Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 Oct:210:114290.
doi: 10.1016/j.ejca.2024.114290. Epub 2024 Aug 22.

BRAF + EGFR +/- MEK inhibitors after immune checkpoint inhibitors in BRAF V600E mutated and deficient mismatch repair or microsatellite instability high metastatic colorectal cancer

Margherita Ambrosini  1 , David Tougeron  2 , Dominik Modest  3 , Rosine Guimbaud  4 , Scott Kopetz  5 , Marie Decraecker  6 , Stefano Kim  7 , Clelia Coutzac  8 , Geraldine Perkins  9 , Emily Alouani  4 , Federica Marmorino  10 , Simon Pernot  11 , Frank A Sinicrope  12 , Elena Elez  13 , Pauline Parent  14 , Chiara Cremolini  10 , Filippo Pietrantonio  15 , Sara Lonardi  16 , Claire Gallois  17 , Julien Taieb  18
Affiliations

BRAF + EGFR +/- MEK inhibitors after immune checkpoint inhibitors in BRAF V600E mutated and deficient mismatch repair or microsatellite instability high metastatic colorectal cancer

Margherita Ambrosini et al. Eur J Cancer. 2024 Oct.

Abstract

Background: Immune checkpoint inhibitors (ICIs) are the guideline endorsed first choice for patients with deficient mismatch repair or microsatellite instability high (dMMR/MSI-H) mCRC, however a significant proportion experience primary or secondary resistance. BRAF V600E mutated (BRAFm) and dMMR/MSI-H mCRC can be treated with BRAF + EGFR inhibitors but specific data on the efficacy after progression to ICIs are missing.

Methods: We collected consecutive patients with BRAFm dMMR/MSI-H mCRC treated from 2017 to 2024 with a combination of BRAFi+EGFRi+/-MEKi, after disease progression on ICIs. A control cohort of BRAFm pMMR/MSS mCRC patients treated with encorafenib+cetuximab+/-binimetinib from 2nd line was used.

Results: dMMR/MSI-H (n = 50) BRAFm mCRC patients were more often > 70-year-old, with right-sided primary tumors, without liver but more lymphnode metastases than pMMR/MSS (n = 170). They were treated more frequently beyond 2nd line and 45 % were primary progressors to ICIs. Lower ORR (18 % versus 32 %, p = 0.09) and DCR (60 % versus 73 %, p = 0.11) was seen without reaching significance in dMMR/MSI-H as compared to pMMR/MSS patients. After a median follow-up of 14.04 months, no differences in PFS (median 5.13 versus 4.50 months, HR 0.83, 95 %CI: 0.57-1.20, p = 0.31) and OS (median 10.75 versus 9.11 months, HR 0.89, 95 %CI: 0.59-1.32, p = 0.55) were observed.

Conclusions: Our results show that BRAFm dMMR/MSI-H mCRC patients benefit from BRAFi+EGFRi+/-MEKi after progression under ICIs. Despite lower ORR and DCR, the outcome is not different from that observed in pMMR/MSS BRAFm CRC and is in line with the results of the BEACON registration trial.

Keywords: BRAF mutation; Cetuximab; Deficient mismatch repair; Encorafenib; Immune checkpoint inhibitors; Metastatic colorectal cancer; Microsatellite instability high.

PubMed Disclaimer

Conflict of interest statement

Declaration of Competing Interest DT reports personal fees from AstraZeneca, Sanofi, Amgen, BMS, MSD, Roche, Servier, and Pierre Fabre. DM participated in advisory board for Amgen, Servier, Merck, MSD, Takeda, G1, Onkowissen, Pierre Fabre, AstraZeneca, Regeneron; received honoraria as invited speaker for Medison, COR2ED, JE, 21up, Seagen, Takeda, Taiho, Amgen, Servier, Merck, Onkowissen, MSD, AstraZeneca, Pierre Fabre, GSK; reports institutional non-financial interests for Amgen and Servier. GP reports grant from Merck Serono, honoraria from Servier and Sanofi. EE has received personal honoraria from Amgen, Bayer, BMS, Boehringer Ingelheim, Cure Teq AG, Hoffman La – Roche, Janssen, Lilly, Medscape, Merck Serono, MSD, Novartis, Organon, Pfizer, Pierre Fabre, Repare Therapeutics Inc., RIN Institute Inc., Sanofi, Seagen International, GmbH, Servier, and Takeda. CC served as expert testimony for Amgen; received honoraria as invited speaker for Bayer, Merck Serono, Servier; participated in advisory board for MSD, Nordic Pharma, Pierre- Fabre, Roche, Takeda; reports institutional financial interest for Bayer as Coordinating PI, Hutchinson as Local PI, Merck as Coordinating PI, Roche as Coordinating PI, Seagen as Local PI, Servier as Coordinating PI. FP reported receiving institutional research grants from BMS, Incyte, Agenus, Amgen, Lilly and AstraZeneca, and personal fees from BMS, MSD, Amgen, Merck-Serono, Pierre-Fabre, Servier, Bayer, Takeda, Astellas, Johnson&Johnson, Rottapharm, Ipsen, AstraZeneca, GSK, Daiichi-Sankyo, Seagen/Pfizer, Beigene. SL reports research funding to institution from Amgen, Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Daichii Sankyo, Hutchinson, Incyte, Merck Serono, Mirati, MSD, Pfizer, Roche, Servier; personal honoraria as invited speaker from Amgen, Bristol- Myers Squibb, Incyte, GSK, Lilly, Merck Serono, MSD, Pierre- Fabre, Roche, Servier; participation in advisory board for Amgen, Astellas, Astra Zeneca, Bayer, Bristol-Myers Squibb, Daiichi-Sankyo, GSK, Incyte, Lilly, Merck Serono, MSD, Servier, Takeda. CG has participated in consulting and/or advisory boards for Servier, Sanofi, Merck, Pierre Fabre, MSD and has received support for travel to meetings from Pierre Fabre and Servier. JT received honoraria as invited speaker for Amgen, Astellas, BMS, Merk, MSD, Novartis; participated in advisory board for Amgen, BMS, Merck, MSD, Novartis, Pfizer, Pierre Fabre, Rottapharm, Sanofi, Servier, Takeda and as expert testimony for Takeda; participated in steering committee of clinical trial for Novartis. All the other authors declare no competing interest.

MeSH terms