• Overall response rate (ORR) [ Time Frame: 30 months ]
  Response to treatment according to RECIST 1.1 criteria or iRECIST 1.1 criteria
• Progression-free survival rate [ Time Frame: 30 months ]
  Percentage of patients without progression of disease (PD) calculated from the date of treatment initiation with first-line chemotherapy and nivolumab until the date of first documentation of PD as per RECIST v1.1 or death.
• Median Overall Survival [ Time Frame: 30 months ]
  Length of time between start of treatment and death
• Predictive biomarkers [ Time Frame: 30 months ]
  Assess biochemical response in patients with baseline elevation of chromogranin A and/or enolase, IFN-γ, IL-6, IL-1,TNF-α, NSE and CGA and correlate it with clinical outcome.
• Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] [ Time Frame: 30 months ]
  Number and type of adverse events reported throughout the study period according to CTCAE 5.0 criteria.
• Median progression-free survival [ Time Frame: 30 months ]
  Length of time between date of evidenced response and progression of disease or death

• Overall response rate (ORR) [ Time Frame: 30 months ]
  Response to treatment according to RECIST 1.1 criteria or iRECIST 1.1 criteria
• Progression-free survival rate [ Time Frame: 30 months ]
  Percentage of patients without progression of disease (PD) calculated from the date of treatment initiation with first-line chemotherapy and nivolumab until the date of first documentation of PD as per RECIST v1.1 or death.
• Median Overall Survival [ Time Frame: 30 months ]
  Length of time between start of treatment and death
• Predictive biomarkers [ Time Frame: 30 months ]
  Assess biochemical response in patients with baseline elevation of chromogranin A and/or enolase, and correlate it with clinical outcome.
• Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] [ Time Frame: 30 months ]
  Number and type of adverse events reported throughout the study period according to CTCAE 5.0 criteria.
• Median progression-free survival [ Time Frame: 30 months ]
  Length of time between date of evidenced response and progression of disease or death

• Neuroendocrine Tumors
• Neuroendocrine Neoplasm
• Gastroenteropancreatic Neuroendocrine Tumor

• Drug: Nivolumab

  Subjects will receive Nivolumab 360 mg every 3 weeks (Q3W) first day of each cycle plus Carboplatin AUC5 Q3W first day of each cycle plus Etoposide 100 day 1-3 of each cycle up to 6 cycles of combined therapy (Induction Phase).

  At the time of completion of 6 cycles of chemotherapy and nivolumab, participants who have not experienced disease progression will continue to receive nivolumab at a dose of 480 mg as 30 minute infusion every 4 weeks for up to 2 years (24 months) (maintenance phase).

  Cycles are defined by 4 weeks or 28 days.

• Drug: Carboplatin

  Subjects will receive Nivolumab 360 mg every 3 weeks (Q3W) first day of each cycle plus Carboplatin AUC5 Q3W first day of each cycle plus Etoposide 100 day 1-3 of each cycle up to 6 cycles of combined therapy (Induction Phase).

  At the time of completion of 6 cycles of chemotherapy and nivolumab, participants who have not experienced disease progression will continue to receive nivolumab at a dose of 480 mg as 30 minute infusion every 4 weeks for up to 2 years (24 months) (maintenance phase).

  Cycles are defined by 4 weeks or 28 days.

• Drug: Etoposide

  Subjects will receive Nivolumab 360 mg every 3 weeks (Q3W) first day of each cycle plus Carboplatin AUC5 Q3W first day of each cycle plus Etoposide 100 day 1-3 of each cycle up to 6 cycles of combined therapy (Induction Phase).

  At the time of completion of 6 cycles of chemotherapy and nivolumab, participants who have not experienced disease progression will continue to receive nivolumab at a dose of 480 mg as 30 minute infusion every 4 weeks for up to 2 years (24 months) (maintenance phase).

  Cycles are defined by 4 weeks or 28 days.

Inclusion Criteria:

• Confirmed G3 NENs originated in the gastroenteropancreatic tract (WHO 2010 classification). Patients with a G3 NEN of unknown primary will also be eligible for this trial.
• Ki-67 >20% or mitotic rate > 20 per 10 HPF.
• Metastatic or locally advanced unresectable disease not amenable to treatment with curative intent.
• No prior systemic treatment for advanced disease nor as adjuvant therapy.
• Availability of fresh or archive formalin-fixed, paraffin-embedded tumor tissue for biomarker assessment.
• Patients must have clinically and/or radiographically documented measurable disease. At least one site of disease must be unidimensionally measurable as per RECIST 1.1.

