Tarlatamab vs Standard of Care Chemotherapy in Patients With Pre-treated Advanced, Pulmonary or Gastroenteropancreatic Poorly Differentiated Neuroendocrine Carcinomas (NECs)

Inclusion Criteria:

1. Signed Informed consent:

• Subjects must have signed and dated an IRB/IEC approved written informedconsent form in accordance with regulatory and institutional guidelines. Thismust be obtained before the performance of any protocol related procedures thatare not part of normal subject care.

• Subjects must be willing and able to comply with scheduled visits, treatmentschedule, and laboratory testing

2. Age ≥ 18 years.

3. WHO Performance status 0 - 1.

4. Life expectancy > 12 weeks.

5. Histologically proven and centrally confirmed poorly differentiated neuroendocrinecarcinoma (NEC): large cells for lung NEC (WHO 2015 classification), and large andsmall cells for extra-gastroenteropancreatic (assessed on archived tissue, withpossible pre-screening during first-line).

6. Expression of DLL3 in at least 1% of tumor cells (assessed on archived tissue, withpossible pre-screening during first-line)

7. Tumor progression following one platinum based line of therapy.

8. Unresectable locally advanced or metastatic stage.

9. At least one measurable target lesion according to RECIST v1.1 per investigatorassessment. The radiological assessment has to be done within the timelinesindicated.

10. Adequate organ function: creatinine clearance > 50 mL/min, Neutrophils count ≥ 1500/mm3; Platelets > 100 000/mm3 ; Hemoglobin > 9 g/dL; AST and ALT < 3 x ULN (upper limit of normal) with total bilirubin ≤ 2 × ULN except subjects withdocumented Gilbert's syndrome or liver metastasis, who must have AST and ALT ≤ 5 xULN and a baseline total bilirubin ≤ 3.0 mg/dL.

11. Full recovery from all toxicities associated with prior treatment, to acceptablebaseline status, or a National Cancer Institute Common Terminology Criteria forAdverse Events (NCI CTCAE v5.0) grade of 0 or 1, except for toxicities notconsidered a safety risk, such as alopecia or vitiligo.

12. Availability of tumor material for central review processes and translationalresearch projects.

13. Absence of any unstable systemic disease and any psychological, familial,sociological or geographical factors potentially hampering compliance with the studyprotocol and follow-up schedule.

14. Females of childbearing potential who are sexually active with a non-sterilized malepartner must use a highly effective method of contraception for 28 days prior to thefirst dose of investigational product, and must agree to continue using suchprecautions for 7 months after the final dose of investigational product; cessationof contraception after this point should be discussed with a responsible physician.Periodic abstinence, the rhythm method, and the withdrawal method are not acceptablemethods of contraception. They must also refrain from egg cell donation for 7 monthsafter the final dose of investigational product.

15. Men who are sexually active with women of childbearing potential will be instructedto adhere to contraception for a period of 6 months after the last dose oftreatment.

16. Patient covered by a national health insurance.

Exclusion Criteria:

1. Well-differentiated neuroendocrine tumor (NET G1, G2 and G3 according to digestiveWHO 2017 classification or typical/atypical carcinoid tumor according to lung WHO 2015 classification)

2. Previous treatment targeting DLL3

3. More than one line of systemic therapy in the metastatic setting. Chemotherapy fornon-metastatic stage is not considered as first-line if there is a time interval ofat least 6 months between the last dose of chemotherapy for non-metastatic stage andthe initiation of first-line chemotherapy for metastatic/recurrent disease.

4. Small cell lung NEC (except as a minor <30% component in mixed tumors)

5. Known EGFR activating mutation or ALK or ROS1 rearrangement for lung NEC

6. Untreated or symptomatic central nervous system (CNS) metastases:

• Subjects with asymptomatic CNS metastases are eligible if clinically stable forat least 4 weeks and do not require intervention (including use ofcorticosteroids).

• Subjects with treated brain metastases are eligible provided the followingcriteria are met:

• Subject is asymptomatic from brain metastases

• Whole brain radiation or surgery was completed at least 2 weeks prior tofirst dose of study treatment (stereotactic radiosurgery completed atleast 7 days prior to first dose of study treatment)

• Any CNS disease is clinically stable, subject is off steroids for CNSdisease for at least 5 days (unless steroids are indicated for a reasonunrelated to CNS disease), and subject is off or on stable doses ofanti-epileptic drugs at least 14 days prior to first dose of studytreatment

7. Leptomeningeal metastasis

8. Patients with a recent history of other malignancies except adequately treatednon-melanoma skin cancer, and curatively treated in-situ cancer. Patients withhistory of solid tumors, including adenocarcinoma, treated in a curative way with orwithout chemotherapy and without any evidence of disease >2 years beforerandomisation can be included as well.

9. Major surgery within 28 days prior to initiation of study treatment.

10. Myocardial infarction and/or symptomatic congestive heart failure (New York HeadAssociation class > class II) within 12 months prior to initiation of studytreatment.

11. History of arterial thrombosis (e.g. stroke or transient ischemic attack) within 12months prior to initiation of study treatment.

12. Symptoms and/or clinical and/or radiological signs suggestive of uncontrolled and/oracute active systemic infection within 7 days prior to first administration ofstudytreatment. Patient with active infection requiring parenteral antibiotic therapy.Upon completion of parental antibiotic therapy and resolution of symptoms, thepatient may be considered eligible under the infection criterion.

13. Known sensitivity and/or immediate hypersensitivity to any component of studytreatment.

14. History of primary immunodeficiency, history of organ transplant that requirestherapeutic immunosuppression and the use of immunosuppressive agents within 28 daysof randomization or a prior history of severe (grade 3 or 4) immune mediatedtoxicity from other immune therapy.

15. Patients with immune pneumonitis, pituitary or thyroid disorders, or pancreatitisunder treatment with immuno-oncology agents.

16. Patients reporting infusion-related reactions or severe, life-threatening orrecurrent immune-mediated adverse events (grade 2 or higher), including eventsleading to permanent discontinuation of immuno-oncology agents.

17. Presence of an indwelling line or drain (including the following: percutaneousnephrostomy tube, indwelling Foley catheter, biliary drain, peritoneal drain orcatheter, pericardial drain or catheter, drain catheter or thoracic drain forpleural fluid collection).

18. Patient with a diagnosis of immunodeficiency or undergoing systemic corticotherapyor any other form of immunosuppressive therapy within 7 days prior to administrationof the first dose of study treatment.

19. Known acute or chronic B or C hepatitis by serological evaluation. Patients withserological sequellae of hepatitis (antibodies test serologically positive forvirus) without hepatitis could be included.

20. Known Human immunodeficiency virus infection

21. Patients who are pregnant or breast-feeding, or planning to become pregnant orbreast-feed during the trial and within 7 months after the last dose of studytreatment.

22. Male not wishing to abstain from sperm donation during the trial and within 6 monthsof the last study treatment.

23. Vaccination with live or attenuated virus vaccines is not permitted during the 28days prior to administration of the first dose of treatment, and for the duration ofthe study. Vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) should be avoided during selection, at least 14 days before the firstday of treatment. Live, non-replicating smallpox vaccines (such as Jynneos) againstmonkeypox infection are permitted during the study (except during cycle 1) inaccordance with the center's standard of care and internal recommendations.

24. Active autoimmune disease requiring systemic therapy (except replacement therapy)within the last 2 years or any other disease requiring immunosuppressive therapyduring the study.

25. Patients with other concurrent severe and/or uncontrolled medical disease whichcould compromise participation in the study.