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Ref Type Journal Article
PMID (39313594)
Authors 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
Title Molecular profiling of BRAF-V600E-mutant metastatic colorectal cancer in the phase 3 BEACON CRC trial.
Journal Vol Issue Date Pages Journal Short Title
Nature medicine 30 11 2024 Nov 3261-3271 Nat Med
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BRAF V600E MAP2K1 F53L colorectal cancer predicted - resistant Binimetinib + Cetuximab + Encorafenib Case Reports/Case Series Actionable In a Phase III (BEACON CRC) trial, two patients with colorectal cancer harboring BRAF V600E demonstrated resistance to treatment with the combination of Braftovi (encorafenib), Mektovi (binimetinib), and Erbitux (cetuximab), and were found to have acquired MAP2K1 F53L in end-of-treatment ctDNA samples (PMID: 39313594; NCT02928224). 39313594