COMBI-d
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.
Overview
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.
- Median 11 vs 8.8 months with Dabrafenib + trametinib compared with Dabrafenib + placebo; about 2.2 months longer for half the group.
- A median is a midpoint: half the people did better than this and half did worse, so it is not a prediction for any one person.
- Put another way, the treated group had about 33 percent lower chance of the event at any given time (hazard ratio 0.67).
- This is a surrogate endpoint: it measures the cancer being controlled or absent on scans and tests, which often, but not always, translates into living longer.
- Median 25.1 vs 18.7 months with Dabrafenib + trametinib compared with Dabrafenib + placebo; about 6.4 months longer for half the group.
- A median is a midpoint: half the people did better than this and half did worse, so it is not a prediction for any one person.
- Put another way, the treated group had about 29 percent lower chance of the event at any given time (hazard ratio 0.71).
- Overall survival counts deaths from any cause, so it is the most direct measure of whether a treatment helps people live longer.
- These results apply to the people the trial enrolled: Untreated unresectable or metastatic BRAF V600E or V600K melanoma: dabrafenib plus trametinib versus dabrafenib plus placebo. People in a different situation may not see the same effect.
- The trial selected people by a biomarker (BRAF); the result should not be assumed for people whose cancer does not have it.
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 participants 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 |
Similar pages
not linked directly; found by shared links- TrialCOMBI-AD
Shares Georgina V. Long, Dabrafenib, Trametinib, BRAF V600-mutant melanoma.
- TrialcoBRIM
Shares MEK1/2, BRAF V600-mutant melanoma, Advanced melanoma (unresectable stage III and stage IV), BRAF.
- PathwayMelanoma (KEGG map)
Shares Dabrafenib, MEK1/2, Trametinib, BRAF V600-mutant melanoma.
- TrialDREAMseq (ECOG-ACRIN EA6134)
Shares BRAF V600-mutant melanoma, Dabrafenib + trametinib, Advanced melanoma (unresectable stage III and stage IV), BRAF.
- TrialStudy of Efficacy and Safety of LXH254 Combinations in Patients With Previously Treated Unresectable or Metastatic Melanoma
Shares Trametinib, BRAF V600-mutant melanoma, Novartis, Melanoma.
- TrialStudy of Efficacy and Safety of Dabrafenib in Combination With Trametinib in Previously Treated Patients With Metastatic, Radio-active Iodine Refracto
Shares Dabrafenib, Trametinib, Novartis.
- PairingBRAF inhibitor + MEK inhibitor
Shares Dabrafenib + trametinib, BRAF, RAS / RAF / MEK / ERK (MAPK), Melanoma.
- TrialCOLUMBUS
Shares BRAF V600-mutant melanoma, Advanced melanoma (unresectable stage III and stage IV), BRAF, RAS / RAF / MEK / ERK (MAPK).