BRAF V600-mutant melanoma

aka BRAF-mutant melanoma, BRAF V600E melanoma, BRAF V600K melanoma, BRAF-positive melanoma

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.

Part ofMelanoma

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.

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.

Red cards

From the labels and guidelines behind the standard of care. Your team's thresholds win.

Emergency services now
Fainting or palpitations
Fainting, near-fainting, or an irregular or racing heartbeat; several kinase inhibitors prolong the QT interval and the labels require ECG and electrolyte monitoring.
Binimetinib Cobimetinib Dabrafenib Dabrafenib + trametinib Encorafenib Trametinib Vemurafenib source
Emergency services now
Hypophysitis or adrenal crisis
Persistent headache with extreme tiredness, nausea, dizziness on standing or low blood pressure. Vomiting, severe weakness or collapse is adrenal crisis.
Atezolizumab Nivolumab Pembrolizumab Relatlimab + nivolumab source
Check before combining
Encorafenib with Vemurafenib: major interaction
QT: both Encorafenib and Vemurafenib prolong the QT interval (known and known risk).. Avoid other QT-prolonging drugs where possible; check ECG and correct potassium and magnesium before and during treatment.
Encorafenib Vemurafenib source
Check before combining
Food and drink: Dabrafenib + trametinib
Dabrafenib: take on an empty stomach. Trametinib: take on an empty stomach; both cause pyrexia.
Dabrafenib + trametinib source
Check before combining
Food and drink: Pembrolizumab
No pharmacokinetic interactions expected (antibody). See the irAE guide for toxicity management.
Pembrolizumab source
Check before combining
Food and drink: Vemurafenib
Severe photosensitivity: sun protection.
Vemurafenib source

See all on the product pages:Atezolizumab Binimetinib Cobimetinib Dabrafenib Dabrafenib + trametinib Encorafenib Nivolumab Pembrolizumab Relatlimab + nivolumab Trametinib Vemurafenib·Printable cards in the navigator

Anatomy and lymph node drainage

Skin (cross-section): subsites and node stations · wireframe schematic, not to scale

Organ atlas →

Each skin cancer comes from a different cell layer: melanocytes and basal cells at the base of the epidermis, keratinocytes above them, Merkel cells and blood vessels in the dermis; depth of invasion decides the risk.

Subsites

Epidermis (in situ)
Basal layer (melanocytes, basal cells)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)
Keratinocytes (squamous)
Dermis (invasive; Breslow depth)
Merkel cells (dermal-epidermal)
Dermal vessels (Kaposi)
Acral and mucosal sites

Regional lymph nodes

sentinel node in the draining basin
regional basin (axilla, groin, neck)

Same organ: Melanoma, Basal cell carcinoma, Cutaneous squamous cell carcinoma, Merkel cell carcinoma, Kaposi sarcoma, Skin cancer (all types), Stage III melanoma (after surgery), Stage IIB and IIC melanoma, Advanced melanoma (unresectable stage III and stage IV), Mucosal melanoma, Acral melanoma, Advanced cutaneous squamous cell carcinoma, Locally advanced and metastatic basal cell carcinoma, Dermatofibrosarcoma protuberans

Who gets it and what has changed

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.

Group

skin

Cases by country

Cases by country · GLOBOCAN 2022

All countries →

No country-level case numbers. This cancer is not mapped to a GLOBOCAN site.

Standard of care

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Lines of therapy by subgroup →Staging and risk scores →

Decisions you may face

5 with more than one option · full decision page →

One section per setting: the options named, what each is for, the trials behind them, the recorded trade-offs and the questions to ask.

Advanced, first line6 Advanced, after immunotherapy4 Resected stage III3 Brain metastases2 Triplet therapy3

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.

NCCN Guidelines: Melanoma: Cutaneous

DREAMseq (ECOG-ACRIN EA6134)CheckMate 067Relatlimab + nivolumabDabrafenib + trametinibEncorafenibBinimetinibVemurafenibCobimetinib

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.

NCCN Guidelines: Melanoma: Cutaneous

COMBI-d coBRIM COLUMBUSDabrafenibTrametinibEncorafenibBinimetinib

Resected stage III

A year of adjuvant dabrafenib-trametinib (COMBI-AD) or of adjuvant nivolumab or pembrolizumab; neoadjuvant immunotherapy for macroscopic nodal disease.

NCCN Guidelines: Melanoma: Cutaneous

COMBI-ADDabrafenib + trametinibNivolumabPembrolizumabNADINA

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.

NCCN Guidelines: Melanoma: Cutaneous

CheckMate 204Dabrafenib + trametinibStereotactic radiosurgery (Gamma Knife, CyberKnife, linac SRS)Brain metastases (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.

