Phase I/II trial of encorafenib, cetuximab, and nivolumab in microsatellite stable, BRAFV600E metastatic colorectal cancer [dataset 2]

The BRAF inhibitor encorafenib and anti-EGFR antibody cetuximab modestly improve survival for patients with microsatellite stable (MSS) BRAFV600E metastatic colorectal cancer (mCRC), characterized by higher immune activation than MSS BRAFwild-type CRC. In this phase I/II study (NCT04017650) of 26 participants with MSS BRAFV600E 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 MAP kinase 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 BRAFV600E mCRC with baseline MAP kinase activation and immune activation signatures may benefit from the triple combination but not with complement pathway activation. RNA sequencing was performed on baseline tissue samples from twelve cases using the KAPAr Stranded RNA-Seq kit with RiboErase (HMR) (KAPA, Roche, cat. # 08098140702) and libraries were sequenced on a NextSeq 500 sequencer (Illumina, San Diego, CA, USA). Raw reads quality and adapter sequences were checked using FastQC (v. 0.11.8, RRID:SCR_014583). Sequencing reads were mapped using STAR (RRID:SCR_004463)43 against the human genome build (UCSC hg38), and gene level quantification was performed with featureCounts (RRID:SCR_012919)