Adaptive encorafenib/binimetinib (BRAF/MEK) + nivolumab cuts Grade 3+ AEs while preserving long-run disease control in BRAF V600E melanoma

Encorafenib (BRAF inhibitor) + binimetinib (MEK inhibitor) were given either continuously or via patient-specific adaptive scheduling (ctDNA- and imaging-calibrated mathematical model), with nivolumab (anti–PD-1) dosed continuously in both arms, in a randomized pilot feasibility study in previously untreated advanced BRAF V600E melanoma with detectable baseline plasma ctDNA (n=10; NCT03543969). Drug exposure diverged sharply—median time on ENCO+BINI was 61 weeks (89% of on-study time) with continuous dosing vs 11 weeks (24%) with adaptive dosing—yet at 45.5 months’ median follow-up, PFS was 26.9 months in Arm A vs not reached in Arm B (log-rank p=0.5) and OS was 32 months vs not reached (2-year OS 60% vs 75%; p=0.18), with fewer treatment-related Grade 3 AEs in the adaptive arm (6 vs 16). Efficacy looks directionally within the range of frontline PD-1–based standards (e.g., pembrolizumab ORR ~33% and median PFS ~5–8 months in KEYNOTE-006; nivolumab+ipilimumab median PFS ~15.5 months in the BRAF-mutant subgroup of CheckMate 067), but this tiny n and imbalanced ORR (100% vs 60%, all PRs) make cross-trial comparisons—and the “non-inferiority” claim—statistically fragile.