A hierarchical genomic framework associated with response to BRAF-directed therapy across solid tumors

BRAF-directed therapy achieves variable responses across solid tumors, and molecular predictors beyond mutation status remain poorly defined. We retrospectively analyzed 67 patients with BRAF-altered solid tumors across nine histologies treated with BRAF-directed therapy. VAF-defined clonality (≥5 vs <5%) and co-mutational complexity (Simple [0–1], Moderate [2–3], Complex [4+] co-altered pathways) were assessed as predictive biomarkers. Among 60 evaluable patients, ORR was 55% (95% CI: 42–67%). Patients with VAF ≥5% had significantly longer PFS than <5% (mPFS 13.2 vs 7.5 months; HR 0.36, 95% CI: 0.14–0.90; p = 0.021; clonal vs subclonal) and higher ORR (55 vs 33%). Increasing co-mutational complexity was associated with shorter PFS (HR 1.84 per tier; p = 0.009). VAF ≥5% with a simple co-mutational profile was the most favorable subgroup (ORR 70%). External validation in 17,033 BRAF-mutant samples from AACR GENIE v19.0 confirmed reproducibility of VAF distributions across institutions. We propose a hierarchical genomic framework integrating clonality and co-mutational complexity that warrants prospective validation.