Vemurafenib Plus Cobimetinib After Radiosurgery in Patients With BRAF-mutant Melanoma Brain Metastases

Inclusion criteria * Signed informed consent * Female and male patients ≥ 18 years of age * Histologically confirmed metastatic melanoma (stage IV, per AJCC staging), carrying BRAF V600-mutation * Performed SRS 14 ±7 days before baseline using a harmonized protocol in patients with at least one measurable intracranial target lesion for which the following criteria are met: * Previously untreated (Lesions in previously irradiated area should not be selected) * Largest diameter of ≥ 0.5 but ≤ 4 cm as determined by contrast-enhanced MRI and * ≤ 10 brain metastases * ECOG performance status 0 - 2 * Life expectancy ≥ 12 weeks * Adequate bone marrow function as indicated by the following: * ANC ≥ 1500/µL, * Platelets ≥ 100,000/µL and * Hemoglobin ≥ 9 g/dL * Adequate renal function, as indicated by creatinine ≤ 1.5 x ULN * Adequate liver function, as indicated by bilirubin \< 1.5 x ULN and AST and ALT \< 3 x ULN (documented liver metastases: AST and ALT \< 5 x ULN) * Adequate coagulation within 28 days prior to baseline visit * Patients without therapeutic anticoagulation: INR or aPTT ≤ 1.5 x ULN * Patients receiving therapeutic anticoagulation: stable anticoagulation regimen and stable INR * Able to swallow pills Exclusion criteria * Symptomatic brain metastases requiring immediate local interventions such as neurosurgery or radiosurgery * Leptomeningeal disease (also synchronous with brain metastases) * Prior therapy with BRAF or MEK inhibitors within 12 weeks prior to baseline visit (prior therapies for metastatic melanoma including chemo-, cytokine-, immuno-, biological and vaccine-therapy will be al-lowed) A period of at least 6 weeks must be observed between the last dose of ipilimumab and the first administration of the study treatments. Prior treatment with anti-programmed cell death (PD)-1 or anti-PD ligand 1 (PD-L1) is allowed. * Prior whole brain irradiation (Patients with prior local therapy of brain metas-tases are eligible) * Patients receiving therapeutic steroids are not stable on corticoster-oids 2 weeks before SRS * Active and uncontrolled infection * Known HIV infection or active HBV or HCV infection * Active HBV infection (chronic and acute), defined as having a posi-tive hepatitis B surface antigen (HBsAg) test at screening (past or resolved HBV infection, defined as negative HBsAg test and a posi-tive total hepatitis B core antibody test at screening, are eligible) * Active HCV infection, defined as positive HCV antibody test and positive HCV RNA test at screening * Intracranial radiation therapy within 14 days prior to SRS * Extracranial radiation therapy within the last 14 days prior to baseline visit * Treatment with strong CYP3A4/5 inhibitors (e.g. ketoconazole) and inducers (e.g. phenytoin, carbamazepine). (anticonvulsant levetiracetam is allowed; patient should be stable on levetiracetam for 2 weeks) * Unresolved toxicity of National Cancer Institute Common Terminology Crite-ria for Adverse Events, version 4.0 (NCI v4.0) \[NCI, 2009\] Grade 2 or higher from previous anti-cancer therapy, except alopecia. * Conditions that will interfere significantly with the absorption of drugs (e.g. Colitis ulcerosa) * Inability to undergo MRI secondary to: * Metal, * Claustrophobia, or * Gadolinium contrast allergy * Previous malignancies active within the last 3 years, with the exception of locally curable cancers that have been treated to complete remis-sion or untreated stage I chronic lymphoid leukemia. * Unwillingness or inability to comply with study and follow-up procedures * Known hypersensitivity to any of the excipients of cobimetinib and vemuraf-enib * The following foods/supplements are prohibited at least 7 days prior to initia-tion of and during study treatment: * St. John's wort or hyperforin (potent cytochrome P450 CYP3A4 enzyme inducer) * Grapefruit juice (potent cytochrome P450 CYP3A4 enzyme inhibitor) * Patient is included in another interventional trial * Use of any investigational or non-registered product within 4 weeks prior to baseline visit * Woman of childbearing age with the exception they meet at least one of the following criteria: * Post-menopausal, * Sterilization, * Consistently \& correct application of contraceptives (Pearl Index \< 1%), * sexual abstinence, or * vasectomy of the partner * Pregnant or lactating women * History, risk factor or retinal pathology that increases the risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR): evidence of retinal pathology that is considered a risk factor for RVO or CSR, or a history of retinal detachment, central serous chorioretinopathy or reti-nal vein thrombosis. The risk factors for RVO are listed below: * Uncontrolled glaucoma with intraocular pressures \> 21 mm Hg, * Serum cholesterol ≥ Grade 2 (≥ 7.75 mmol/L), * Hypertriglyceridemia ≥ Grade 2 (≥ 3.42 mmol/L), Hyperglycemia (fasting) ≥ Grade 2 (≥ 8.9 mmol/L). * History of clinically significant cardiac dysfunction including: * Myocardial infarction, * Severe/unstable angina pectoris, * Symptomatic congestive heart failure (NYHA stage ≥ 2), * cerebrovascular accident or transient ischemic attack within the previous 6 months, * History of congenital long QT syndrome or mean QTcF \> 450 msec or uncorrectable electrolyte abnormalities, * Hypertension \> Grade 2 not controlled by medications * Left ventricular ejection fraction (LVEF) \< 50%, or * Uncontrolled arrhythmias