# BRAF V600-mutant melanoma

Source: https://onco.cc/cancers/braf-v600-melanoma/  
OnCo record `braf-v600-melanoma` (Cancer). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

BRAF V600-mutant melanoma has a single faulty switch that drives it to grow, and two pills, a BRAF inhibitor with a MEK inhibitor, can shut that switch off and shrink the cancer within weeks. Immunotherapy is usually given first because its effect lasts longer, and the pills are kept for later or given for a year after surgery to prevent relapse.

## Summary

BRAF V600 mutations lock the BRAF kinase on and drive the MAPK pathway, and every melanoma beyond stage I is tested for them. Vemurafenib was the first inhibitor (BRIM-3, 2011): it shrank about half of tumours where dacarbazine shrank one in twenty, but responses lasted a median of six to seven months, resistance came through MAPK reactivation, and paradoxical pathway activation in normal skin caused squamous cell carcinomas. Adding a MEK inhibitor deepened the responses and removed most of that toxicity.

COMBI-d (dabrafenib-trametinib, median overall survival 25.1 against 18.7 months), coBRIM (vemurafenib-cobimetinib, 22.3 against 17.4 months) and COLUMBUS (encorafenib-binimetinib, progression-free survival 14.9 against 7.3 months and median overall survival 33.6 months) established three doublets; a pooled analysis of COMBI-d and COMBI-v found 34 percent of patients alive at five years. DREAMseq then settled the order question: starting with nivolumab plus ipilimumab and switching to dabrafenib-trametinib at progression gave two-year survival of 71.8 percent against 51.5 percent for the reverse sequence, because targeted therapy still works after immunotherapy while immunotherapy after targeted-therapy failure works poorly. Targeted therapy is now used first only when the disease is growing so fast or so symptomatically that a response within weeks is needed. IMspire150 added atezolizumab to vemurafenib-cobimetinib and lengthened progression-free survival (15.1 against 10.6 months) without a clear survival gain, and the triplet is little used.

After surgery for stage III disease a year of dabrafenib-trametinib halved the relapse risk in COMBI-AD (ten-year relapse-free survival 48 against 32 percent) and is the alternative to adjuvant PD-1 blockade for BRAF-mutant patients. In the brain, dabrafenib-trametinib produced intracranial responses in 58 percent of patients in COMBI-MB, though shorter-lived than in the body. Resistance arises through NRAS mutations, BRAF amplification or splice variants and MEK1 mutations that reactivate the pathway, and rechallenge after a break can work again; next-generation RAF dimer inhibitors and combinations with ERK inhibitors are in trials.

## Fields

- Kind: Cancer
- Last checked: 2026-09-17
- Also known as: BRAF-mutant melanoma; BRAF V600E melanoma; BRAF V600K melanoma; BRAF-positive melanoma
- Tags: subtype-page
- Group: skin
- Burden: About half of cutaneous melanomas carry a BRAF V600 mutation, most often V600E, less often V600K; it is commoner in younger patients and in melanomas on skin without chronic sun damage, and rare in acral and mucosal melanoma.
- Subtypes: BRAF V600E-mutant melanoma (about nine in ten BRAF-mutant cases); BRAF V600K-mutant melanoma (older patients, more sun damage, shorter responses); BRAF non-V600 or class 2 and 3 mutations (do not respond to V600 inhibitors); BRAF-mutant melanoma after immunotherapy (targeted therapy second line); BRAF-mutant melanoma with brain metastases (COMBI-MB)
- Biomarkers: BRAF V600 mutation by sequencing or immunohistochemistry (required for targeted therapy); Lactate dehydrogenase (prognostic for targeted therapy benefit); Number of metastatic sites (fewer than three predicts long-term benefit); NRAS, MEK1 and BRAF splice variants at resistance; Circulating tumour DNA BRAF V600 for response monitoring (trials)

