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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.
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.
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.
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.
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, Bowen's disease (squamous cell carcinoma in situ), Dermatofibrosarcoma protuberans
Nivolumab plus ipilimumab or nivolumab plus relatlimab first (DREAMseq); dabrafenib-trametinib, encorafenib-binimetinib or vemurafenib-cobimetinib first only when a rapid response is needed.
BRAF plus MEK inhibitor doublet (COMBI-d, coBRIM, COLUMBUS); encorafenib-binimetinib has the longest median survival and least fever of the three.
A year of adjuvant dabrafenib-trametinib (COMBI-AD) or of adjuvant nivolumab or pembrolizumab; neoadjuvant immunotherapy for macroscopic nodal disease.
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.
Atezolizumab with vemurafenib-cobimetinib (IMspire150) is approved but little used because it lengthened progression-free survival without a clear survival gain.
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Immunotherapy first is the standard for BRAF-mutant advanced melanoma in patients who can wait for a response; targeted therapy is reserved for rapid control or after immunotherapy.
Encorafenib-binimetinib is one of three standard BRAF-MEK doublets for advanced melanoma and is often chosen for its tolerability.
Adjuvant dabrafenib-trametinib is a standard for resected stage III BRAF-mutant melanoma alongside adjuvant PD-1 blockade; the choice weighs a finite year of oral therapy against immune side effects.
BRAF plus MEK inhibitor doublets replaced BRAF monotherapy, and dabrafenib-trametinib became the reference regimen for BRAF-mutant melanoma, later extended to adjuvant use in COMBI-AD.
BRAF testing became mandatory in advanced melanoma and vemurafenib the first approved BRAF inhibitor; combination with MEK inhibitors soon replaced monotherapy.
Query for this cancer: (TITLE:"BRAF V600-mutant melanoma" OR ABSTRACT:"BRAF V600-mutant melanoma" OR TITLE:"BRAF-mutant melanoma" OR ABSTRACT:"BRAF-mutant melanoma" OR TITLE:"BRAF V600E melanoma" OR ABSTRACT:"BRAF V600E melanoma" OR TITLE:"BRAF V600K melanoma" OR ABSTRACT:"BRAF V600K melanoma" OR TITLE:"BRAF-positive melanoma" OR ABSTRACT:"BRAF-positive melanoma") AND (treatment OR therapy OR trial OR survival OR diagnosis). Results are unfiltered search hits about BRAF V600-mutant melanoma, not a curated reading list.
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Fainting, near-fainting, or an irregular or racing heartbeat; several kinase inhibitors prolong the QT interval and the labels require ECG and electrolyte monitoring.
Persistent headache with extreme tiredness, nausea, dizziness on standing or low blood pressure. Vomiting, severe weakness or collapse is adrenal crisis.
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.
Dabrafenib: take on an empty stomach. Trametinib: take on an empty stomach; both cause pyrexia.
No pharmacokinetic interactions expected (antibody). See the irAE guide for toxicity management.
Severe photosensitivity: sun protection.
See all on the product pages:AtezolizumabBinimetinibCobimetinibDabrafenibDabrafenib + trametinibEncorafenibNivolumabPembrolizumabRelatlimab + nivolumabTrametinibVemurafenib·Printable cards in the navigator
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