Nivolumab Plus Radiotherapy in Advanced Melanoma

Inclusion Criteria: 1. Willing and able to give written informed consent 2. Men and women, ≥ 18 years of age 3. Histologically confirmed Stage III (unresectable) or Stage IV melanoma. Unknown primary melanoma will be accepted. 4. Measurable disease by CT per RECIST 1.1 criteria 5. Indication of radiotherapy 6. Patient MUST be untreated for his/her Stage III (unresectable) or Stage IV melanoma 7. Prior treatment with INTERFERON in the adjuvant setting is authorized. 8. BRAF status must be determinate but patient will be eligible regardless the status (BRAF wildtype and BRAF V600 mutation positive patients could be included) 9. A pre-treatment recent core, excision or punch biopsy must be provided for PD-L1 status determination prior to start the treatment and for exploratory biomarker analyses. The biopsy must be from an unresectable or metastatic site, and the subject must have had no intervening systemic therapy between the time of biopsy and the start of inclusion 10. Patient must consent to allow the acquisition of existing formalin-fixed paraffin-embedded (FFPE) material (" archival ") (block or a minimum of 10 unstained slides) if available, for performance of correlatives studies 11. Subjects must consent to allow the acquisition of blood samples: one during the week before the first nivolumab injection; the second 15 days +- 2 days after the first injection of nivolumab; the third between 15 and 30 days after the first radiotherapy session and the fourth at relapse, for performance of correlative studies, 12. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤1 13. Within the last 2 weeks prior to study day 1 the following laboratory parameters, which should be within the ranges specified: 14. Subjects affiliated to an appropriate social security system NB: Patients will be included regardless of the level of LDH. Exclusion Criteria: 1. The patient requires concomitant chronic treatment with systemic corticosteroids or any other immunosuppressive agents 7 days prior to inclusion, 2. Patient with brain(s) metastase(s), symptomatic(s) or not, 3. Ocular or mucosal melanoma (unknown primary melanoma will be accepted), 4. The patient has concurrent severe medical problems, unrelated to the malignancy, that would significantly limit full compliance with the study or expose the patient to unacceptable risk such as but not limited to: Cardiac insufficiency (III or IV as per NYHA classification), Renal insufficiency, ongoing infection, 5. Subjects with previous malignancies (except non-melanoma skin cancers, in situ bladder cancer, gastric or colon cancers, cervical cancers/dysplasia or breast carcinoma in situ) are excluded unless a complete remission was achieved at least 2 years prior to study entry and no additional therapy is required or anticipated to be required during the study period, 6. Uncontrolled infectious diseases - requires negative tests for clinically suspected HIV, hepatitis B virus (HBV) and hepatitis C virus (HCV). If positive results are not indicative of true active or chronic infection, the subject may enter the study after discussion and agreement between the Investigator and the Medical Monitor, 7. Active Autoimmune disease: subjects with a documented history of inflammatory bowel disease, including ulcerative colitis and Crohn's disease are excluded from this study as are subjects with a history of symptomatic disease (e.g., rheumatoid arthritis, systemic progressive sclerosis \[scleroderma\], Systemic Lupus Erythematosus, autoimmune vasculitis \[e.g., Wegener's Granulomatosis\]); subjects 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, 8. Subjects with motor neuropathy considered of autoimmune origin (e.g., Guillain Barré Syndrome) are excluded from this study, 9. Previous treatment with, chemotherapy, a CTLA-4 or PD-1/PD-L1 antagonist agent, including treatment in adjuvant setting for immunotherapy, 10. The patient has psychiatric or addictive disorders that may compromise his/her ability to give informed consent or to comply with the trial procedures, 11. Lack of availability for clinical follow-up assessments, 12. Pregnant or lactating women (a blood pregnancy test will be conducted) and effective contraception will be used throughout the treatment for women of childbearing age, 13. Participation in another clinical trial protocol within 30 days prior to enrolment, 14. Persons protected by a legal regime (guardianship, trusteeship), 15. Vulnerable patients, patients kept in detention