The integration of tarlatamab, a bispecific T-cell engager molecule targeting both DLL3 and CD3, into the treatment algorithm for SCLC will substantially improve the prognosis of patients. Nevertheless, disease progression will inevitably occur.

Major challenges for further improving tarlatamab therapy are the molecular understanding of resistance to tarlatamab and the selection of the optimal systemic therapy upon progression. Patients who experience platinum-sensitive progression more than 90 days after first-line chemoimmunotherapy (platinum-free interval (PFI) = day of last administration of platinum-containing chemotherapy until progression) and subsequently progress on tarlatamab therapy may benefit from a platinum-based chemotherapy re-challenge while remaining on tarlatamab treatment. We hypothesize that patients who progress while on tarlatamab may benefit more from the combination of both therapies than from sequential therapy due to synergistic effects. We assume that, besides the cytotoxic effects of platinumbased chemotherapy, additional T-cell modifying effects could support this concept. The disruption of the tumor stroma, which has been described in various chemotherapies, could increase T-cell infiltration and thus have additional immunostimulatory effects (Hoff et al., 2011). The lymphodepletion triggered by chemotherapy and the resulting release of interleukins such as IL-15 could also have an enhancing effect on therapy with bispecific T-cell engagers (Kochenderfer et al., 2017). In addition, it has been shown preclinically that chemotherapeutic agents that have an inhibitory effect on topoisomerase (e.g. doxorubicin) also have a selective inhibitory effect on MDSCs. Here, the administration of the topoisomerase inhibitor etoposide could counteract possible resistance mechanisms (Alizadeh et al., 2014). Different cut-off values for chemotherapy-sensitive progression in small cell lung cancer between 60 - 90 days PFI have been discussed for decades. It has been shown that a platinum re-challenge as a second chemotherapy regimen is superior in a patient population with a PFI greater than 90 days compared to topotecan (Baize et al., 2020). This is expected to apply to approximately 40% of patients receiving standard first-line platinum-based therapy with PD-L1 inhibitors (Torsawa et al., 2023). If tarlatamab is added to first-line therapy in the near future, the proportion of patients with a PFI of more than 90 days could increase further. In the future, platinum-containing chemotherapy could become an increasingly important role as second-line chemotherapy. In parallel with the clinical evaluation of the re-challenge concept, we will conduct an extensive rebiopsy program. This will include a re-biopsy during progression to tarlatamab therapy at screening and a re-biopsy at the time of progression to the study treatment. Whole exome sequencing and transcriptomic analyses of tumor bulks as well as transcriptomic analysis at the single-cell level will be performed to elucidate molecular mechanisms of resistance in the tumor cells and in the tumor microenvironment. Additional immunohistochemical

Open-label, single-arm, multicenter phase II trial. In total, up to 12 trial sites will be opened for recruitment. Patients over 18 years of age with advanced/inoperable or metastatic small cell lung cancer (UICC stage III or IV, who cannot be treated with curative radiochemotherapy) are eligible to participate. They must have previously received platinum-containing chemoimmunotherapy and must currently have progressed on tarlatamab (+/- PD-L1 inhibitor). Tarlatamab must be continued before and during the screening and must not have been discontinued for more than 4 weeks after the last regular intake date. During screening, patients will receive appropriate baseline quantification of disease status, including an MRI scan of the brain. Patients with CNS metastases are eligible to participate in the study, provided they are not receiving elevated doses of steroids and are clinically stable. Local therapy for brain metastases, such as radiation therapy or surgery, must be completed at least 2 weeks prior to study entry. Treatment is administered as described in Figure 2. Study treatment starts with cycle 1, day 1 (C1D1) of platinum-containing re-challenge therapy. The rechallenge therapy is administered in a 21-day cycle for four cycles, with tarlatamab 10 mg continued at a two-week interval. During these 4 cycles of re-challenge, tarlatamab is administered on day 1 and day 15 of cycles 1 and 3. Administration in cycles 2 and 4 occurs on day 8. After the end of the re-induction therapy (these 4 cycles), maintenance therapy with tarlatamab follows on day 1 and day 15 of each subsequent 28-day cycle until progression, unacceptable toxicity, or discontinuation for other reasons as described later in this protocol. Treatment efficacy will be assessed by CT scans of the thorax, abdomen and all other involved areas, and by MRI scans of the brain. Imaging will be performed every 8 weeks during cycles C1-C5 (after week 8, 16, 24), and every three months from C6 onward. Scans will be evaluated according to RECIST 1.1 for all efficacy endpoints.

