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<sup>V600E</sup> metastatic colorectal cancer (mCRC), characterized by higher immune activation than MSS BRAF<sup>wild-type</sup> colorectal cancer (CRC). In this phase 1/2 study (NCT04017650) of 26 participants with MSS BRAF<sup>V600E</sup> 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<sup>V600E</sup> mCRC with baseline MAPK activation and immune activation signatures may benefit from the triple combination but not with complement pathway activation.
Authors
- Michael J. Overman (ORCID: https://orcid.org/0000-0001-5377-135X)
- Christine Megerdichian Parseghian (ORCID: https://orcid.org/0000-0002-2047-097X)
- Wai Chin Foo (ORCID: https://orcid.org/0000-0002-0471-4911)
- Van Karlyle Morris (ORCID: https://orcid.org/0000-0002-4911-2252)
- Nourhan Abdelfattah (ORCID: https://orcid.org/0000-0002-0556-0977)
- Kyuson Yun (ORCID: https://orcid.org/0000-0003-2253-4153)
- Kanwal Raghav
- Anirban Maitra (ORCID: https://orcid.org/0000-0003-4249-251X)
- Thomas D. Gallup (ORCID: https://orcid.org/0000-0003-2471-4342)
- Michelle Escano
- Arvind Dasari
- Kangyu Lin (ORCID: https://orcid.org/0000-0003-0140-2557)
- Phat H. Le (ORCID: https://orcid.org/0000-0002-9447-8149)
- Ryan Bruce Corcoran (ORCID: https://orcid.org/0000-0001-8173-5778)
- Robert A. Wolff (ORCID: https://orcid.org/0000-0002-6614-1610)
- Hey Min Lee (ORCID: https://orcid.org/0000-0001-7792-4226)
- Kimal Rajapakshe (ORCID: https://orcid.org/0000-0002-0472-858X)
- Scott Kopetz
- Li Shen (ORCID: https://orcid.org/0000-0002-1263-2940)
- Kelsey Pan (ORCID: https://orcid.org/0000-0001-9687-5677)
- Cori Margain
- Bryan K. Kee (ORCID: https://orcid.org/0000-0001-5553-2213)
- David G. Menter (ORCID: https://orcid.org/0000-0003-2967-4095)
- Paola A. Guerrero (ORCID: https://orcid.org/0000-0002-7345-1246)
- Ryan W. Huey (ORCID: https://orcid.org/0000-0002-7887-8484)
- Jason A. Willis (ORCID: https://orcid.org/0000-0001-8238-8552)
- Lianchun Xiao (ORCID: https://orcid.org/0000-0003-0972-2766)
- Alda L. Tam (ORCID: https://orcid.org/0000-0002-6065-1556)
- Anjali Agrawal (ORCID: https://orcid.org/0000-0002-6725-7500)
- Dave Gallup
- Vahid Bahrambeigi (ORCID: https://orcid.org/0000-0002-7964-6087)
- Jing Wang (ORCID: https://orcid.org/0000-0002-9996-0815)
- Yunyu Baig
Institutions
- Houston Methodist (US)
- Texas Medical Center (US)
- The University of Texas MD Anderson Cancer Center (US)
- Cornell University (US)
- Massachusetts General Hospital (US)
- Society of Interventional Radiology (US)
- Cancer Research And Biostatistics (US)
- Methodist Hospital (US)
- Dayton Interventional Radiology (US)
- Energetic Materials and Products Incorporation (United States) (US)
- Children's Cancer Center (US)
- The University of Texas at Austin (US)
Publication Details
- Journal
- Cancer Cell
- Published
- 2025-08-28
- DOI
- https://doi.org/10.1016/j.ccell.2025.08.002
- Citations
- 15
- Primary Topic
- Colorectal Cancer Treatments and Studies
- Type
- article
- Field-Weighted Citation Impact
- 15.68