AtezolizumabVemurafenibCobimetinib

Subtypes & biomarkers

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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 clinicians test

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)

How often this target appears

History

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2002BRAF mutations found in about half of melanomas (Davies and colleagues, Nature)
BRAF
2011BRIM-3: vemurafenib beats dacarbazine; first BRAF inhibitor approved
VemurafenibDacarbazine
2013Dabrafenib and trametinib approved as single agents
DabrafenibTrametinib
2014COMBI-d and coBRIM: BRAF plus MEK doublets beat BRAF inhibitor alone
COMBI-d coBRIMDabrafenib + trametinib
2017COMBI-AD: adjuvant dabrafenib-trametinib halves relapse risk; COMBI-MB shows intracranial responses
COMBI-ADDabrafenib + trametinib
2018COLUMBUS: encorafenib-binimetinib approved
COLUMBUSEncorafenibBinimetinib
2020IMspire150: atezolizumab triplet approved on progression-free survival
Atezolizumab
2021DREAMseq: immunotherapy first, targeted therapy second
DREAMseq (ECOG-ACRIN EA6134)

What changed

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Dated changes read from the records linked to this cancer: approvals, regulatory steps, reported trials, guideline versions and milestones. Newest first; no date is inferred.

All 25 changes by month →

FollowWatch this cancer and Saved shows what changed since you last looked.Follow by feed

In development

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What is in development for BRAF V600-mutant melanoma, drawn from the whole corpus: 12 items. Drugs are grouped by the most advanced trial phase they have reached anywhere; approved treatments sit under standard of care. Technologies are the methods being tested for this cancer, trials are the studies recorded here, and ideas are proposals not yet in a trial.

Drugs in phase 3 · 1

Phase 3small molecule

Naporafenib

Trials under way · 5

A Study to Assess Naporafenib (ERAS-254) Administered With Trametinib in Patients With NRAS-mutant Melanoma (SEACRAFT-2) · phase 3 · Erasca
Belvarafenib in Combination With Cobimetinib in Patients With Locally Advanced or Metastatic NRAS-Mutant Melanoma · phase 2 · Hanmi Pharmaceutical Company Limited
Study of Efficacy and Safety of LXH254 Combinations in Patients With Previously Treated Unresectable or Metastatic Melanoma · phase 2 · Novartis Pharmaceuticals
A Clinical Trial of Three Study Medicines (Encorafenib, Binimetinib, and Pembrolizumab) in Patients With Advanced or Metastatic Melanoma · phase 3 · Pfizer
Adjuvant Encorafenib and Binimetinib in High-risk Stage II Melanoma With a BRAF Mutation. · phase 3 · Pierre Fabre Medicament

Trials reported · 5

coBRIM · phase 3 · 2014 · positive
COLUMBUS · phase 3 · 2018 · positive
COMBI-AD · phase 3 · 2017 · positive
COMBI-d · phase 3 · 2014 · positive
DREAMseq (ECOG-ACRIN EA6134) · phase 3 · 2021 · positive

Ideas not yet in a trial · 1

ctDNA-guided adjuvant therapy in stage II-III melanoma

Open problems and what is being done

Responses to targeted therapy are almost universal but most are not durable, and resistance through MAPK reactivation has no approved answer.
What is being done about this
Resistance to treatment
and how the field plans to fix it →
Available now
Small-molecule kinase inhibitorsStandard of care
In trials
Nothing recorded yet.
Ideas and roadmaps
Nothing recorded yet.
Also on OnCo: Resistance atlas · Lines of therapy.
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.

Trials

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Trials recruiting now

Recruiting trials near you · live from ClinicalTrials.gov

BRAF V600-mutant melanoma

condition: BRAF V600-mutant melanoma

Open on ClinicalTrials.gov →

within

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Landmark trials

A Clinical Trial of Three Study Medicines (Encorafenib, Binimetinib, and Pembrolizumab) in Patients With Advanced or Metastatic Melanoma A Study to Assess Naporafenib (ERAS-254) Administered With Trametinib in Patients With NRAS-mutant Melanoma (SEACRAFT-2)Adjuvant Encorafenib and Binimetinib in High-risk Stage II Melanoma With a BRAF Mutation.Belvarafenib in Combination With Cobimetinib in Patients With Locally Advanced or Metastatic NRAS-Mutant Melanoma CheckMate 067 CheckMate 204 coBRIM COLUMBUS COMBI-AD COMBI-d DREAMseq (ECOG-ACRIN EA6134)NADINA Study of Efficacy and Safety of LXH254 Combinations in Patients With Previously Treated Unresectable or Metastatic Melanoma

Expert centres

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Where the expertise is

Expert centres

40 centres in 15 countries · 4 with a trial for this cancer on record · second-opinion finder →

Choose a region from the globe in the header to mark centres near you.

