BEACON CRC Biomarker Analysis Reveals Resistance Mechanisms to BRAF-Targeted Therapy via ctDNA Profiling
This prespecified biomarker analysis of the phase 3 BEACON CRC trial characterized genomic and transcriptomic correlates of outcomes with encorafenib plus cetuximab in BRAF-V600E-mutant metastatic colorectal cancer using whole-exome sequencing and ctDNA profiling. Acquired resistance was polyclonal and subclonal, with RAS, MAP2K1, and MET alterations emerging most commonly, particularly in patients with high baseline cell-cycle signatures. Higher immune gene signatures trended toward increased survival benefit, offering a potential biomarker for treatment stratification.
The original study
Molecular profiling of BRAF-V600E-mutant metastatic colorectal cancer in the phase 3 BEACON CRC trial.
- Authors
- Kopetz S, Murphy DA, Pu J, Ciardiello F, Desai J, Van Cutsem E, et al.
- Journal
- Nature medicine
- Type
- Clinical Trial, Phase III, Journal Article, Multicenter Study, Randomized Controlled Trial
- PMID
- 39313594
Original 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.