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10 slides generated from the cancer page, with a quiz from the open benchmark and speaker notes that cite the sources. Arrow keys move between slides; Print gives one slide per page.
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.
| Setting | Approach | Guideline |
|---|---|---|
| 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. | not mapped |
| 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. | not mapped |
| Resected stage III | A year of adjuvant dabrafenib-trametinib (COMBI-AD) or of adjuvant nivolumab or pembrolizumab; neoadjuvant immunotherapy for macroscopic nodal disease. | not mapped |
| 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. | not mapped |
| Triplet therapy | Atezolizumab with vemurafenib-cobimetinib (IMspire150) is approved but little used because it lengthened progression-free survival without a clear survival gain. | not mapped |