Background
Phase III double-blind RCT of 495 treatment-naïve patients with unresectable stage IIIC/IV BRAF V600-mutant melanoma, testing addition of the MEK inhibitor cobimetinib to vemurafenib.
Interventions and follow up
Arm A: vemurafenib 960mg BID + cobimetinib 60mg daily (21 days on / 7 days off)
Arm B: vemurafenib 960mg BID + placebo
Primary endpoint: PFS
Median follow up: 14.2mo
Arm B: vemurafenib 960mg BID + placebo
Primary endpoint: PFS
Median follow up: 14.2mo
Results
mPFS: 12.3mo vs 7.2mo (A vs B); HR 0.58, 95%CI 0.46-0.72, P<.0001
mOS: 22.3mo vs 17.4mo; HR 0.70, 95%CI 0.55-0.90, P=.005
CR: 16% vs 10%
PR: 54% vs 40%
Elevated baseline LDH: associated with worse PFS and OS
mOS: 22.3mo vs 17.4mo; HR 0.70, 95%CI 0.55-0.90, P=.005
CR: 16% vs 10%
PR: 54% vs 40%
Elevated baseline LDH: associated with worse PFS and OS
Adverse events
Overall (A vs B): serious AEs 37% vs 28%, grade ≥3 60% vs 52%
More with combination: diarrhea, central serous retinopathy, decreased ejection fraction (5% vs 12% lower vs vemurafenib), photosensitivity
More with vemurafenib alone: cutaneous squamous cell carcinoma (4% vs 13% combination); rash and arthralgia similar across arms
More with combination: diarrhea, central serous retinopathy, decreased ejection fraction (5% vs 12% lower vs vemurafenib), photosensitivity
More with vemurafenib alone: cutaneous squamous cell carcinoma (4% vs 13% combination); rash and arthralgia similar across arms
Conclusions
Adding cobimetinib to vemurafenib significantly improved PFS and OS in BRAF V600-mutant melanoma, supporting combined BRAF/MEK inhibition as superior to BRAF monotherapy.
Key Limitations
Restricted to BRAF V600 disease; no head-to-head against other BRAF/MEK pairs or immunotherapy; added MEK-related toxicity (ocular, cardiac); acquired resistance over time.
Clinical Context
Supported FDA and EMA approval of vemurafenib plus cobimetinib for BRAF V600-mutant melanoma. ASCO and ESMO endorse combined BRAF/MEK inhibition as a standard targeted-therapy option.