Phase 1/2 trial of encorafenib, cetuximab, and nivolumab in microsatellite stable BRAF^V600E metastatic colorectal cancer

Van K Morris¹, Christine M Parseghian², Vahid Bahrambeigi³, Nourhan Abdelfattah⁴, Lianchun Xiao⁵, Anjali Agrawal⁶, Kangyu Lin², Kanwal P S Raghav², Robert A Wolff², Arvind Dasari², Ryan W Huey², Bryan K Kee², Michael J Overman², Jason A Willis², Phat H Le², Michelle Escano², Yunyu C Baig², Kelsey Pan⁷, David Menter², Alda L Tam⁸, Wai C Foo⁹, Li Shen¹⁰, Hey Min Lee¹¹, Thomas D Gallup¹², Cori Margain¹², Dave Gallup¹², Kimal I Rajapakshe³, Paola A Guerrero³, Jing Wang⁵, Ryan B Corcoran¹³, Anirban Maitra¹⁴, Kyuson Yun¹⁵, Scott Kopetz²

Affiliations

¹ Departments of Gastrointestinal Medical Oncology, Houston, TX 77030, USA. Electronic address: vkmorris@mdanderson.org.
² Departments of Gastrointestinal Medical Oncology, Houston, TX 77030, USA.
³ Departments of Translational Molecular Pathology, Houston, TX 77030, USA; Sheikh Ahmed Center for Pancreatic Cancer, The University of Texas - MD Anderson Cancer Center, Houston, TX 77030, USA.
⁴ Department of Neurology, Houston Methodist Research Institute, Houston, TX 77030, USA.
⁵ Departments of Biostatistics, Houston, TX 77030, USA.
⁶ Department of Computer Science, The University of Texas at Austin, Austin, TX 78712, USA.
⁷ Departments of Cancer Medicine, Houston, TX 77030, USA.
⁸ Departments of Interventional Radiology, Houston, TX 77030, USA.
⁹ Departments of Pathology, Houston, TX 77030, USA.
¹⁰ Bioinformatics and Computational Biology, The University of Texas- MD Anderson Cancer Center, Houston, TX 77030, USA; The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030, USA.
¹¹ Departments of Gastrointestinal Medical Oncology, Houston, TX 77030, USA; The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030, USA.
¹² EMPIRI, Houston, TX 77030 USA.
¹³ Massachussetts General Hospital, Boston, MA 02114, USA.
¹⁴ Departments of Translational Molecular Pathology, Houston, TX 77030, USA; Sheikh Ahmed Center for Pancreatic Cancer, The University of Texas - MD Anderson Cancer Center, Houston, TX 77030, USA; Departments of Pathology, Houston, TX 77030, USA.
¹⁵ Department of Neurology, Houston Methodist Research Institute, Houston, TX 77030, USA; EMPIRI, Houston, TX 77030 USA; Department of Neurology, Weill Cornell Medical College, Houston, TX 77030, USA.

PMID: 40882637
PMCID: PMC12431688 (available on 2026-08-21)
DOI: 10.1016/j.ccell.2025.08.002

Phase 1/2 trial of encorafenib, cetuximab, and nivolumab in microsatellite stable BRAF^V600E metastatic colorectal cancer

Van K Morris et al. Cancer Cell. 2025.

. 2025 Aug 21:S1535-6108(25)00340-X.

doi: 10.1016/j.ccell.2025.08.002. Online ahead of print.

Authors

Affiliations

¹ Departments of Gastrointestinal Medical Oncology, Houston, TX 77030, USA. Electronic address: vkmorris@mdanderson.org.
² Departments of Gastrointestinal Medical Oncology, Houston, TX 77030, USA.
³ Departments of Translational Molecular Pathology, Houston, TX 77030, USA; Sheikh Ahmed Center for Pancreatic Cancer, The University of Texas - MD Anderson Cancer Center, Houston, TX 77030, USA.
⁴ Department of Neurology, Houston Methodist Research Institute, Houston, TX 77030, USA.
⁵ Departments of Biostatistics, Houston, TX 77030, USA.
⁶ Department of Computer Science, The University of Texas at Austin, Austin, TX 78712, USA.
⁷ Departments of Cancer Medicine, Houston, TX 77030, USA.
⁸ Departments of Interventional Radiology, Houston, TX 77030, USA.
⁹ Departments of Pathology, Houston, TX 77030, USA.
¹⁰ Bioinformatics and Computational Biology, The University of Texas- MD Anderson Cancer Center, Houston, TX 77030, USA; The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030, USA.
¹¹ Departments of Gastrointestinal Medical Oncology, Houston, TX 77030, USA; The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030, USA.
¹² EMPIRI, Houston, TX 77030 USA.
¹³ Massachussetts General Hospital, Boston, MA 02114, USA.
¹⁴ Departments of Translational Molecular Pathology, Houston, TX 77030, USA; Sheikh Ahmed Center for Pancreatic Cancer, The University of Texas - MD Anderson Cancer Center, Houston, TX 77030, USA; Departments of Pathology, Houston, TX 77030, USA.
¹⁵ Department of Neurology, Houston Methodist Research Institute, Houston, TX 77030, USA; EMPIRI, Houston, TX 77030 USA; Department of Neurology, Weill Cornell Medical College, Houston, TX 77030, USA.