Inclusion Criteria:

1. Capable of providing signed informed consent, which includes compliance with the requirements and restrictions outlined in the informed consent form (ICF) and this protocol. Written informed consent and any locally required authorization (e.g., European Union [EU] Data Privacy Directive) must be obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations.

2. Provision of signed and dated, written ICF prior to any mandatory study-specific procedures, sampling, and analyses.

3. Age ≥ 18 years at the time of signing the informed consent.

4. Willing and able to comply with the protocol for the duration of the study including treatment and scheduled visits, examinations, and follow-up.

5. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1.

6. Patients must have a life expectancy of ≥ 12 weeks.

7. Histologically or cytologically confirmed locally advanced or metastatic SCLC (UICC stage III not amenable to curative radiochemotherapy or stage IV). Note: Assignment of stage must be done according to the 9th edition of American Joint Committee on Cancer (AJCC)/Union for Interational Cancer Control (UICC) TNM staging system

8. Disease progression or relapse after first-line platinum-based therapy with a platinum-free interval (PFI) ≥ 90 days (time between last platinum administration and first documented progression).

   • Patients who received first-line systemic platinum-based chemotherapy for extensive stage (ES) disease are eligible.
   • Patients must have failed or be ineligible for PD-L1 inhibitor therapy.
   • Only one prior line of systemic chemotherapy is permitted. Patients who have previously been treated with chemotherapy as part of a limited stage (LS) disease may participate if there was a period of >6 months between the end of chemotherapy during the LS disease and chemotherapy as part of the ES disease.

9. Radiological evidence of disease progression while on treatment with tarlatamab. Patients who show progression on tarlatamab in combination with a PD-L1 inhibitor may be included.

10. Before starting study therapy (C1D1), a new biopsy of the tumor must be performed after progression under tarlatamab.

    • Lesions that show progression under tarlatmab should be prioritized. Appropriate documentation (e.g., radiological report) must be available to demonstrate progress under Tarlatamab.
    • Patients must be eligible for a biopsy of the tumor tissue in accordance with the guidelines of the treating institution.
    • The tumor sample must be provided to the sponsor in accordance with the provisions of this protocol. The shipment should be made as soon as possible.
    • If a tumor sample has already been taken after progression under tarlatmab for other reasons, the archived material can also be used for inclusion, and no new tumor biopsy is required for study inclusion.
    • If a biopsy is not possible during tarlatamab treatment and no archived tumor sample is available after progression under tarlatamab, inclusion may be possible after discussion with the sponsor.

11. Availability of a tumor sample obtained prior to the start of first-line treatment.

    • The tumor sample must be provided to the sponsor in accordance with the provisions of this protocol. The tumor sample should have been sent to the sponsor prior to C1D1.
    • If unavailable, inclusion may be possible after discussion with the sponsor.

12. There must be a maximum of 28 days between the last dose of tarlatamab and the first dose of tarlatamab as part of the study treatment. Patients may receive tarlatamab beyond progression as standard therapy during the screening phase. If tarlatamab was last administered with a PD-L1 inhibitor, this therapy may be continued during screening as part of standard of care. No PD-L1 inhibitor may be administered after C1D1.

13. Adequate tumor imaging (CT or MRI) within 28 days prior to enrollment. Imaging from the standard of care can be used for inclusion. For adequate imaging a slice thickness of 5 mm in CT and 5 mm in MRI with contrast agent should not be exceeded. More detailed information can be found in the Radiology Manual.

