Phase 1/2 trial of encorafenib, cetuximab, and nivolumab in microsatellite stable BRAFV600E metastatic colorectal cancer

Abstract

The BRAF inhibitor encorafenib and anti-epidermal growth factor receptor (EGFR) antibody cetuximab modestly improve survival for patients with microsatellite stable (MSS) BRAF V600E metastatic colorectal cancer (mCRC), characterized by higher immune activation than MSS BRAF wild-type colorectal cancer (CRC). In this phase 1/2 study ( NCT04017650 ) of 26 participants with MSS BRAF V600E mCRC who received encorafenib, cetuximab, and anti-PD-1 antibody nivolumab, we report an overall response rate of 50% (95% confidence interval [CI] 29–71) and median progression-free survival of 7.4 months (95% CI, 5.6–9.6). Transcriptomic profiling of pretreatment biopsies and extracellular vesicle RNA (evRNA) isolated from plasma show enrichment of non-canonical mitogen-activated protein kinase (MAPK) signaling and immune activation signatures for responders. Complement pathway activation enriches in non-responder biopsies. On serial evRNA profiling, decreased MAPK signature and increased interferon gamma response signature associate with sustained treatment benefit. MSS BRAF V600E mCRC with baseline MAPK activation and immune activation signatures may benefit from the triple combination but not with complement pathway activation. • Targeting BRAF+EGFR+PD-1 shows clinical efficacy for MSS BRAF V600E metastatic CRC • Tissue and plasma RNA signatures for immune and MAPK activation link to response • Non-responding MSS BRAF V600E CRC harbors higher complement activation signature • Increased IFNγ signature in paired evRNA samples is observed for study responders Microsatellite stable BRAF V600E CRC is characterized by higher immune activation and clinically poor prognosis. Morris et al. demonstrate durable clinical benefit to encorafenib, cetuximab, and nivolumab in this phase 1/2 clinical trial. Extracellular vesicle and tumor RNA profiling both link specific immune activation signatures to treatment efficacy.