Phase 1/2 trial of encorafenib, cetuximab, and nivolumab in microsatellite stable BRAFV600E metastatic colorectal cancer
Van K. Morris, Christine M. Parseghian, Vahid Bahrambeigi, Nourhan Abdelfattah, Lianchun Xiao, Anjali Agrawal, Kangyu Lin, Kanwal Raghav, Robert A. Wolff, Arvind Dasari, Ryan Huey, Bryan K. Kee, Michael J. Overman, Jason Willis, Phat H. Le, Michelle Escano, Yunyu Baig, Kelsey Pan, David G. Menter, Alda L. Tam, Wai Chin Foo, Li Shen, Hey Min Lee, Thomas D. Gallup, Cori Margain, Dave Gallup, Kimal Rajapakshe, Paola A. Guerrero, Jing Wang, Ryan B. Corcoran, Anirban Maitra, Kyuson Yun, Scott Kopetz
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.