Phase I/II trial of encorafenib, cetuximab, and nivolumab in microsatellite stable, BRAFV600E metastatic colorectal cancer [dataset 1]

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. Paired pre-treatment and post-treatment blood samples collected together from twenty-five patients were utilized for evRNA isolation and RNA sequencing as recently described. Briefly, evRNA was isolated from four milliliters of plasma by ultracentrifugation. RNA extraction was performed using the total exosome RNA & Protein Isolation kit (Invitrogen, cat # 4478545) and the SMART-Seq® v4 Ultra® low input RNA kit (Takara, cat. # 634891) was used for cDNA amplification. Globin RNA and ribosomal RNA were depleted by the riboPOOLs gRNA/rRNA depletion kit (siTOOLsBiotech, cat. # dp-K096-001002). Library preparation was performed with the Nextera XT DNA Library Preparation Kit (Illumina, cat. # FC-131-1096) and libraries were sequenced in a NovaSeq6000 at the Advanced Technology Genomics Core at MD Anderson.