14. Measurable disease as defined per RECIST 1.1 within the 28-day screening period.

15. Adequate hematologic and organ function:

    1. Haemoglobin ≥9 g/dL
    2. Absolute neutrophil count (ANC) ≥1.5 × 109 /L
    3. Platelet count ≥100 × 109/L
    4. Aspartate aminotransferase (AST) / Alanine aminotransferase (ALT) ≤ 2.5 x institutional upper limit of normal unless liver metastases are present in which case they must be ≤ 5x ULN
    5. Measured creatinine clearance >41 mL/min or Calculated creatinine creatinine clearance >41 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance. Estimated creatinine clearance = (140-age [years]) x weight (kg) (x F) serum creatinine (mg/dL) x 72 where F=0.85 for females and F=1 for males.

16. Before enrollment, a woman must be either:

    1. Not of childbearing potential: premenarchal; postmenopausal (for definition, see section 4.5)
    2. Of childbearing potential: practicing effective method(s) of birth control consistent with local regulations regarding the use of birth control methods for patients participating in clinical studies (see section 4.5 and Annex 13.1)
    3. Patients must agree to continue using contraception throughout the study and for 2 months after the last dose of tarlatamab and for 6 months after the last dose of carboplatin/etoposide. Note: If the childbearing potential changes after start of the study (eg, woman who is not heterosexually active becomes active, premenarchal woman experiences menarche) the woman must begin a highly effective method of birth control, as described above.

17. A woman of childbearing potential must have a negative serum (b-human chorionic gonadotropin [b-hCG]) at screening. A woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during the study and for 2 months after the last dose of tarlatamab and 6 months after receiving the last dose of carboplation and/or etoposide .

18. A man who is sexually active with a woman of childbearing potential must agree to use a condom with spermicidal foam/gel/film/cream/suppository and his partner must also be practicing a highly effective method of contraception (see section 4.5). If the subject is vasectomized, he must still use a condom (with or without spermicide), but his female partner is not required to use contraception.

The subject must also not donate sperm during the study and for 2 months after the last dose of tarlatamab and 6 months after receiving the last dose of carboplatin and/or etoposide .

Exclusion Criteria:

1. Symptomatic CNS metastases. Subjects with treated or untreated brain metastases are eligible provided the following criteria are met:

   • Subject is asymptomatic from brain metastases. If, in the opinion of the investigator, asymptomatic, untreated brain metastases do not require local therapy, patients may be included.
   • Whole brain radiation or surgery was completed at least 2 weeks prior to first dose of study treatment
   • Stereotactic radiosurgery completed at least 7 days prior to first dose of study treatment
   • Any CNS disease is clinically stable, subject is off steroids for CNS disease for at least 5 days (unless steroids are indicated for a reason unrelated to CNS disase), and subject is off or on stable doses of anti epileptic drugs at least 14 days prior to first dose of study treatment

2. History of leptomeningeal carcinomatosis.

3. Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.

4. Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy. Exceptions are:

   1. Alopecia (any Grade)
   2. Vitiligo (any Grade)
   3. Dysgeusia (any Grade)
   4. Hypothyroidism stable on hormone replacement (Grade ≤2)
   5. Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the sponsor
   6. Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment may be included only after consultation with the sponsor.
   7. For special requirements in the laboratory see Point 14 at inclusion criteria. Note: Grading of toxicities must be done according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0.

5. History of another primary malignancy in the past 2 years. Exceptions are:

   1. Malignancy treated with curative intent and with no known active disease >1 years before the first dose of study treatment and of low potential risk for recurrence
   2. Adequately treated non melanoma skin cancer or lentigo maligna without evidence of disease
   3. Adequately treated carcinoma in situ without evidence of disease
   4. Curatively treated localized prostate cancer receiving androgen deprivation therapy and considered to have a very low risk of recurrence
   5. Lobular carcinoma in situ or ductal carcinoma in situ of the breast that is considered completely cured
   6. Curatively treated in situ cancer of the cervix, ductal carcinoma in situ, Stage 1, grade 1 endometrial carcinoma
   7. Curatively treated localized breast cancer receiving antihormonal agents and considered to have a very low risk of recurrence.

