Prespecified exploratory genomic and transcriptomic profiling of tumour tissues and circulating tumour DNA from patients with BRAFV600E-mutated metastatic colorectal cancer (mCRC), who participated in the phase III BEACON CRC study, identifies biomarkers of response and mechanisms of acquired resistance to treatment with the BRAF inhibitor encorafenib plus the anti-EGFR antibody cetuximab, with or without the MEK inhibitor binimetinib.
Results support the use of encorafenib plus cetuximab with or without binimetinib for the treatment of patients with BRAFV600E-mutated mCRC. Integrated tumour and plasma molecular profiling analyses provide comprehensive data from the largest randomised study in BRAFV600E-mutated mCRC.The findings are published by Dr. Scott Kopetz of the University of Texas MD Anderson Cancer Center in Houston, TX, US and colleagues on 23 September 2024 in the Nature Medicine.
BRAFV600E mutations occur in approximately 10% of tumours among patients with mCRC and are associated with poor prognosis relative to wild-type BRAF tumours. The BEACON CRC study demonstrated that the BRAF inhibitor encorafenib plus the anti-EGFR monoclonal antibody cetuximab, with or without the MEK inhibitor binimetinib, improved overall survival (OS), objective response rate and progression-free survival (PFS) compared with cetuximab plus chemotherapy in patients with BRAFV600E-mutated mCRC who had been previously treated.
A greater understanding of the BRAF-mutated biological landscape and prognostic and predictive determinants is important for optimising therapy. Clinical associations with molecular subtypes and mechanisms of acquired resistance following treatment with a BRAF inhibitor plus an anti-EGFR antibody, with or without a MEK inhibitor, versus conventional cytotoxic chemotherapy plus an anti-EGFR antibody, have not been studied in large, randomised trials.
Through genomic and transcriptional profiling of tumour tissue and genomic profiling of plasma samples obtained from the BEACON CRC study cohort, the study team characterised the molecular landscape of BRAFV600E-mutated mCRC treated with encorafenib plus cetuximab with or without binimetinib versus cetuximab plus chemotherapy to understand the evolving biology of these tumours on treatment. The objective of this analysis was to identify molecular correlates of clinical outcomes and define resistance mechanisms acquired following treatment.
In this prespecified, exploratory biomarker analysis of the BEACON CRC study, the study team characterised 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 tumour DNA genomic profiling.
Tumours with higher immune signatures showed a trend towards increased OS benefit with encorafenib plus binimetinib plus cetuximab. RAS, MAP2K1 and MET alterations were most commonly acquired with encorafenib plus cetuximab with or without binimetinib, 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 tumour mutation rate with encorafenib plus cetuximab with or without binimetinib and mutational signatures.
The authors commented that the biomarkers predictive of response and resistance to encorafenib plus cetuximab with or without binimetinib, in BRAFV600E-mutated mCRC need to be further evaluated prospectively. In addition, as acquired mutations were assessed using the samples from the end of treatment, the exact timing of the occurrence of these mutations was unknown, which might limit interpretation of the association between acquired alterations and OS outcomes.
The BEACON CRC study was sponsored by Pfizer and was conducted with support from Merck KGaA, Darmstadt, Germany (for sites outside of North America), ONO Pharmaceutical and Pierre Fabre. This study was also supported by a Cancer Center Core Grant to Memorial Sloan Kettering Cancer Center.
Reference
Kopetz S, Murphy DA, Pu J, et al. Molecular profiling of BRAF-V600E-mutant metastatic colorectal cancer in the phase 3 BEACON CRC trial. Nature Medicine; Published online 23 September 2024. DOI: https://doi.org/10.1038/s41591-024-03235-9