## Standard of care

- Advanced, first line: Nivolumab plus ipilimumab or nivolumab plus relatlimab first (DREAMseq); dabrafenib-trametinib, encorafenib-binimetinib or vemurafenib-cobimetinib first only when a rapid response is needed. ([DREAMseq (ECOG-ACRIN EA6134)](https://onco.cc/trials/dreamseq/), [CheckMate 067](https://onco.cc/trials/checkmate-067/), [Relatlimab + nivolumab](https://onco.cc/drugs/relatlimab-nivolumab/), [Dabrafenib + trametinib](https://onco.cc/drugs/dabrafenib-trametinib/), [Encorafenib](https://onco.cc/drugs/encorafenib/), [Binimetinib](https://onco.cc/drugs/binimetinib/), [Vemurafenib](https://onco.cc/drugs/vemurafenib/), [Cobimetinib](https://onco.cc/drugs/cobimetinib/))
- Advanced, after immunotherapy: BRAF plus MEK inhibitor doublet (COMBI-d, coBRIM, COLUMBUS); encorafenib-binimetinib has the longest median survival and least fever of the three. ([COMBI-d](https://onco.cc/trials/combi-d/), [coBRIM](https://onco.cc/trials/cobrim/), [COLUMBUS](https://onco.cc/trials/columbus/), [Dabrafenib](https://onco.cc/drugs/dabrafenib/), [Trametinib](https://onco.cc/drugs/trametinib/), [Encorafenib](https://onco.cc/drugs/encorafenib/), [Binimetinib](https://onco.cc/drugs/binimetinib/))
- Resected stage III: A year of adjuvant dabrafenib-trametinib (COMBI-AD) or of adjuvant nivolumab or pembrolizumab; neoadjuvant immunotherapy for macroscopic nodal disease. ([COMBI-AD](https://onco.cc/trials/combi-ad/), [Dabrafenib + trametinib](https://onco.cc/drugs/dabrafenib-trametinib/), [Nivolumab](https://onco.cc/drugs/nivolumab/), [Pembrolizumab](https://onco.cc/drugs/pembrolizumab/), [NADINA](https://onco.cc/trials/nadina/))
- Brain metastases: Nivolumab plus ipilimumab for asymptomatic lesions (CheckMate 204); dabrafenib-trametinib when a fast intracranial response is needed (COMBI-MB); radiosurgery for symptomatic or progressing lesions. ([CheckMate 204](https://onco.cc/trials/checkmate-204/), [Dabrafenib + trametinib](https://onco.cc/drugs/dabrafenib-trametinib/), [Stereotactic radiosurgery (Gamma Knife, CyberKnife, linac SRS)](https://onco.cc/technologies/radiosurgery-srs/), [Brain metastases (secondary brain tumours)](https://onco.cc/cancers/secondary-brain-tumours/))
- Triplet therapy: Atezolizumab with vemurafenib-cobimetinib (IMspire150) is approved but little used because it lengthened progression-free survival without a clear survival gain. ([Atezolizumab](https://onco.cc/drugs/atezolizumab/), [Vemurafenib](https://onco.cc/drugs/vemurafenib/), [Cobimetinib](https://onco.cc/drugs/cobimetinib/))

## State of the art

- Three BRAF plus MEK doublets give response rates of about two thirds and a third of patients alive at five years in metastatic disease.
- DREAMseq established immunotherapy first and targeted therapy second as the standard sequence.
- Adjuvant dabrafenib-trametinib halves relapse risk after surgery for stage III disease with benefit still visible at ten years.

## Open problems

- Responses to targeted therapy are almost universal but most are not durable, and resistance through MAPK reactivation has no approved answer.
- Whether a short targeted-therapy induction before immunotherapy helps has not been settled in a phase 3 trial.
- BRAF V600K and non-V600 mutations respond less well and have no dedicated drugs.