• Adequate organ function as defined by the following criteria (within 7 days prior to enrollment):

  1. absolute neutrophil count (ANC) ≥1500 cells/mm3
  2. platelets ≥100,000 cells/mm3
  3. hemoglobin ≥9.0 g/dL
  4. AST and ALT ≤2.5 x upper limit of normal (ULN); in patients with liver metastases AST and ALT ≤5.0 x ULN
  5. total bilirubin ≤1.5 x ULN
  6. serum creatinine ≤1.5 x ULN or calculated creatinine clearance ≥60 mL/min.
• Male or female, age ≥18 years.
• ECOG performance status of 0-2.
• Life expectancy of ≥12 weeks.
• Women of childbearing potential must have a negative serum or urine pregnancy test within 7 days prior to treatment initiation.
• Highly effective contraception (i.e. methods with a failure rate of less than 1 % per year) for both fertile, sexually active male and female subjects. Highly effective contraception must be used 28 days prior to first trial treatment administration, for the duration of trial treatment, and at least for 60 days after stopping trial treatment.
• Signed and dated informed consent document must be given according to ICH/GCP, and national/local regulations indicating that the patient (or legally acceptable representative) has been informed of all pertinent aspects of the trial prior to enrolment.

Exclusion Criteria:

• The following endocrine tumor types may not be included: paraganglioma, adrenal, thyroid parathyroid or pituitary endocrine tumors. Large or small cell lung neuroendocrine carcinoma of the lung will also be excluded.
• Prior therapy with any immune checkpoint inhibitor.
• Major surgery, except diagnostic biopsy, in <4 weeks or radiation therapy <2 weeks prior to starting study treatment. Prior palliative radiotherapy to metastatic lesion(s) is permitted, provided there is at least one measurable lesion that has not been irradiated.
• Prior organ transplantation, including allogeneic stem-cell transplantation.
• Prior history of non-infectious pneumonitis requiring steroids or current pneumonitis.
• Systemic chronic steroid therapy (> 10 mg/day prednisone or equivalent) or other immunosuppressive agents or use of any investigational drug within 28 days before the start of trial treatment. Short-term administration of steroids for allergic reactions or management of immune-related adverse events is allowed. Topical, inhaled, nasal and ophthalmic steroids are also allowed.
• Use of any live vaccines against infectious diseases within 4 weeks of initiation of study treatment.
• Known history of positive testing for Human Immunodeficiency Virus (HIV) infection, known history of or positive tests for Hepatitis B virus surface antigen (HBVsAg) or Hepatitis C ribonucleic acid (HCV RNA) indicating acute or chronic infection or other significant acute or chronic infections requiring medication at study entry.
• Active, known or suspected autoimmune disease or a documented history of autoimmune disease, including ulcerative colitis and Crohn's disease. (Patients with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll).
• Active seizure disorder or evidence of brain metastases, spinal cord compression, or carcinomatous meningitis.
• A serious uncontrolled medical disorder or active infection that would impair their ability to receive study treatment will not be allowed to enter the study. Any of the following within the 12 months prior to study drug administration: myocardial infarction, uncontrolled angina, coronary/peripheral artery bypass graft, NYHA class > III congestive heart failure, cerebrovascular accident or transient ischemic attack and 6 months for deep vein thrombosis or pulmonary embolism.
• Known hypersensitivity reactions to monoclonal antibodies (≥ grade 3 according to NCI Common Terminology Criteria for Adverse Events (CTCAE) v 5.0 [xliii] or any past medical history of anaphylaxis or uncontrolled asthma (i.e., 3 or more asthma characteristics partially controlled).
• Any other prior malignancy within 5 years of study entry, with the exception of adequately treated in-situ carcinoma of the cervix, breast or uteri, or non-melanomatous skin cancer.
• Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial.
• Dementia or significantly altered mental status that would prohibit the understanding or rendering of informed consent and compliance with the requirements of this protocol.
• Female patients who are pregnant or lactating, or men and women of reproductive potential not willing or not able to employ an effective method of birth control/contraception to prevent pregnancy during treatment and for 6 months after discontinuing study treatment The definition of effective contraception should be in agreement with local regulation and based on the judgment of the principal investigator or a designated associate.
• Other severe acute or chronic medical or psychiatric condition, or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, and in the judgment of the investigator would make the patient inappropriate for study entry.