1. Age ≥ 18 years.
2. WHO Performance status 0 - 2
3. Life expectancy > 12 weeks
4. Poorly differentiated neuroendocrine carcinoma (NEC): large and small cells for
gastroenteropancreatic NEC (WHO 2010 classification) and only large cells for lung NEC
(WHO 2015 classification), independently from PD-L1 expression status by tumor cells;
mixed tumors with a prominent (>70%) NEC component are eligible
5. Tumor progression after one or two lines of treatment, including at least one line of
6. Unresectable locally advanced or metastatic stage
7. Measurable disease according to RECIST 1.1 guidelines for solid tumors
8. Patients must have adequate organ function: creatinine clearance > 50 mL/min
(Cockcroft formula), Neutrophiles count ≥ 1500/mm3; Platelets > 100 000/mm3 ;
Hemoglobin > 9 g/dL; hepatic enzymes < 3 x ULN (upper limit of normal) with total
bilirubin ≤ 2 × ULN except subjects with documented Gilbert's syndrome (≤ 5 × ULN) or
liver metastasis, who must have a baseline total bilirubin ≤ 3.0 mg/dL
9. Patients must have recovered from all toxicities associated with prior treatment, to
acceptable baseline status, or a National Cancer Institute Common Terminology Criteria
for Adverse Events(NCI CTCAE v4.0) Grade of 0 or 1, except for toxicities not
considered a safety risk, such as alopecia or vitiligo
10. Availability of tumor material for central review processes and translational research
11. Absence of any unstable systemic disease and any psychological, familial, sociological
or geographical factors potentially hampering compliance with the study protocol and
12. Before patient inclusion, written informed consent must be given according to ICH/GCP,
and national/local regulations.
13. Females of childbearing potential who are sexually active with a non-sterilized male
partner must use a highly effective method of contraception for 28 days prior to the
first dose of investigational product, and must agree to continue using such
precautions for 6 months after the final dose of investigational product; cessation of
contraception after this point should be discussed with a responsible physician.
Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable
methods of contraception. They must also refrain from egg cell donation for 6 months
after the final dose of investigational product. Men receiving nivolumab and who are
sexually active with women of childbearing potential will be instructed to adhere to
contraception for a period of 31 weeks after the last dose of nivolumab.
14. Patient must be affiliated to or a beneficiary of social security insurance.
1. Patients <18 years old
2. Well-differentiated neuroendocrine tumor (NET G1 and G2 according to digestive WHO
2010 classification or typical/atypical carcinoid tumor according to lung WHO 2015
3. Small cell lung NEC (except as a minor <30% component in mixed tumors)
4. Known EGFR activating mutation or ALK or ROS1 rearrangement for lung NEC
5. Brain metastasis, except if surgically resected or treated with stereotaxic
radiotherapy with no evolution within the 3 months before inclusion, and asymptomatic
6. Patients with a recent history of other malignancies except adequately treated
non-melanoma skin cancer, and curatively treated in-situ cancer. Patients with history
of solid tumors, including adenocarcinoma, treated in a curative way with or without
chemotherapy and without any evidence of disease >2 years before randomisation can be
included as well.
7. History of primary immunodeficiency, history of organ transplant that requires
therapeutic immunosuppression and the use of immunosuppressive agents within 28 days
of randomization or a prior history of severe (grade 3 or 4) immune mediated toxicity
from other immune therapy.
8. Subjects with a condition requiring systemic treatment with either corticosteroids (>
10 mg daily prednisone equivalent) or other immunosuppressive medications within 14
days of randomization. Intranasal/inhaled or topical steroids, and adrenal replacement
steroid doses ≤ 10 mg daily prednisone equivalent, are permitted in the absence of
active autoimmune disease.
9. Live attenuated vaccination administered within 30 days prior to randomization.
10. Known history of interstitial lung disease or CT-scan signs of interstitial lung
11. Subjects with an active, known or suspected autoimmune disease, including systemic
lupus erythematosis or Wegener's granulomatosis. Subjects with type I diabetes
mellitis, or hypothyroidism only requiring hormone replacement, or skin disorders
(such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, are
permitted to enroll.
12. Active or history of inflammatory or irritable bowel disease (eg, diverticulitis,
colitis, Crohn's), irritable bowel disease, celiac disease or other serious
gastrointestinal chronic conditions associated with diarrhea. Note that diverticulosis
13. Patients with active or uncontrolled infections or with serious illnesses or medical
conditions which would not permit the patient to be managed according to the protocol.
This includes but is not limited to:
- known prior history of active tuberculosis-disease;
- known acute or chronic B or C hepatitis by serological evaluation. Patients with
serological sequelae of hepatitis (antibodies test serologically positive for
virus) without hepatitis could be included.
- known Human immunodeficiency virus infection.
14. Concurrent administration of any anti-cancer therapies (e.g., chemotherapy, other
targeted therapy, experimental drug, etc.) other than those administered in this study
15. Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or
any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint
16. The last dose of prior chemotherapy or radiation therapy (with the exception of
palliative radiotherapy) was received less than 3 weeks prior to randomization;
17. Patients with a psychiatric history that hinders the comprehension of the information
18. Individual deprived of liberty or placed under the authority of a tutor.
19. Unwillingness to practice effective birth control. Pregnant or lactating women.
20. Patients with other concurrent severe and/or uncontrolled medical disease which could
compromise participation in the study