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/BRAF_(gene)
- COMBI-d final analysis (Lancet 2015): https://doi.org/10.1016/S0140-6736(15)60898-4
- DREAMseq (JCO 2023): https://ascopubs.org/doi/10.1200/JCO.22.01763
- Wikipedia: https://en.wikipedia.org/wiki/BRAF_(gene)

## Connected records

- cancers: [Advanced melanoma (unresectable stage III and stage IV)](https://onco.cc/cancers/advanced-melanoma/), [Brain metastases (secondary brain tumours)](https://onco.cc/cancers/secondary-brain-tumours/), [Melanoma](https://onco.cc/cancers/melanoma/)
- technologies: [Immune checkpoint inhibitors](https://onco.cc/technologies/checkpoint-inhibitor/), [Small-molecule kinase inhibitors](https://onco.cc/technologies/kinase-inhibitors/), [Stereotactic radiosurgery (Gamma Knife, CyberKnife, linac SRS)](https://onco.cc/technologies/radiosurgery-srs/)
- targets: [BRAF](https://onco.cc/targets/braf/), [MEK1/2](https://onco.cc/targets/mek/)
- drugs: [Atezolizumab](https://onco.cc/drugs/atezolizumab/), [Binimetinib](https://onco.cc/drugs/binimetinib/), [Cobimetinib](https://onco.cc/drugs/cobimetinib/), [Dabrafenib](https://onco.cc/drugs/dabrafenib/), [Dabrafenib + trametinib](https://onco.cc/drugs/dabrafenib-trametinib/), [Dacarbazine](https://onco.cc/drugs/dacarbazine/), [Encorafenib](https://onco.cc/drugs/encorafenib/), [Naporafenib](https://onco.cc/drugs/naporafenib/), [Nivolumab](https://onco.cc/drugs/nivolumab/), [Pembrolizumab](https://onco.cc/drugs/pembrolizumab/), [Relatlimab + nivolumab](https://onco.cc/drugs/relatlimab-nivolumab/), [Trametinib](https://onco.cc/drugs/trametinib/), [Vemurafenib](https://onco.cc/drugs/vemurafenib/)
- pathways: [Melanoma (KEGG map)](https://onco.cc/pathways/melanoma-signalling/), [RAS / RAF / MEK / ERK (MAPK)](https://onco.cc/pathways/ras-mapk/)
- terms: [BRAF V600E mutation](https://onco.cc/terms/braf-v600-mutation/)
- trials: [A Clinical Trial of Three Study Medicines (Encorafenib, Binimetinib, and Pembrolizumab) in Patients With Advanced or Metastatic Melanoma](https://onco.cc/trials/nct04657991/), [A Study to Assess Naporafenib (ERAS-254) Administered With Trametinib in Patients With NRAS-mutant Melanoma (SEACRAFT-2)](https://onco.cc/trials/seacraft-2/), [Adjuvant Encorafenib and Binimetinib in High-risk Stage II Melanoma With a BRAF Mutation.](https://onco.cc/trials/nct05270044/), [Belvarafenib in Combination With Cobimetinib in Patients With Locally Advanced or Metastatic NRAS-Mutant Melanoma](https://onco.cc/trials/nct07449754/), [CheckMate 067](https://onco.cc/trials/checkmate-067/), [CheckMate 204](https://onco.cc/trials/checkmate-204/), [coBRIM](https://onco.cc/trials/cobrim/), [COLUMBUS](https://onco.cc/trials/columbus/), [COMBI-AD](https://onco.cc/trials/combi-ad/), [COMBI-d](https://onco.cc/trials/combi-d/), [DREAMseq (ECOG-ACRIN EA6134)](https://onco.cc/trials/dreamseq/), [NADINA](https://onco.cc/trials/nadina/), [Study of Efficacy and Safety of LXH254 Combinations in Patients With Previously Treated Unresectable or Metastatic Melanoma](https://onco.cc/trials/nct04417621/)
- people: [Georgina V. Long](https://onco.cc/people/georgina-long/), [Keith T. Flaherty](https://onco.cc/people/keith-flaherty/), [Paolo A. Ascierto](https://onco.cc/people/paolo-ascierto/)
- ideas: [ctDNA-guided adjuvant therapy in stage II-III melanoma](https://onco.cc/ideas/idea-ctdna-guided-adjuvant-melanoma/)

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