Molecular Profile Detail

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Profile Name BRAF V600E/K
Gene Variant Detail

BRAF V600E/K (gain of function)

Relevant Treatment Approaches BRAF Inhibitor MEK inhibitor (Pan) MEK1 Inhibitor MEK2 Inhibitor RAF Inhibitor (Pan)

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Molecular Profile Indication/Tumor Type Response Type Relevant Treatment Approaches Therapy Name Approval Status Evidence Type Efficacy Evidence References
BRAF V600E/K melanoma sensitive MEK inhibitor (Pan) MEK1 Inhibitor MEK2 Inhibitor Trametinib Phase I Actionable In a Phase I trial, Mekinist (trametinib) resulted in complete response in 7% (2/30), partial response in 33% (10/30), and stable disease in 37% (11/30) of BRAF-mutant melanoma patients (PMID: 22805292; NCT00687622). 22805292
BRAF V600E/K melanoma sensitive BRAF Inhibitor MEK inhibitor (Pan) MEK1 Inhibitor MEK2 Inhibitor Dabrafenib + Trametinib FDA approved - On Companion Diagnostic Actionable In a Phase III trial (COMBI-v) that supported FDA approval, the combination of Tafinlar (dabrafenib) and Mekinist (trametinib) resulted in an improved overall survival rate at 12 months (72% vs 65%, HR=0.69, p=0.005), median progression-free survival (11.4 vs 7.3 months, HR=0.56, p<0.001), and objective response rate (64% vs 51%, p<0.001) compared to Zelboraf (vemurafenib) in melanoma patients harboring BRAF V600E or V600K (PMID: 25399551; NCT01597908). detail... detail... 25399551
BRAF V600E/K melanoma sensitive MEK inhibitor (Pan) MEK1 Inhibitor MEK2 Inhibitor Trametinib FDA approved - On Companion Diagnostic Actionable In a Phase III trial (METRIC) that supported FDA approval, Mekinist (trametinib) treatment, as compared to Deticine (dacarbazine) or Taxol (paclitaxel) treatment, resulted in improved progression-free survival of 4.8 months versus 1.5 months and an overall six month survival rate of 81% versus 67% in patients with BRAF V600E/K positive metastatic melanoma (PMID: 22663011; NCT01245062). 22663011 detail... detail...
BRAF V600E/K melanoma sensitive BRAF Inhibitor MEK inhibitor (Pan) MEK1 Inhibitor MEK2 Inhibitor Dabrafenib + Trametinib FDA approved - On Companion Diagnostic Actionable In a Phase III trial (COMBI-AD) that supported FDA approval, adjuvant treatment with the combination of Tafinlar (dabrafenib) and Mekinist (trametinib) resulted in an improved estimated 3-year relapse-free survival rate (58% vs 39%, HR=0.47, P<0.001) and 3-year overall survival rate (86% vs 77%, HR=0.57; 95% CI, 0.42 to 0.79, P=0.0006) compared to placebo in stage III melanoma patients harboring BRAF V600E or V600K mutations (PMID: 28891408; NCT01682083). detail... 28891408 detail...
BRAF V600E/K melanoma sensitive MEK inhibitor (Pan) MEK1 Inhibitor MEK2 Inhibitor RAF Inhibitor (Pan) Cobimetinib + Vemurafenib FDA approved - On Companion Diagnostic Actionable In a Phase III trial (coBRIM) that supported FDA approval, treatment with the combination of Zelboraf (vemurafenib) and Cotellic (cobimetinib) resulted in an improved progression-free survival of 12.3 months, compared to 7.2 months with Zelboraf (vemurafenib) plus placebo, among patients with BRAF V600-mutated metastatic melanoma, and BRAF V600E and BRAF V600K are on the companion diagnostic (PMID: 27480103; NCT01689519). detail... detail... 27480103
