<br>        Inclusion Criteria:<br><br>          1. Patients of either sex aged = 18 years;<br><br>          2. Histologically confirmed stage III (unresectable) or stage IV melanoma with the BRAF<br>             V600 mutation. Patients with mucosal melanoma (but not those with ocular melanoma) are<br>             eligible for study participation;<br><br>          3. Treatment naïve for metastatic disease patients. Previous adjuvant treatment, included<br>             checkpoint inhibitors anti CTLA-4, anti PD-1/PDL-1 is allowed, except for stage IV (if<br>             completed at least 6 weeks prior to randomization, and all related adverse events have<br>             either returned to baseline or stabilized). BRAF inhibitor treatment in adjuvant<br>             setting is not permitted.<br><br>          4. Measurable disease by computed tomography (CT) or Magnetic Resonance Imaging (MRI) per<br>             RECIST 1.1 criteria;<br><br>          5. Presence of BRAF V600E or V600K mutation in tumor tissue prior to enrollment;<br><br>          6. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1;<br><br>          7. Tumor tissue from an unresectable or metastatic site of disease must be provided for<br>             biomarker analyses. An archive sample is mandatory at the screening visit; however, a<br>             new sample collection would be preferable;<br><br>          8. Female subjects of childbearing potential must have a negative pregnancy test result<br>             at baseline and must practice two highly effective methods of contraception for the<br>             total study duration plus 23 weeks (i.e. 30 days plus the time required for nivolumab<br>             to undergo five half lives) after the last dose of nivolumab and ipilimumab and 30<br>             days after the last dose of binimetinib and encorafenib for female subjects.<br>             Additional pregnancy testing must be performed every 6 weeks during the treatment<br>             Combo-Immuno and every 4 weeks during the treatment Combo-Target, as well as at the<br>             end of the systemic exposure;<br><br>          9. Men who are sexually active with women of childbearing potential must practice a<br>             reliable method of contraception for the total study duration plus 31 weeks (i.e. 80<br>             days plus the time required for nivolumab to undergo five half lives) after the last<br>             dose of nivolumab and ipilimumab and 90 days after the last dose of binimetinib and<br>             encorafenib;<br><br>         10. Adequate bone marrow haematological function: absolute neutrophil count (ANC) = 1.5 x<br>             109/L AND platelet count = 100 x 109/L AND haemoglobin = 9 g/dL;<br><br>         11. Adequate liver function: total bilirubin = 1.5 x upper limit of normal (ULN) AND<br>             aspartate aminotransferase (AST)/alanine aminotransferase (ALT) = 2.5 X ULN (< 5 x ULN<br>             if liver metastases);<br><br>         12. Adequate renal function: serum creatinine = 1.5 mg/dL OR creatinine clearance = 60<br>             mL/min in males and = 50 mL/min in females (calculated according to Cockroft-Gault<br>             formula);<br><br>         13. Serum calcium levels, international normalised ratio (INR) and partial thromboplastin<br>             time were within normal limits;<br><br>         14. Life expectancy of at least 3 months;<br><br>         15. Ability to understand study-related patient information and provision of written<br>             informed consent for participation in the study.<br><br>         16. Adequate electrolytes at Baseline, defined as serum potassium and magnesium levels<br>             within institutional normal limits (Note: replacement treatment to achieve adequate<br>             electrolytes will be allowed).<br><br>         17. Adequate cardiac function:<br><br>               -  left ventricular ejection fraction (LVEF) = 50% as determined by a multigated<br>                  --acquisition (MUGA) scan or echocardiogram,<br><br>               -  QTc interval = 480 ms (preferably the mean from triplicate ECGs)<br><br>        Exclusion Criteria:<br><br>          1. Active brain metastases. Subjects with brain metastases are eligible if these have<br>             been treated and there is no magnetic resonance imaging (MRI) evidence of progression<br>             for at least 4 weeks after treatment is complete and within 28 days prior to first<br>             dose of study drug administration. There must also be no requirement for<br>             immunosuppressive doses of systemic corticosteroids (> 10 mg/day prednisone<br>             equivalents) for at least 2 weeks prior to study drug administration;<br><br>          2. Subjects with active, known or suspected autoimmune disease;<br><br>          3. Subjects with a condition requiring systemic treatment with either corticosteroids<br>             (>10 mg daily prednisone equivalents) or other immunosuppressive medications within 14<br>             days of treatment;<br><br>          4. Prior treatment for stage III (unresectable) or stage IV melanoma with an<br>             anti-Programmed Death receptor-1 (PD-1), anti-Programmed Death-1 ligand-1 (PD-L1),<br>             anti-PD-L2, or anti-cytotoxic T lymphocyte associated antigen-4 (anti-CTLA-4)<br>             antibody;<br><br>          5. Female subjects who are pregnant (positive pregnancy test), breast-feeding, or who are<br>             of childbearing potential and not practicing a reliable method of birth control;<br><br>          6. Evidence of severe or uncontrolled systemic disease or any concurrent condition which<br>             in the investigator's opinion makes it undesirable for the patient to participate in<br>             the study, or which would jeopardize compliance with the protocol, or would interfere<br>             with the results of the study;<br><br>          7. Patients with a history of uncontrolled cardiovascular or interstitial lung disease<br>             and evidence or risk of retinal vein occlusion or central serous retinopathy (patients<br>             with a history of cardiovascular or interstitial lung disease and evidence or risk of<br>             retinal vein occlusion or central serous retinopathy (past or present evidence of<br>             rethinophaty central serous retinopathy - CSR -, occlusion of retinal - RVOo retinal<br>             degenerative disease) or ophthalmopathy, which according to the ophthalmologic<br>             evaluation at baseline could be considered a risk factor for CSR / RVO ( eg. cupping<br>             of the optic disc, visual field defect, intraocular pressure - (eg: central IOP - > 21<br>             mmHg);<br><br>          8. Previous or concurrent malignancy. Exceptions: adequately treated basal cell or<br>             squamous cell skin cancer; in situ carcinoma of the cervix, treated curatively and<br>             without evidence of recurrence for at least 3 years prior to study entry; or other<br>             solid tumor treated curatively, and without evidence of recurrence for at least 3<br>             years prior to study entry<br><br>          9. History of Gilbert's syndrome;<br><br>         10. Inability to regularly access centre facilities for logistical or other reasons;<br><br>         11. History of poor co-operation, non-compliance with medical treatment, or unreliability;<br><br>         12. Participation in any interventional drug or medical device study within 30 days prior<br>             to treatment start.<br><br>         13. Positive test for human immunodeficiency virus (HIV), hepatitis B virus surface<br>             antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating<br>             acute or chronic in