40 centres


MD Anderson Cancer Center Houston · cancer center	United States	NCI comprehensive	0	6,724	95,007	CAR-NK & CAR-macrophage Proton therapy Proton therapy machines: cyclotrons, synchrotrons and single-room systems Gamma Knife +2	#2
Samsung Medical Center Seoul · hospital	South Korea	none recorded	0	1,312	17,172	Proton therapy Proton therapy machines: cyclotrons, synchrotrons and single-room systems Gamma Knife Stereotactic radiosurgery (Gamma Knife, CyberKnife, linac SRS)	#3
Mayo Clinic Rochester, MN · hospital	United States	NCI comprehensive	0	4,511	44,748	Carbon-ion therapy Proton therapy Proton therapy machines: cyclotrons, synchrotrons and single-room systems Gamma Knife +1	#5
Gustave Roussy Villejuif · cancer center	France	none recorded	0	1,855	31,182	ZAP-X gyroscopic radiosurgery Stereotactic radiosurgery (Gamma Knife, CyberKnife, linac SRS)	#6
Seoul National University Hospital Seoul · hospital	South Korea	none recorded	0	1,607	24,676	Gamma Knife Stereotactic radiosurgery (Gamma Knife, CyberKnife, linac SRS)	#8
Johns Hopkins Hospital / Sidney Kimmel Comprehensive Cancer Center Baltimore · cancer center	United States	NCI comprehensive	0	2,955	41,449	Multi-cancer early detection (MCED)Liquid biopsy (ctDNA)Proton therapy Proton therapy machines: cyclotrons, synchrotrons and single-room systems +2	#10
Charité Universitätsmedizin Berlin Berlin · university	Germany	none recorded	0	1,563	17,749	Proton therapy Proton therapy machines: cyclotrons, synchrotrons and single-room systems CyberKnife robotic radiosurgery Stereotactic radiosurgery (Gamma Knife, CyberKnife, linac SRS)	#12
Massachusetts General Hospital Cancer Center Boston · hospital	United States	NCI comprehensive	0	3,582	54,857	Proton therapy Small-molecule kinase inhibitors Proton therapy machines: cyclotrons, synchrotrons and single-room systems Gamma Knife +1	#16
Cleveland Clinic Taussig Cancer Institute Cleveland · hospital	United States	NCI comprehensive	0	2,264	29,412	Off-the-shelf cancer vaccines Proton therapy Proton therapy machines: cyclotrons, synchrotrons and single-room systems Gamma Knife +1	#20
Severance Hospital, Yonsei University Seoul · hospital	South Korea	none recorded	0	464	3,248	Carbon-ion therapy Robotic & minimally invasive surgery Carbon-ion synchrotrons and facilities Gamma Knife +1	#22
Vall d'Hebron University Hospital / VHIO Barcelona · cancer center	Spain	none recorded	0	966	23,221	none recorded	#28
Stanford Health Care / Stanford Cancer Institute Stanford · university	United States	NCI comprehensive	0	3,000	50,162	CAR-T cell therapy SBRT / SABR (stereotactic radiotherapy)CyberKnife robotic radiosurgery Stereotactic radiosurgery (Gamma Knife, CyberKnife, linac SRS)+1	#30
UCSF Helen Diller Family Comprehensive Cancer Center San Francisco · cancer center	United States	NCI comprehensive	0	2,800	46,704	PSMA PET Gamma Knife Stereotactic radiosurgery (Gamma Knife, CyberKnife, linac SRS)	#33
Karolinska University Hospital Stockholm · university	Sweden	none recorded	0	987	12,440	Gamma Knife Stereotactic radiosurgery (Gamma Knife, CyberKnife, linac SRS)	#39
Netherlands Cancer Institute (NKI-AvL) Amsterdam · cancer center	Netherlands	none recorded	1	1,451	25,873	TIL therapy Immune checkpoint inhibitors MR-guided adaptive radiotherapy	#45

(showing the first 15)

These are the things we can measure; they are not a ranking of quality. Each column is a field on the institution record or a count over what OnCo has linked; a centre that treats many patients with BRAF V600-mutant melanoma but is thinly recorded here will look small.

Not known: OnCo holds no case-volume or outcome figures for centres, so none are shown. Where a national audit or registry publishes them, the centre's page links to it. Default order: Newsweek rank, then trials for this cancer, then research output.

Seeking a second opinion: ask your oncologist for a referral to a high-volume centre; most accept records and pathology by mail or telehealth. In the US, use the NCI's Find a Cancer Center tool or the nonprofit Cancer Commons, which navigates options for advanced cancers at no cost. The second-opinion finder explains how referral works in your country.

