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 P.S. Raghav; Robert A. Wolff; Arvind Dasari; Ryan W. Huey; Bryan K. Kee; Michael J. Overman; Jason A. Willis; Phat H. Le; Michelle Escano; Yunyu C. Baig; Kelsey Pan; David Menter; Alda L. Tam; Wai C. Foo; Li Shen; Hey Min Lee; Thomas D. Gallup; Cori Margain; Dave Gallup; Kimal I. Rajapakshe; Paola A. Guerrero; Jing Wang; Ryan B. Corcoran; Anirban Maitra; Kyuson Yun; Scott Kopetz

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, Christine M. Parseghian, Vahid Bahrambeigi, Nourhan Abdelfattah, Lianchun Xiao, Anjali Agrawal, Kangyu Lin, Kanwal P.S. Raghav, Robert A. Wolff, Arvind Dasari, Ryan W. Huey, Bryan K. Kee, Michael J. Overman, Jason A. Willis, Phat H. Le, Michelle Escano, Yunyu C. Baig, Kelsey Pan, David Menter, Alda L. TamWai C. Foo, Li Shen, Hey Min Lee, Thomas D. Gallup, Cori Margain, Dave Gallup, Kimal I. Rajapakshe, Paola A. Guerrero, Jing Wang, Ryan B. Corcoran, Anirban Maitra, Kyuson Yun, Scott Kopetz

Research output: Contribution to journal › Article › peer-review

14 Scopus citations

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.

Original language	English (US)
Pages (from-to)	2106-2118.e3
Journal	Cancer Cell
Volume	43
Issue number	11
DOIs	https://doi.org/10.1016/j.ccell.2025.08.002
State	Published - Nov 10 2025

Keywords

biomarker
BRAF
clinical trial
colorectal cancer
complement pathway
evRNA
immunotherapy
MAPK
metastasis
PD-1
targeted therapy
Nivolumab/administration & dosage
Microsatellite Instability
Humans
Middle Aged
Proto-Oncogene Proteins B-raf/genetics
Male
Neoplasm Metastasis
Female
Adult
Cetuximab/administration & dosage
Sulfonamides/administration & dosage
Colorectal Neoplasms/drug therapy
Antineoplastic Combined Chemotherapy Protocols/therapeutic use
Carbamates/administration & dosage
Aged
Mutation

ASJC Scopus subject areas

Oncology
Cancer Research

Access to Document

10.1016/j.ccell.2025.08.002

Cite this

Morris, V. K., Parseghian, C. M., Bahrambeigi, V., Abdelfattah, N., Xiao, L., Agrawal, A., Lin, K., Raghav, K. P. S., Wolff, R. A., Dasari, A., Huey, R. W., Kee, B. K., Overman, M. J., Willis, J. A., Le, P. H., Escano, M., Baig, Y. C., Pan, K., Menter, D., ... Kopetz, S. (2025). Phase 1/2 trial of encorafenib, cetuximab, and nivolumab in microsatellite stable BRAF^V600E metastatic colorectal cancer. Cancer Cell, 43(11), 2106-2118.e3. https://doi.org/10.1016/j.ccell.2025.08.002

Morris, VK, Parseghian, CM, Bahrambeigi, V, Abdelfattah, N, Xiao, L, Agrawal, A, Lin, K, Raghav, KPS, Wolff, RA, Dasari, A, Huey, RW, Kee, BK, Overman, MJ, Willis, JA, Le, PH, Escano, M, Baig, YC, Pan, K, Menter, D, Tam, AL, Foo, WC, Shen, L, Lee, HM, Gallup, TD, Margain, C, Gallup, D, Rajapakshe, KI, Guerrero, PA, Wang, J, Corcoran, RB, Maitra, A, Yun, K & Kopetz, S 2025, 'Phase 1/2 trial of encorafenib, cetuximab, and nivolumab in microsatellite stable BRAF^V600E metastatic colorectal cancer', Cancer Cell, vol. 43, no. 11, pp. 2106-2118.e3. https://doi.org/10.1016/j.ccell.2025.08.002

@article{e206478a149e4dfb916f1de54b7d55ae,

title = "Phase 1/2 trial of encorafenib, cetuximab, and nivolumab in microsatellite stable BRAFV600E metastatic colorectal cancer",

abstract = "The BRAF inhibitor encorafenib and anti-epidermal growth factor receptor (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 colorectal cancer (CRC). In this phase 1/2 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 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 BRAFV600E mCRC with baseline MAPK activation and immune activation signatures may benefit from the triple combination but not with complement pathway activation.",

