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.