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