Trial of FOLFIRI + Zimberelimab + Domvanalimab vs FOLFIRI With a Hybrid Synthetic Control Arm in Second Line Treatment of Neuroendocrine Carcinoma of Gastro-enteropancreatic or Unknown Origin (REWENEC 01)

Inclusion Criteria:

* Man or woman aged ≥ 18 years old,
* Poorly differentiated neuroendocrine carcinoma (NEC) \[or mixed tumor with NEC component is \> 30%, the patient is eligible\] with ki 67 \> 20% from a gastrointestinal tract (from esophagus to anal canal) or biliopancreatic primary or an unknown primary cancer, locally advanced and/or metastatic,
* Centralized review of the diagnostic by a consulting pathologist specialized in NET (TENPATH network),
* Recommendation of a second-line chemotherapy after progression (documented using the RECIST criteria v.1.1) and after a first-line chemotherapy treatment by cisplatin (or carboplatin) + etoposide or in the event of progression in the 6 months following the discontinuation of this first-line treatment,
* Patient presenting at least one measurable target lesion according to the RECIST criteria v.1.1, in an area not previously irradiated,
* General condition ≤ 1 (ECOG-PS),
* Patient of childbearing age accepting to use a highly effective method of contraception during treatment and until 6 months after discontinuation of chemotherapy and 4 months after the last dose of domvanalimab and zimberelimab. Men sexually active must agree to use a highly effective method of contraception during treatment and for at least 6 months after discontinuation of chemotherapy and 4 months after the last dose of domvanalimab and zimberelimab,
* Patient who signed the informed consent form.
* Patient affiliated to National French social security system

Exclusion Criteria:

* Well differentiated neuroendocrine tumor whatever the grade,
* First-line chemotherapy other than cisplatin (or carboplatin) and etoposide,
* Prior immunotherapy,
* Prior malignancy active within the previous 2 years except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix, breast, or prostate cancer,
* Pregnant or breastfeeding woman,
* Lack of efficient contraception (for men or women of reproductive age),
* All medical, geographical, social, and psychological conditions or a legal situation that will not allow the patient to finish the study or sign an informed consent form,
* Patient with asymptomatic brain metastasis or with previously treated brain metastasis relating to the study drugs
* Any of the following uncontrolled progressive diseases in the 6 months before randomization: liver failure, renal insufficiency, respiratory distress, congestive heart failure (NYHA III-IV), unstable angina, myocardial infarction, significant arrhythmia,
* Partial and complete dihydropyrimidine dehydrogenase (DPD) deficiency: uracil level ≥ 16 ng/ml,
* Known Gilbert's syndrome,
* Total bilirubin level \>1.5 x the upper limit of normal (ULN); ASAT and/or ALAT \> 5 x ULN; TP \< 50 % (Except for patient's treated with Vitamin K antagonists or direct oral anticoagulants with INR \<3 ),
* Neutrophils \<1.5x109/l, platelets \<100x109/l, hemoglobin \< 9 g/dl,
* Chronic uncontrolled diarrhea, unresolved intestinal occlusion or subocclusion,
* History of anaphylactic reaction or known intolerance to atropine (sulfate) or to loperamide or to antiemetics administered in association with Folfiri,
* All treatment with concomitant anticonvulsive agents, CYP3A4 inducers (phenytoin, phenobarbital, carbamazepine); patients with these treatments should have stopped them, for at least 7 days before inclusion in the study,
* Chronic medical condition requiring the ongoing use of supra-physiologic doses of systemic corticosteroids (\>10 mg/day of oral prednisone or equivalent) or systemic immunosuppressive medications. Immunosuppressive medications, including chronic systemic corticosteroids at supraphysiologic doses should have been stopped 14 days before the first dose (except for participants who require hormone replacement therapy such as hydrocortisone).
* Active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
* History of (non-infectious) pneumonitis that required steroids, or current pneumonitis.
* History of severe hypersensitivity reaction to any monoclonal antibody (mAb) therapy.
* Live attenuated vaccines within 28 days prior enrolment.
* Any concurrent anticancer therapy, including chemotherapy, radiotherapy (except palliative radiotherapy), immunotherapy, biologic, or hormonal treatment. Concurrent use of hormones for noncancer-related conditions is permitted.
* Known hypersensitivity to any investigational product (IP), or any excipient contained in the formulations of the study interventions.
* Known immunodeficiency or human immunodeficiency virus (HIV) infection with HIV viral load ≥200 copies/mL or CD4+ T-cell count \<350 cells/μL, or taking medications that may interfere with metabolism of study drugs.
* Known acute hepatitis B, known chronic hepatitis B infection with active untreated disease, or known active hepatitis C infection. In participants with a history of HBV or HCV, participants with detectable viral loads will be excluded.