Questions to ask

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Bring to your appointment

Questions to ask your oncologist about BRAF V600-mutant melanoma

Generated from this cancer's standard of care, biomarkers, and pipeline · 23 questions

Newly diagnosed

What is my exact diagnosis, stage, and grade, and which tests established them?
Why: Everything else follows from an accurate stage and subtype.
Which biomarkers have been tested on my tumour (for example BRAF V600 mutation by sequencing or immunohistochemistry, Lactate dehydrogenase, Number of metastatic sites, NRAS, MEK1 and BRAF splice variants at resistance, Circulating tumour DNA BRAF V600 for response monitoring), and what were the results?
Why: These results decide eligibility for targeted therapy, immunotherapy, and trials.
Which subtype is my cancer, and does that change the recommended treatment?
Why: Recognised subtypes for this cancer include BRAF V600E-mutant melanoma, BRAF V600K-mutant melanoma, BRAF non-V600 or class 2 and 3 mutations.
Is germline (inherited) genetic testing recommended for me or my family?
Why: Inherited variants can change treatment and matter for relatives.

Advanced, first line

For my situation (advanced, first line), which of the standard options do you recommend and why?
Why: Guideline options include: Nivolumab plus ipilimumab or nivolumab plus relatlimab first (DREAMseq); dabrafenib-trametinib, encorafenib-binimetinib or vemurafenib-cobimetinib first only when a rapid response is needed.
Am I a candidate for Relatlimab + nivolumab, Dabrafenib + trametinib, Encorafenib or related drugs, and what side effects should I expect?
Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
How do the results of DREAMseq (ECOG-ACRIN EA6134) and CheckMate 067 apply to someone like me?
Why: Trial populations differ from individual patients; ask how closely you match.

Advanced, after immunotherapy

For my situation (advanced, after immunotherapy), which of the standard options do you recommend and why?
Why: Guideline options include: BRAF plus MEK inhibitor doublet (COMBI-d, coBRIM, COLUMBUS); encorafenib-binimetinib has the longest median survival and least fever of the three.
Am I a candidate for Dabrafenib, Trametinib, Encorafenib or related drugs, and what side effects should I expect?
Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
How do the results of COMBI-d and coBRIM apply to someone like me?
Why: Trial populations differ from individual patients; ask how closely you match.

Resected stage III

For my situation (resected stage iii), which of the standard options do you recommend and why?
Why: Guideline options include: A year of adjuvant dabrafenib-trametinib (COMBI-AD) or of adjuvant nivolumab or pembrolizumab; neoadjuvant immunotherapy for macroscopic nodal disease.
Am I a candidate for Dabrafenib + trametinib, Nivolumab, Pembrolizumab, and what side effects should I expect?
Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
How do the results of COMBI-AD and NADINA apply to someone like me?
Why: Trial populations differ from individual patients; ask how closely you match.

Brain metastases

For my situation (brain metastases), which of the standard options do you recommend and why?
Why: Guideline options include: 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.
Am I a candidate for Dabrafenib + trametinib, and what side effects should I expect?
Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
How do the results of CheckMate 204 apply to someone like me?
Why: Trial populations differ from individual patients; ask how closely you match.

Triplet therapy

For my situation (triplet therapy), which of the standard options do you recommend and why?
Why: Guideline options include: Atezolizumab with vemurafenib-cobimetinib (IMspire150) is approved but little used because it lengthened progression-free survival without a clear survival gain.
Am I a candidate for Atezolizumab, Vemurafenib, Cobimetinib, and what side effects should I expect?
Why: Knowing the expected toxicities helps you plan work, family, and supportive care.

Any stage

Are there clinical trials I could join, for example of A Study to Assess Naporafenib (ERAS-254) Administered With Trametinib in Patients With NRAS-mutant Melanoma (SEACRAFT-2), Naporafenib, Belvarafenib in Combination With Cobimetinib in Patients With Locally Advanced or Metastatic NRAS-Mutant Melanoma, Study of Efficacy and Safety of LXH254 Combinations in Patients With Previously Treated Unresectable or Metastatic Melanoma?
Why: Trials are how the next standard of care is set; asking early keeps options open.
Would a second opinion at a high-volume centre change anything, and can you help arrange it?
Why: Rare or high-stakes decisions benefit from a centre that treats many similar patients.
What supportive care (symptom control, nutrition, exercise, mental health, financial help) is available from the start?
Why: Supportive care improves quality of life and helps patients complete treatment.
I read that “Responses to targeted therapy are almost universal but most are not durable, and resistance through MAPK reactivation has no approved answer”. How does that affect my plan?
Why: Open problems are where trials and second opinions matter most.
I read that “Whether a short targeted-therapy induction before immunotherapy helps has not been settled in a phase 3 trial”. How does that affect my plan?
Why: Open problems are where trials and second opinions matter most.