Neoadjuvant Ipilimumab Plus Nivolumab Versus Standard Adjuvant Nivolumab in Macroscopic Stage III Melanoma

Inclusion Criteria: * Men and women, at least 16 years of age; * World Health Organization (WHO) Performance Status 0 or 1; * Cytologically or histologically confirmed resectable stage III melanoma of cutaneous or unknown primary origin with one or more macroscopic lymph node metastases (clinical detectable), that can be biopsied and a maximum of 3 additional resectable in-transit metastases. A concurrent resectable primary melanoma is allowed. Clinical detectable lymph nodes are defined as either a palpable node, confirmed as melanoma by pathology, or a non-palpable but enlarged lymph node according to RECISTv1.1 (at least 15 mm in short axis), confirmed as melanoma by pathology, or a PET scan positive lymph node of any size confirmed as melanoma by pathology; * No other malignancies, except adequately treated and with a cancer-related life-expectancy of more than 5 years; * No prior immunotherapy targeting CTLA-4, PD-1 or PD-L1; * No prior targeted therapy targeting BRAF and/or MEK; * No immunosuppressive medications within 6 months prior study inclusion (steroids equivalent to prednisolone ≤10 mg are allowed); * Screening laboratory values must meet the following criteria: WBC ≥2.0x109/L, neutrophils ≥1.5x109/L, platelets ≥100x109/L, hemoglobin ≥5.5 mmol/L, creatinine ≤1.5xupper limit of normal (ULN), AST ≤1.5x ULN, ALT ≤1.5x ULN, bilirubin ≤1.5x ULN (except for subjects with Gilbert syndrome who must have a total bilirubin \<3.0 mg/dL); * LDH level \<1.5x ULN; * Women of childbearing potential (WOCP) must use appropriate method(s) of contraception, i.e. methods with a failure rate of \<1% per year when used consistently and correctly, to avoid pregnancy for 23 weeks post last ipilimumab + nivolumab infusion; * Males who are sexually active with WOCP must use appropriate method(s) of contraception, i.e. methods with a failure rate of \<1% per year when used consistently and correctly, to avoid pregnancy for 31 weeks post last ipilimumab + nivolumab infusion; * Patient willing and able to understand the protocol requirements and comply with the treatment schedule, scheduled visits, electronic patient outcome reporting, tumor biopsies and extra blood withdrawal during screening and in case of recurrence, and other requirements of the study; * Patient has signed the Informed Consent document. Exclusion Criteria: * Distantly metastasized melanoma; * Uveal/ocular or mucosal melanoma; * In-transit metastases only (without cytological or histological proven lymph node involvement) * Subjects with any active autoimmune disease or a documented history of autoimmune disease, or history of syndrome that required systemic steroids or immunosuppressive medications. Subjects with resolved childhood asthma/atopy, type I diabetes mellitus, residual hypothyroidism due to autoimmune thyroiditis only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, are permitted to enroll; * Prior radiotherapy; * Subjects will be excluded if they test positive for hepatitis B virus surface antigen (HBsAg) or hepatitis C virus ribonucleic acid (HCV antibody), indicating acute or chronic infection. Subjects treated and being at least one year free from HCV are allowed to participate; * Subjects will be excluded if they have known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS); * Subjects with history of allergy to study drug components or history of severe hypersensitivity reaction to monoclonal antibodies. * Subjects with underlying medical conditions or active infection that, in the investigator's opinion, will make the administration of study drug hazardous or obscure the interpretation of toxicity or adverse events; * Women who are pregnant or breastfeeding; * Concurrent medical condition requiring the use of immunosuppressive medications, or immunosuppressive doses of systemic or absorbable topical corticosteroids \>10 mg prednisolone daily equivalent; * Use of other investigational drugs before study drug administration 30 days or 5 half-times before study inclusion; * Psychological, familial, sociological, or geographical conditions that potentially hamper compliance with the study protocol and follow-up schedule; those conditions should be discussed with the subject before registration in the trial.