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Inclusion Criteria:

1. Written informed consent obtained from the subject prior to performing any protocol-related procedures.
2. Age ≥ 18 years
3. ECOG performance status 2
4. Histologically confirmed small-cell lung cancer (initial mixed histology / combined SCLC permitted if re-biopsy of current progression shows SCLC)
5. Recurrent or metastatic disease. In case of local-only recurrence, availability of local treatment options must have been excluded
6. Has received at least one prior line of treatment in the recurrent or metastatic setting
7. Has received a prior treatment line with platinum, etoposide, and a PD-L1 antibody. Treatment with chemotherapy only is acceptable if the patient had a contraindication for CPI treatment
8. Measurable disease according to RECIST v1.1

Exclusion Criteria:

1. ECOG performance status 0, 1, 3 or 4
2. Life expectancy less than three months
3. Active brain metastases with unstable symptoms (new or progressive neurological symptoms within the last 3 weeks)
4. Bone marrow insufficiency:

   1. neutrophil count \< 1.5/nl or
   2. hemoglobin \<8 mg/dl or
   3. platelets \<100/nl
5. Advanced liver disease:

   1. Subjects with pre-existing chronic liver disease:

      iii. Total bilirubin \> 1.5xULN or iv. ALT or AST \> 3xULN
   2. Subjects with no relevant prior chronic liver disease and elevated liver parameters due to liver metastases:

   v. Total bilirubin \> 3xULN or vi. ALT or AST \> 10xULN c. International normalized ratio (INR) \> 2.0 and partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT) ≥ 1.5 x ULN, except for subjects undergoing new class anticoagulant therapy (eg, Apixaban, Rivaroxaban, Edoxaban) with stable dose for 2 weeks prior to enrollment
6. Advanced kidney disease:

   CKD-EPI GFR \<20 ml/min/1.73m²
7. Heart failure with reduced ejection fraction (EF \< 40%, assessed by echochardiography performed within 3 months prior to C1D1)
8. Hemodynamically significant pericardial effusion
9. Clinically significant pleural effusion (Clinically significant pleural effusions must be managed by drainage. Re-check within 3 days prior to initiation of treatment.)
10. Respiratory compromise leading to an unjustifiable risk in case of higher-grade CRS, in the judgment of the investigator (possible criteria leading to such judgment: oxygen support at rest \>2l/min, active pneumonia or pneumonitis)
11. Prior DLL3-directed treatment
12. Prior systemic therapy (chemotherapy, CPI) within 14 days prior to first dose of study treatment
13. Previous treatment in the present study (does not include screening failure)
14. History of immune-mediated encephalitis
15. Concurrent malignancy other than SCLC requiring active treatment
16. HIV infection not on stable antiviral treatment
17. Women of childbearing potential or men with partners of childbearing potential who are not adhering to contraceptive measures
18. Female subjects of childbearing potential

    1. unwilling to use appropriate method(s) of contraception. WOCBP should use an adequate method to avoid pregnancy for 60 days after the last dose of tarlatamab
    2. who are breastfeeding or who plan to breastfeed while on study through 60 days after the last dose of tarlatamab
    3. planning to become pregnant or donate eggs while on study through 60 days after the last dose of tarlatamab
    4. with a positive pregnancy test at screening
19. Male subjects

    1. 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
    2. 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
    3. unwilling to abstain from donating sperm during treatment and for an additional 60 days after the last dose of tarlatamab
20. Patient who has been incarcerated or involuntarily institutionalized by court order or by the authorities \[§ 40 Abs. 1 S. 3 Nr. 4 AMG\].
21. Patients who are unable to consent because they do not understand the nature, significance and implications of the clinical trial and therefore cannot form a rational intention in the light of the facts \[§ 40 Abs. 1 S. 3 Nr. 3a AMG\].

• Berlin, Germany
• Dresden, Germany
• Essen, Germany
• Flensburg, Germany
• Frankfurt, Germany
• Minden, Germany
• München, Germany
• Stuttgart, Germany