keywords = "biomarker, BRAF, clinical trial, colorectal cancer, complement pathway, evRNA, immunotherapy, MAPK, metastasis, PD-1, targeted therapy, Nivolumab/administration \& dosage, Microsatellite Instability, Humans, Middle Aged, Proto-Oncogene Proteins B-raf/genetics, Male, Neoplasm Metastasis, Female, Adult, Cetuximab/administration \& dosage, Sulfonamides/administration \& dosage, Colorectal Neoplasms/drug therapy, Antineoplastic Combined Chemotherapy Protocols/therapeutic use, Carbamates/administration \& dosage, Aged, Mutation",

author = "Morris, \{Van K.\} and Parseghian, \{Christine M.\} and Vahid Bahrambeigi and Nourhan Abdelfattah and Lianchun Xiao and Anjali Agrawal and Kangyu Lin and Raghav, \{Kanwal P.S.\} and Wolff, \{Robert A.\} and Arvind Dasari and Huey, \{Ryan W.\} and Kee, \{Bryan K.\} and Overman, \{Michael J.\} and Willis, \{Jason A.\} and Le, \{Phat H.\} and Michelle Escano and Baig, \{Yunyu C.\} and Kelsey Pan and David Menter and Tam, \{Alda L.\} and Foo, \{Wai C.\} and Li Shen and Lee, \{Hey Min\} and Gallup, \{Thomas D.\} and Cori Margain and Dave Gallup and Rajapakshe, \{Kimal I.\} and Guerrero, \{Paola A.\} and Jing Wang and Corcoran, \{Ryan B.\} and Anirban Maitra and Kyuson Yun and Scott Kopetz",

note = "Publisher Copyright: {\textcopyright} 2025 The Authors",

year = "2025",

month = nov,

day = "10",

doi = "10.1016/j.ccell.2025.08.002",

language = "English (US)",

volume = "43",

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T1 - Phase 1/2 trial of encorafenib, cetuximab, and nivolumab in microsatellite stable BRAFV600E metastatic colorectal cancer

AU - Morris, Van K.

AU - Parseghian, Christine M.

AU - Bahrambeigi, Vahid

AU - Abdelfattah, Nourhan

AU - Xiao, Lianchun

AU - Agrawal, Anjali

AU - Lin, Kangyu

AU - Raghav, Kanwal P.S.

AU - Wolff, Robert A.

AU - Dasari, Arvind

AU - Huey, Ryan W.

AU - Kee, Bryan K.

AU - Overman, Michael J.

AU - Willis, Jason A.

AU - Le, Phat H.

AU - Escano, Michelle

AU - Baig, Yunyu C.

AU - Pan, Kelsey

AU - Menter, David

AU - Tam, Alda L.

AU - Foo, Wai C.

AU - Shen, Li

AU - Lee, Hey Min

AU - Gallup, Thomas D.

AU - Margain, Cori

AU - Gallup, Dave

AU - Rajapakshe, Kimal I.

AU - Guerrero, Paola A.

AU - Wang, Jing

AU - Corcoran, Ryan B.

AU - Maitra, Anirban

AU - Yun, Kyuson

AU - Kopetz, Scott

PY - 2025/11/10

Y1 - 2025/11/10

N2 - The BRAF inhibitor encorafenib and anti-epidermal growth factor receptor (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 colorectal cancer (CRC). In this phase 1/2 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 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 BRAFV600E mCRC with baseline MAPK activation and immune activation signatures may benefit from the triple combination but not with complement pathway activation.

AB - The BRAF inhibitor encorafenib and anti-epidermal growth factor receptor (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 colorectal cancer (CRC). In this phase 1/2 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 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 BRAFV600E mCRC with baseline MAPK activation and immune activation signatures may benefit from the triple combination but not with complement pathway activation.

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KW - BRAF

KW - clinical trial

KW - colorectal cancer

KW - complement pathway

KW - evRNA

KW - immunotherapy

KW - MAPK

KW - metastasis

KW - PD-1

KW - targeted therapy

KW - Nivolumab/administration & dosage

KW - Microsatellite Instability

KW - Humans

KW - Middle Aged

KW - Proto-Oncogene Proteins B-raf/genetics

KW - Male

KW - Neoplasm Metastasis

KW - Female

KW - Adult

KW - Cetuximab/administration & dosage

KW - Sulfonamides/administration & dosage

KW - Colorectal Neoplasms/drug therapy

KW - Antineoplastic Combined Chemotherapy Protocols/therapeutic use

KW - Carbamates/administration & dosage

KW - Aged

KW - Mutation

UR - https://www.scopus.com/pages/publications/105016817796

UR - https://www.scopus.com/inward/citedby.url?scp=105016817796&partnerID=8YFLogxK

U2 - 10.1016/j.ccell.2025.08.002

DO - 10.1016/j.ccell.2025.08.002

M3 - Article

C2 - 40882637

AN - SCOPUS:105016817796

SN - 1535-6108

VL - 43

SP - 2106-2118.e3

JO - Cancer Cell

JF - Cancer Cell

IS - 11

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