6. Any acute, chronic or uncontrolled medical, mental or psychological condition, which in the opinion of the investigator would not permit the subject to participate in the study, complete the study or understand the patient information. These may include, but are not limited to:

   1. Uncontrolled infection

   2. Uncontrolled diabetes

   3. Uncontrolled major seizure disorder

   4. Superior vena cava syndrome

   5. Active, chronic or ongoing infection requiring systemic anti-infective treatment (e.g.

      tuberculosis). For a (HIV) and viral hepatitis, please see exclusion criteria below.

   6. Intestitial lung disease

   7. Psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent

7. Patient has a history of clinically significant cardiovascular disease including, but not limited to the following:

   1. Pericarditis
   2. Recent (within 3 months) myocardial infarction
   3. Symptomatic congestive heart failure
   4. Uncontrolled hypertension
   5. Unstable angina pectoris
   6. Pericardial effusion (pericardial effusion considered due to the disease under study is permitted if clinically stable at screening)
   7. Myocarditis that is clinically unstable
   8. Resting ECG indicating uncontrolled, potentially reversible cardiac conditions, as judged by the investigator (eg. unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart failure, electrolyte disturbances, etc.), or patients with congenital long QT syndrome. Every patient must have triple baseline ECG in the screening. Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥470 ms calculated from 3 ECGs (within 15 minutes at 5 minutes apart)

8. History of active primary immunodeficiency

9. Known active hepatitis infection, positive hepatitis C virus (HCV) antibody, hepatitis B virus (HBV) surface antigen (HBsAg) or HBV core antibody (anti-HBc) at screening. Participants with a past or resolved HBV infection (defined as the presence of anti-HBc and absence of HBsAg) are eligible.

   Participants positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA.

   - Participants co-infected with HBV and HCV, or co-infected with HBV and HDV, namely: HBV positive (presence of HBsAg and/or anti HBcAb with detectable HBV DNA)

   - HCV positive (presence of anti-HCV antibodies)

10. Patient is known to be positive for HIV with 1 or more of the following:

    • Not receiving highly active antiretroviral therapy (ART)
    • Had a change in ART within 6 months of the start of screening
    • Receiving ART that may interfere with study treatment
    • CD4+ count <350 /mm3 at screening
    • AIDS-defining opportunistic infection within 6 months of start of screening
    • Does not agree to start ART and be on ART >4 weeks plus having HIV viral load <400 copies/mL at end of 4-week period (to ensure ART is tolerated and HIV controlled).

11. History of solid organ transplantation.

12. Current or prior use of immunosuppressive medication within 7 days before the first dose of trial treatment. The following are exceptions to this criterion:

    • Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection)
    • Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent
    • Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)
    • Prophylaxis during therapy with tarlatamab
    • Any anti-emetic

13. Receipt of live attenuated vaccine within 14 days prior to the first dose of study medication. Inactive vaccines (eg, non-live or non-replicating agent) and live viral non-replicating vaccines (eg, Jynneos for Monkeypox infection) within 3 days prior to first dose of study treatment.

14. Major surgery within 4 weeks of starting study treatment.

    • Patients must have recovered from any effects of any major surgery or an anticipated need for major surgery during the study.
    • Local surgery of isolated lesions for palliative intent is acceptable, as long as this does not affect the only target lesion.

15. Any herbal or prescription/non-prescription medications known to inhibit membrane transporters Pglycoprotein (P-gp) and/or breast cancer resistance protein (BCRP) (including but not limited to cyclosporine, clarithromycin, itraconazol, or ketoconazole) within 7 days prior to the first dose of study treatment

16. Any herbal or prescription/non-prescription medications known to be moderate or strong inhibitors of cytochrome P450 3A (CYP3A) enzymes (including but not limited to clarithromycin, itraconazole, ketoconazole) within 7 days prior to the first dose of study treatment.

17. Any herbal or prescription/non-prescription medications known to be moderate or strong inducers of CYP3A enzymes (including but not limited to efavirenz, penobarbital, phenytoin, rifampin, St John's Wort) within 28 days prior to first odse of study treatment.

18. Treatment with live virus, including live-attenuated vaccination, within 14 days prior to the first dose of study treatment. Inactive vaccines (eg, non-live or non-replicating agent) and live viral nonreplicating vaccines (eg Jynneos for Monkeypox infection) within 3 days prior to first dose of study treatment.