Molecular profiling of BRAF-V600E-mutant metastatic colorectal cancer in the phase 3 BEACON CRC trial

Kopetz, S; Murphy, DA; Pu, J; Ciardiello, F; Desai, J; Van Cutsem, E; Wasan, HS; Yoshino, T; Saffari, H; Zhang, X; Hamilton, P; Xie, T; Yaeger, R; Tabernero, J

Molecular profiling of BRAF-V600E-mutant metastatic colorectal cancer in the phase 3 BEACON CRC trial

Author(s): Kopetz, S; Murphy, DA; Pu, J; Ciardiello, F; Desai, J; Van Cutsem, E; Wasan, HS; Yoshino, T; Saffari, H; Zhang, X; Hamilton, P; Xie, T; Yaeger, R; Tabernero, J;
Details: Publication Year 2024-11,Volume 30,Issue #11,Page 3261-3271
Journal Title: Nature Medicine
Publication Type: Research article
Abstract: The BEACON CRC study demonstrated that encorafenib (Enco)+cetuximab (Cetux)±binimetinib (Bini) significantly improved overall survival (OS) versus Cetux + chemotherapy in previously treated patients with BRAF-V600E-mutant mCRC, providing the basis for the approval of the Enco+Cetux regimen in the United States and the European Union. A greater understanding of biomarkers predictive of response to Enco+Cetux±Bini treatment is of clinical relevance. In this prespecified, exploratory biomarker analysis of the BEACON CRC study, we characterize genomic and transcriptomic correlates of clinical outcomes and acquired resistance mechanisms through integrated clinical and molecular analysis, including whole-exome and -transcriptome tissue sequencing and circulating tumor DNA genomic profiling. Tumors with higher immune signatures showed a trend towards increased OS benefit with Enco+Bini+Cetux. RAS, MAP2K1 and MET alterations were most commonly acquired with Enco+Cetux±Bini, and more frequent in patients with a high baseline cell-cycle gene signature; baseline TP53 mutation was associated with acquired MET amplification. Acquired mutations were subclonal and polyclonal, with evidence of increased tumor mutation rate with Enco+Cetux±Bini and mutational signatures (SBS17a/b). These findings support treatment with Enco+Cetux±Bini for patients with BRAF-V600E-mutant mCRC and provide insights into the biology of response and resistance to MAPK-pathway-targeted therapy. ClinicalTrials.gov registration: NCT02928224.
Publisher: Springer Nature
Keywords: Humans; *Proto-Oncogene Proteins B-raf/genetics; *Colorectal Neoplasms/genetics/drug therapy/pathology; *Mutation; *Sulfonamides/therapeutic use; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use; *Cetuximab/therapeutic use; Carbamates/therapeutic use; Female; Azetidines/therapeutic use; Male; Neoplasm Metastasis; Biomarkers, Tumor/genetics; Middle Aged; Drug Resistance, Neoplasm/genetics; Gene Expression Profiling; Benzimidazoles
Department(s): Medical Oncology
Publisher's Version: https://doi.org/10.1038/s41591-024-03235-9
Open Access at Publisher's Site: https://doi.org/10.1038/s41591-024-03235-9
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2024-12-17 03:14:00

Last Modified: 2024-12-17 03:15:01