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COMBI-d showed that adding a MEK inhibitor to a BRAF inhibitor delays progression and lengthens life in BRAF-mutant melanoma, and that the pairing causes fewer of the skin cancers that BRAF inhibitors alone provoke.
COMBI-d randomised 423 patients with untreated BRAF V600E or V600K metastatic melanoma to dabrafenib plus trametinib or dabrafenib plus placebo. The trial tested the idea that blocking MEK downstream of BRAF would both deepen the response and prevent the paradoxical MAPK activation in BRAF wild-type skin cells that causes squamous cell carcinomas on BRAF inhibitor monotherapy.
The primary progression-free survival endpoint was met, and in the final analysis (Lancet 2015) median progression-free survival was 11.0 months against 8.8 months and median overall survival 25.1 months against 18.7 months (hazard ratio 0.71). Cutaneous squamous cell carcinomas fell from 9 percent to 2 percent, while fever became the characteristic toxicity of the doublet. A pooled analysis of COMBI-d and COMBI-v (NEJM 2019) found 34 percent of patients alive and 19 percent progression free at five years, with the best outcomes in patients with normal lactate dehydrogenase and fewer than three disease sites.
COMBI-d, with COMBI-v against vemurafenib, made BRAF plus MEK inhibition the standard form of targeted therapy in melanoma and the template for the same pairing in lung, thyroid and brain tumours with BRAF V600 mutations.
Numbers are from the trial as recorded here; see the source links in the table below. This is orientation, not medical advice: ask your team how closely the trial population matches you.
423 enrolled.
| Endpoint | Arm | n | Value | HR (95% CI) | p | Source |
|---|---|---|---|---|---|---|
| Progression-free survivalprimary | Dabrafenib + trametinib | 211 | 11 months | 0.67 | - | link |
| Dabrafenib + placebo | 212 | 8.8 months | ||||
| Overall survival | Dabrafenib + trametinib | 211 | 25.1 months | 0.71 | - | link |
| Dabrafenib + placebo | 212 | 18.7 months |
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.
This is the paper Europe PMC returns for registry id NCT01584648 with the most citations, so it is the natural first reading for anyone following the COMBI-d trial. Read the abstract above alongside the trial page and the registry entry; the record was linked automatically and its figures have not been checked by hand.
Shares Georgina V. Long, Test intermittent dosing of targeted drugs to delay resistance, with honest priors, Dabrafenib, Dabrafenib + trametinib.
Shares Dabrafenib, Dabrafenib + trametinib, Trametinib, BRAF.
Shares Test intermittent dosing of targeted drugs to delay resistance, with honest priors, MEK1/2, BRAF V600-mutant melanoma, Advanced melanoma (unresectable stage III and stage IV).
Shares Test intermittent dosing of targeted drugs to delay resistance, with honest priors, BRAF V600-mutant melanoma, Advanced melanoma (unresectable stage III and stage IV), BRAF.
Shares Trametinib, BRAF V600-mutant melanoma, Advanced melanoma (unresectable stage III and stage IV), Novartis.
Shares Dabrafenib, Dabrafenib + trametinib, Trametinib, BRAF.
Shares Dabrafenib, Trametinib, Novartis, Small-molecule kinase inhibitors.
Shares MEK1/2, Dabrafenib, Trametinib, BRAF V600-mutant melanoma.