first dose of study treatment.
  • Symptoms and/or radiographic signs that indicate an acute and/or uncontrolled active systemic infection requiring antibiotics within 7 days prior to the first dose study treatment.
  • Evidence of interstitial lung disease or active, non-infectious pneumonitis.

• Prior/Concomitant Therapy

  • Prior therapy with tarlatamab or any of the standard of care chemotherapy included as part of this trial or participation in any tarlatamab or any other DLL3 targeted agent clinical trial.
  • Prior therapy with any selective inhibitor of the DLL3 pathway.
  • Participant received more than one prior systemic therapy regimen for SCLC.
  • Prior anti-cancer therapy within 21 days prior to first dose of study treatment with exceptions defined in protocol.
  • Current anti-cancer therapy such as chemotherapy, immunotherapy, or targeted therapy with exceptions.
  • Use of herbal or prescription/non-prescription medications known to inhibit membrane transporters P-glycoprotein (P-gp) and/or breast cancer resistance protein (BCRP) within 7 days prior to the first dose of study treatment.
  • Use of herbal or prescription/non-prescription medications known to be moderate or strong inhibitors of cytochrome P450 3A (CYP3A) enzymes within 7 days prior to the first dose of study treatment.
  • Use of herbal or prescription/non-prescription medications known to be moderate or strong inducers of CYP3A enzymes within 28 days prior to first dose of study treatment.
  • Participants who have reached the limit dose of prior treatment with cardiotoxic drugs.
  • Major surgical procedures within 28 days prior to first dose of study treatment.
  • Live and live-attenuated vaccines within 14 days prior to the start of study treatment.
  • Inactive vaccines and live viral non-replicating vaccines within 3 days prior to the first dose of study treatment.
  • Currently receiving treatment in another investigational device or drug study, or less than 30 days since ending treatment on another investigational device or drug study(ies). Other investigational procedures while participating in this study are excluded.

• Diagnostic Assessments

  • Any previous diagnosis of transformed non-small cell lung cancer (NSCLC), epidermal growth factor receptor (EGFR) activating mutation positive NSCLC that has transformed to SCLC, with exceptions defined in the protocol.

• Other Exclusions

  • Female participants of childbearing potential unwilling to use protocol specified method of contraception during treatment and for an additional 60 days after the last dose of tarlatamab.
  • Female participants who are breastfeeding or who plan to breastfeed while on study through 60 days after the last dose of tarlatamab.
  • Female participants planning to become pregnant or donate eggs while on study through 60 days after the last dose of tarlatamab.
  • Female participants of childbearing potential with a positive pregnancy test assessed at screening by a serum pregnancy test.
  • Male participants with a female partner of childbearing potential who are unwilling to practice sexual abstinence (refrain from heterosexual intercourse) or use contraception during treatment and for an additional 60 days after the last dose of tarlatamab.
  • Male participants with a pregnant partner who are unwilling to practice abstinence or use a condom during treatment and for an additional 60 days after the last dose of tarlatamab.
  • Male participants unwilling to abstain from donating sperm during treatment and for an additional 60 days after the last dose of tarlatamab.
  • Contraception requirements for male and female participants receiving SOC therapies are based on regional prescribing information.
  • Breastfeeding restrictions for female participants receiving SOC therapies are based on regional prescribing information.
  • Participant has known sensitivity or is contraindicated to any of the products or components to be administered during dosing.
  • Participant likely to not be available to complete all protocol-required study visits or procedures, and/or to comply with all required study procedures.
  • History or evidence of any other clinically significant disorder, condition or disease determined by the investigator or Amgen physician that would pose a risk to the subject safety or interfere with the study evaluation..