Encorafenib and Binimetinib Before Local Treatment in Patients With BRAF Mutant Melanoma Metastatic to the Brain

Inclusion Criteria: * Written informed consent of approved by the investigator's Institutional Review Board (IRB)/Independent Ethics Committee (IEC), prior to the performance of any trial activities. * Histologically confirmed diagnosis of unresectable metastatic cutaneous melanoma, or unknown primary melanoma with one or more brain metastasis with a diameter of 10 to 50 mm, measured by contrast enhanced MRI. * Presence of a BRAF V600E or V600K mutation, or both, in their tumour tissue. * Barthel Index of Activities of Daily Living \> 10. * Subjects aged ≥ 18 years. * ECOG 0-1 in asymptomatic patients (cohort 1), 0-2 in symptomatic patients (cohort 2). * Adequate haematological function (Haemoglobin ≥ 9 g/dL, may have been transfused; Platelet count ≥ 100 × 109/L; Absolute neutrophil count (ANC) ≥ 1.5 × 109/L.) * Adequate hepatic function defined by a total bilirubin level ≤ 2.0 × the upper limit of normality (ULN) and AST and ALT levels ≤ 2.5 × ULN or AST and ALT levels ≤ 5 x ULN (for subjects with documented metastatic disease to the liver). * Serum Creatinine ≤ 2.0 x ULN or estimated creatinine clearance ≥ 30 mL/min according to the Cockcroft-Gault formula (or local institutional standard method). * Evidence of at least one measurable lesion as detected by radiological or photographic methods according to guidelines based on Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. * Naïve untreated patients or patients who have progressed on or after prior first line immunotherapy for unresectable locally advanced or metastatic melanoma, but it must have ended at least 6 weeks prior to randomization; prior adjuvant therapy is permitted (e.g. IFN, IL-2 therapy, any other immunotherapy, radiotherapy or chemotherapy), BRAF or MEK inhibitors can be used in the adjuvant setting, providing the relapse does not occur during the adjuvant treatment or within 12 months after the end of it, and providing the adjuvant treatment with targeted therapy did not cause in the patient any grade 3-4 toxicity not including medically serious and reversible/controlled toxicities (ex: GGT elevation, CPK elevation, vomiting). * Steroids or anticonvulsants are allowed if clinically needed and are not being administered in an increasing dose. * Female subjects must either be of non-reproductive potential (ie, post-menopausal by history: ≥60 years old and no menses for ≥1 year without an alternative medical cause; OR history of hysterectomy, OR history of bilateral tubal ligation, OR history of bilateral oophorectomy) or must have a negative serum pregnancy test upon study entry. * Normal functioning of daily living activities. * Willingness and ability to attend scheduled visits, follow the treatment schedule and undergo clinical tests and other study procedures. Exclusion Criteria: * Uveal or mucosal melanoma. * History of leptomeningeal metastases, with the exception that they are only seen in brain MRI and the patient has ECOG 0-1 and no neurological symptoms (except for cohort 2, where symptomatic patients will be allowed if ECOG is 0-2). * Another cancer in the last five years, except for in situ carcinoma of the cervix or squamous cell carcinoma of the skin adequately treated or limited basal cell skin cancer adequately controlled. * History of or current evidence of central serous retinopathy (CSR), retinal vein occlusion (RVO) or history of retinal degenerative disease (RDD). * Any previous systemic chemotherapy treatment, extensive brain radiotherapy, targeted therapy for locally advanced unresectable or metastatic melanoma; Immunotherapy treatment is allowed but must have ended at least 6 weeks prior to randomization. * History of Gilbert's syndrome. * Previous treatment with a BRAF or MEK inhibitor in metastatic setting. This treatment will be allowed in the adjuvant setting (see above). Previous treatments with immunotherapy will be allowed in both the metastatic and adjuvant setting. * Known positive serology for human immunodeficiency virus, or an active hepatitis B or hepatitis C infection, or both. * Impaired cardiovascular function or clinically significant cardiovascular diseases "Clinically significant (i.e., active) cardiovascular disease: cerebrovascular accident/stroke (\< 6 months prior to enrolment), myocardial infarction (\< 6 months prior to enrolment), unstable angina, congestive heart failure (≥ New York Heart Association Classification Class II), a LVEF \< 50% evaluated by MUGA or echocardiography, or serious cardiac arrhythmia requiring medication or a triplicate average baseline QTc interval \> 500 ms." * Uncontrolled arterial hypertension despite medical treatment. * Moderate (Child Pugh Class B) or severe (Child Pugh Class C) hepatic impairment. * Impairment of gastrointestinal function. * Neuromuscular disorders associated with high concentrations of creatine kinase. * Pregnant or nursing (lactating) women. * Medical, psychiatric, cognitive or other conditions that may compromise the patient's ability to understand the patient information, give informed consent, comply with the study protocol or complete the study. * Known hypersensitivity to encorafenib, binimetinib or their components. * Persisting toxicity related to prior therapy of Grade \>1 NCI-CTCAE v 4.03; however, alopecia and sensory neuropathy Grade ≤ 2 is acceptable. * Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ highly effective birth control from screening to 180 days after the last dose of study treatment. * Known alcohol or drug abuse. * Inability to swallow tablets or capsules. * Total lactase deficiency or glucose-galactose malabsorption.