BRAF V600E/K melanoma sensitive BRAF Inhibitor MEK inhibitor (Pan) MEK1 Inhibitor MEK2 Inhibitor Binimetinib + Encorafenib FDA approved - On Companion Diagnostic Actionable In a Phase III (COLUMBUS) trial that supported FDA approval, Braftovi (encorafenib) in combination with Mektovi (binimetinib) demonstrated improved tolerability profile and efficacy, resulted in a progression-free survival of 14.9 months in patients with advanced melanoma harboring BRAF V600E/K mutations, comparing to 7.3 months in the Zelboraf (vemurafenib) group (HR=0.54, p<0.0001) (PMID: 29573941; NCT01909453) and both BRAF V600E and V600K are on the companion diagnostic. 29573941 detail... detail... detail...
BRAF V600E/K melanoma predicted - sensitive RAF Inhibitor (Pan) Vemurafenib + XL888 Phase I Actionable In a Phase I trial, combined Zelboraf (vemurafenib) and XL888 treatment in patients with unresectable, BRAF inhibitor naive, metastatic melanoma harboring BRAF V600E (n=20) or V600K (n=1) resulted in complete and partial responses in 15% (3/20) and 60% (12/20) of evaluable patients, respectively, a 9.2-month median progression free survival, and a 34.6-month overall survival (PMID: 29674508). 29674508
BRAF V600E/K melanoma sensitive BRAF Inhibitor MEK inhibitor (Pan) MEK1 Inhibitor MEK2 Inhibitor Binimetinib + Encorafenib FDA approved - On Companion Diagnostic Actionable In a Phase III (COLUMBUS) trial that supported FDA approval, Braftovi (encorafenib) in combination with Mektovi (binimetinib) resulted in a median overall survival (OS) of 33.6 months, a 1-year OS rate of 77.5%, and a 2-year OS rate of 57.7% in patients with advanced melanoma harboring BRAF V600E/K mutations compared to a median OS of 16.9 months and 1- and 2-year OS rates of 63.1% and 43.2%, respectively, in the Zelboraf (vemurafenib) treated group (PMID: 30219628; NCT01909453). detail... detail... detail... 30219628
BRAF V600E/K skin melanoma sensitive RAF Inhibitor (Pan) Vemurafenib Guideline Actionable Zelboraf (vemurafenib) and Cotellic (cobimetinib) combination therapy is included in cutaneous melanoma guidelines for patients with metastatic or unresectable disease harboring a BRAF V600 activating mutation (NCCN.org). detail...
BRAF V600E/K skin melanoma sensitive BRAF Inhibitor MEK inhibitor (Pan) MEK1 Inhibitor MEK2 Inhibitor Binimetinib + Encorafenib Guideline Actionable Braftovi (encorafenib) in combination with Mektovi (binimetinib) is included in guidelines as first-line and second-line therapy for patients with metastatic or unresectable cutaneous melanoma harboring BRAF V600E or V600K mutations (PMID: 30959471; NCCN.org). 30959471 detail...
BRAF V600E/K melanoma predicted - sensitive BRAF Inhibitor Lifirafenib Case Reports/Case Series Actionable In a Phase I trial, Lifirafenib (BGB-283) treatment resulted in partial response in 15.1% (8/53) of solid tumor patients with BRAF mutations, including 5 of 23 patients with melanoma harboring BRAF V600E or V600K overall, and in the dose expansion phase 57.1% (4/7) patient with BRAF V600-mutant melanoma had a partial response (PMID: 32182156; NCT02610361). 32182156
BRAF V600E/K melanoma sensitive BRAF Inhibitor MEK inhibitor (Pan) MEK1 Inhibitor MEK2 Inhibitor Dabrafenib + Trametinib Phase II Actionable In a Phase II trial (S1320), intermittent dosing (3-week-off, 5-week-on) of Tafinlar (dabrafenib) and Mekinist (trametinib) did not improve median progression-free survival (5.5 v 9.0 months; HR=1.36, p=0.064, two-sided alpha=0.2) compared to continuous dosing in melanoma patients harboring BRAF V600E or V600K, and there were no significant differences in median overall survival, treatment response, or toxicity between the two treatment groups (PMID: 33020646; NCT02196181). 33020646