786O Tumor biomarker analysis from COLUMBUS part 1: Encorafenib + binimetinib for BRAF V600E/K-mutant advanced or metastatic melanoma

In the randomized, 2-part, multicenter, open-label, phase 3 COLUMBUS study, encorafenib (enco) + binimetinib (bini)—approved in the US, EU, and other countries—and enco alone improved 5-year PFS and OS vs vemurafenib (vemu) in patients (pts) with BRAF V600E/K–mutant metastatic melanoma. We retrospectively investigated genetic and transcriptional correlates of response and intrinsic resistance to enco + bini in an exploratory biomarker (BM) analysis of COLUMBUS Part 1. Baseline (BL) tumor samples were analyzed using the ACE ImmunoID NeXT whole exome and whole transcriptome sequencing assays (Personalis). PFS and OS were analyzed (data cutoff: 15 Sep 2020) based on treatment (tx) type and presence of specific genetic or transcriptomic alterations at BL. High tumor mutation burden (TMB) was defined as above median TMB [8.6 mutations (muts)/megabase]. 366 tissue samples were successfully analyzed. We present results from the comparison of enco + bini (116 pts) vs vemu arms (130 pts). Median (m) PFS in the enco + bini and vemu arms was 14.9 and 5.7 mo, respectively (HR [95% CI], 0.55 [0.40–0.76]), and mOS was 34.8 and 18.6 mo, respectively (HR, 0.67 [0.50–0.90], similar to that observed in the safety cohort. PFS and OS by tx arm and BM status are shown in the table. High TMB, PD-L1 expression (exp), and IFNg signature were associated with longer PFS and OS in the enco + bini arm vs vemu arm. High ErbB2 exp and PI3KCA pathway muts were associated with shorter survival outcomes in the enco + bini arm vs the vemu arm. Pts with high immune-related signatures derived greater clinical benefit from enco + bini vs vemu. High ErbB2 exp and PI3KCA pathway muts are potential resistance mechanisms to enco + bini. Addition of checkpoint inhibitors or PI3KCA pathway–targeted therapies to enco + bini in selected pts may further improve clinical benefit for pts with BRAF V600E/K–mutant metastatic melanoma.Table: 786OEnco + bini vs vemumPFS, moHR;95% CImOS, moHR;95% CITMB, median≤9.2 vs 7.30.60;0.39–0.9426.0 vs 18.60.84;0.56–1.27>24.0 vs 5.70.49;0.30–0.7947.5 vs 16.90.53;0.34–0.82PD-L1 exp, median≤14.5 vs 5.70.56;0.34–0.9222.3 vs 19.40.86;0.54–1.36>33.2 vs 5.60.35;0.20–0.6167.3 vs 15.10.39;0.23–0.65IFNγ signature-14.5 vs 5.60.44;0.27–0.7226.0 vs 16.10.76;0.48–1.19+33.2 vs 7.30.41;0.23–0.7267.3 vs 16.90.41;0.24–0.70PI3K, PTEN, Akt, or mTORwt18.7 vs 5.70.45;0.30–0.6641.8 vs 18.80.56;0.39–0.79mut7.5 vs 7.31.04;0.56–1.9312.5 vs 16.11.23;0.71–2.13ErbB2 exp, median≤34.9 vs 5.60.29;0.17–0.5067.3 vs 15.80.44;0.26–0.72>12.9 vs 7.30.63;0.38–1.0723.4 vs 18.60.74;0.46–1.19 Open table in a new tab