PMID: 40882637
PMCID: PMC12431688 (available on 2026-08-21)
DOI: 10.1016/j.ccell.2025.08.002

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.

Keywords: BRAF; MAPK; PD-1; biomarker; clinical trial; colorectal cancer; complement pathway; evRNA; immunotherapy; metastasis; targeted therapy.

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Conflict of interest statement

Declaration of interests V.K.M. discloses research funding (to institution) from Pfizer, Novartis, Bicara Pharmaceuticals, Bristol Myers Squibb, RedX, and BioNTech and consulting/advisory relationships with Pfizer, BMS, AbbVie, Exelixis, BioNTech, AmMax Bio, Scandion Oncology, and Bicara. K.P.S.R. discloses consulting/advisory relationships with Daiichi, Bayer, AstraZeneca, Seattle Genetics, Eisai/Merck, and Pfizer and research funding (to institution) from Daiichi, Bayer, AstraZeneca, Seattle Genetics, Guardant, Roche, HiberCell, and UCB Biosciences. A.D. discloses consulting/advisory relationships with Ipsen, Novartis, Voluntis, Lexicon, Hutchison MediPharma, and Personalis and research funding (to institution) from Novartis, Eisai, Hutchison MediPharma, Guardant Health, and Ipsen. R.W.H. discloses honoraria from Bayer and Intellisphere, LLC. M.J.O. reports consulting/advisory relationships with Phanes Therapeutics, Takeda Pharmaceuticals, Ipsen Biopharmaceuticals, Pfizer, Merck, GlaxoSmithKline, Promega, 3D Medicine, Nouscom, Gritstone, and Tempus and research funding (to institution) from Roche, Takeda, Merck, Bristol Myers Squibb, AstraZeneca, Nouscom, and Roche. A.L.T. reports research funding (to institution) from Boston Scientific and Johnson & Johnson. T.D.G., D.G., K.Y., and C.M. are stockholders of EMPIRI, Inc. T.D.G. and D.G. are employees of EMPIRI. K.Y. is an inventor on a patent that has been licensed to EMPIRI. A.M. is listed as an inventor on a patent that has been licensed by Johns Hopkins University to Thrive Earlier Detection. A.M. serves as a consultant for Tezcat Biotechnology. S.K. has ownership interest in MolecularMatch, Lutris, and Iylon, is a consultant for Genentech, EMD Serono, Merck, Holy Stone, Novartis, Lilly, Boehringer Ingelheim, Boston Biomedical, AstraZeneca/MedImmune, Bayer Health, Pierre Fabre, Redx Pharma, Ipsen, Daiichi Sankyo, Natera, HalioDx, Lutris, Jacobio, Pfizer, Repare Therapeutics, Inivata, GlaxoSmithKline, Jazz Pharmaceuticals, Iylon, Xilis, AbbVie, Amal Therapeutics, Gilead Sciences, Mirati Therapeutics, Flame Biosciences, Servier, Carina Biotechnology, Bicara Therapeutics, Endeavor BioMedicines, Numab Pharma, and Johnson & Johnson/Janssen, and receives research funding from Sanofi, Biocartis, Guardant Health, Array BioPharma, Genentech/Roche, EMD Serono, MedImmune, Novartis, Amgen, Lilly, and Daiichi Sankyo.

References

1. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, et al. (2002). Mutations of the BRAF gene in human cancer. Nature 417, 949–954. 10.1038/nature00766. - DOI - PubMed
1. Cancer Genome Atlas N (2012). Comprehensive molecular characterization of human colon and rectal cancer. Nature 487, 330–337. 10.1038/nature11252. - DOI - PMC - PubMed
1. De Roock W, Claes B, Bernasconi D, De Schutter J, Biesmans B, Fountzilas G, Kalogeras KT, Kotoula V, Papamichael D, Laurent-Puig P, et al. (2010). Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis. Lancet Oncol 11, 753–762. 10.1016/S1470-2045(10)70130-3. - DOI - PubMed
1. Seligmann JF, Fisher D, Smith CG, Richman SD, Elliott F, Brown S, Adams R, Maughan T, Quirke P, Cheadle J, et al. (2017). Investigating the poor outcomes of BRAF-mutant advanced colorectal cancer: analysis from 2530 patients in randomised clinical trials. Ann Oncol 28, 562–568. 10.1093/annonc/mdw645. - DOI - PubMed
1. Tran B, Kopetz S, Tie J, Gibbs P, Jiang ZQ, Lieu CH, Agarwal A, Maru DM, Sieber O, and Desai J (2011). Impact of BRAF mutation and microsatellite instability on the pattern of metastatic spread and prognosis in metastatic colorectal cancer. Cancer 117, 4623–4632. 10.1002/cncr.26086. - DOI - PMC - PubMed

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Phase 1/2 trial of encorafenib, cetuximab, and nivolumab in microsatellite stable BRAF^V600E metastatic colorectal cancer

Affiliations

Phase 1/2 trial of encorafenib, cetuximab, and nivolumab in microsatellite stable BRAF^V600E metastatic colorectal cancer

Authors

Affiliations

Abstract

Conflict of interest statement

References

Grants and funding

LinkOut - more resources

Full Text Sources

Research Materials

Miscellaneous