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

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.