Background
Phase III open-label RCT (COLUMBUS), N=577 untreated or post-immunotherapy locally advanced unresectable/metastatic BRAF V600-mutant melanoma. 1:1:1 randomization. Stratified by ECOG PS, BRAF type (V600E vs V600K), prior immunotherapy. 162 sites, enrolled 2013–2015.
Interventions and follow up
Arm A: Encorafenib 450 mg PO daily + binimetinib 45 mg PO BID (n=192)
Arm B: Vemurafenib 960 mg PO BID (n=191)
Arm C: Encorafenib 300 mg PO daily (n=194)
Primary endpoint: PFS (Arm A vs Arm B)
mFollow up: 65 mo (5-yr JCO 2022 update)
Arm B: Vemurafenib 960 mg PO BID (n=191)
Arm C: Encorafenib 300 mg PO daily (n=194)
Primary endpoint: PFS (Arm A vs Arm B)
mFollow up: 65 mo (5-yr JCO 2022 update)
Results
mPFS (Arm A vs B): 14.9 vs 7.3 mo, HR 0.54 (95% CI 0.41–0.71), P<.0001
mOS (Arm A vs B): 33.6 vs 16.9 mo, HR 0.61 (95% CI 0.48–0.79)
5-yr PFS: 23% (enco+bini) vs 10% (vem)
5-yr OS: 35% (enco+bini) vs 21% (vem)
ORR (Arm A vs B): 63.5% vs 40.8%
mDOR (Arm A): 18.6 mo
mOS (Arm A vs B): 33.6 vs 16.9 mo, HR 0.61 (95% CI 0.48–0.79)
5-yr PFS: 23% (enco+bini) vs 10% (vem)
5-yr OS: 35% (enco+bini) vs 21% (vem)
ORR (Arm A vs B): 63.5% vs 40.8%
mDOR (Arm A): 18.6 mo
Adverse events
Grade ≥3 AEs: Arm A 56%, Arm B 63%, Arm C 54%
Most common grade ≥3 (Arm A): elevated creatine kinase 7%, hypertension 6%, elevated lipase 5%
Cutaneous SCC: 3% (Arm A) vs 19% (Arm B) — dramatic reduction with MEK inhibition
Other: retinal pigment epithelium detachment 4% (Arm A); pyrexia grade ≥3 4% (Arm A); QTc prolongation less common than vem
Most common grade ≥3 (Arm A): elevated creatine kinase 7%, hypertension 6%, elevated lipase 5%
Cutaneous SCC: 3% (Arm A) vs 19% (Arm B) — dramatic reduction with MEK inhibition
Other: retinal pigment epithelium detachment 4% (Arm A); pyrexia grade ≥3 4% (Arm A); QTc prolongation less common than vem
Conclusions
Encorafenib plus binimetinib significantly improved PFS (HR 0.54) and OS (HR 0.61) vs vemurafenib monotherapy in BRAF V600-mutant advanced melanoma, with best-in-class durability (mOS 33.6 mo, 5-yr OS 35%) and a favorable toxicity profile including dramatically less cutaneous SCC vs vemurafenib.
Key Limitations
No direct comparison with dabrafenib+trametinib or cobimetinib+vemurafenib; cross-trial data suggest similar efficacy but distinct toxicity (enco+bini: less pyrexia, less cuSCC). V600K patients (~20%) had less robust benefit than V600E. Allowed ≤1 prior immunotherapy — heterogeneous population. DREAMseq supports IO-first sequencing for unselected BRAF V600+, reserving 1L BRAF/MEK for rapidly progressing, symptomatic disease.
Clinical Context
FDA approved encorafenib (Braftovi) + binimetinib (Mektovi) for BRAF V600E/K-mutant unresectable/metastatic melanoma in June 2018, based on COLUMBUS. Among the three approved BRAF/MEK combinations, enco+bini is preferred by many centers for superior OS, fewer AEs (especially cuSCC, pyrexia), and cleaner drug-interaction profile. BRAF/MEK remains first-line when rapid disease control is needed; DREAMseq supports IO-first when feasible. ESMO-MCBS: 4.