{"entity":{"id":"combi-d","kind":"trial","name":"COMBI-d","aka":[],"tldr":"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.","summary":"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.\n\nThe 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.\n\nCOMBI-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.","status":"positive","asOf":"2026-09-17","links":[{"label":"ClinicalTrials.gov NCT01584648","url":"https://clinicaltrials.gov/study/NCT01584648"},{"label":"NEJM 2014","url":"https://www.nejm.org/doi/full/10.1056/NEJMoa1406037"},{"label":"Final analysis, Lancet 2015","url":"https://doi.org/10.1016/S0140-6736(15)60898-4"},{"label":"Pooled 5-year analysis, NEJM 2019","url":"https://www.nejm.org/doi/full/10.1056/NEJMoa1904059"}],"tags":[],"related":[],"cancers":["braf-v600-melanoma","advanced-melanoma","melanoma"],"sections":[],"technologies":[],"targets":["braf","mek"],"drugs":["dabrafenib-trametinib","dabrafenib","trametinib"],"companies":["novartis","gsk"],"institutions":[],"pathways":["ras-mapk"],"terms":[],"trials":[],"people":["georgina-long","keith-flaherty"],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"nct":"NCT01584648","phase":"3","setting":"Untreated unresectable or metastatic BRAF V600E or V600K melanoma: dabrafenib plus trametinib versus dabrafenib plus placebo","sponsor":"GSK, then Novartis","result":"Median progression-free survival 11.0 vs 8.8 months; median overall survival 25.1 vs 18.7 months (HR 0.71); pooled COMBI-d/v 5-year overall survival 34%.","yearReported":2014,"enrolled":423,"outcomes":[{"endpoint":"Progression-free survival","primary":true,"unit":"months","arms":[{"name":"Dabrafenib + trametinib","n":211,"value":11},{"name":"Dabrafenib + placebo","n":212,"value":8.8}],"hr":0.67,"source":"https://doi.org/10.1016/S0140-6736(15)60898-4"},{"endpoint":"Overall survival","unit":"months","arms":[{"name":"Dabrafenib + trametinib","n":211,"value":25.1},{"name":"Dabrafenib + placebo","n":212,"value":18.7}],"hr":0.71,"source":"https://doi.org/10.1016/S0140-6736(15)60898-4"}],"replication":"COMBI-v (dabrafenib-trametinib versus vemurafenib), coBRIM (vemurafenib-cobimetinib) and COLUMBUS (encorafenib-binimetinib) all found the same class effect."},"route":"/trials/combi-d/","neighbours":{"cancer":[{"id":"advanced-melanoma","kind":"cancer","name":"Advanced melanoma (unresectable stage III and stage IV)","route":"/cancers/advanced-melanoma/"},{"id":"braf-v600-melanoma","kind":"cancer","name":"BRAF V600-mutant melanoma","route":"/cancers/braf-v600-melanoma/"},{"id":"melanoma","kind":"cancer","name":"Melanoma","route":"/cancers/melanoma/"}],"target":[{"id":"braf","kind":"target","name":"BRAF","route":"/targets/braf/"},{"id":"mek","kind":"target","name":"MEK1/2","route":"/targets/mek/"}],"drug":[{"id":"dabrafenib","kind":"drug","name":"Dabrafenib","route":"/drugs/dabrafenib/"},{"id":"dabrafenib-trametinib","kind":"drug","name":"Dabrafenib + trametinib","route":"/drugs/dabrafenib-trametinib/"},{"id":"trametinib","kind":"drug","name":"Trametinib","route":"/drugs/trametinib/"}],"company":[{"id":"gsk","kind":"company","name":"GSK","route":"/companies/gsk/"},{"id":"novartis","kind":"company","name":"Novartis","route":"/companies/novartis/"}],"pathway":[{"id":"ras-mapk","kind":"pathway","name":"RAS / RAF / MEK / ERK (MAPK)","route":"/pathways/ras-mapk/"}],"person":[{"id":"georgina-long","kind":"person","name":"Georgina V. Long","route":"/people/georgina-long/"},{"id":"keith-flaherty","kind":"person","name":"Keith T. Flaherty","route":"/people/keith-flaherty/"}]}}