The phase 3 BEACON CRC trial demonstrated that treatment with the BRAF inhibitor encorafenib plus anti-EGFR monoclonal antibody cetuximab, with or without MEK inhibitor binimetinib, significantly improved overall survival, objective response rate and disease-free survival in previously treated BRAF V600E-mutated metastatic colorectal cancer (mCRC) versus cetuximab and chemotherapy1,2. These results led to the approval of the encorafenib-cetuximab regimen in the United States and the European Union.
Published open access in Nature Medicine3, prespecified exploratory analysis of the BEACON CRC study dataset has unveiled promising biomarkers of response and resistance that further support the use of encorafenib combined with cetuximab, with or without binimetinib, in this patient population.
“To better understand the BRAF-mutant biological landscape and identify potential biomarkers of response and resistance to therapy, we retrospectively analyzed data from 621 patients enrolled in the BEACON CRC phase 3 trial,” said Josep Tabernero, Head of the Medical Oncology Department at the Vall d’Hebron University Hospital (HUVH), Director of the Vall d’Hebron Institute of Oncology (VHIO) and senior author of this present study.
By the genomic and transcriptional profiling of tumor tissue and plasma samples obtained from the BEACON CRC study cohort, the investigators characterized the molecular make-up of BRAF V600E-mutated mCRC treated with encorafenib plus cetuximab, with the addition of binimetinib or not, compared with the cetuximab-chemotherapy combination.
The objectives of this present study were to unravel the evolving biology of these tumors on treatment, identify potential biomarkers of response to therapy and define mechanisms of acquired resistance. The tumor and liquid biopsy analysis performed included whole-exome and -transcriptome tissue sequencing and circulating tumor DNA (ctDNA) genomic profiling. This integrated approach has provided comprehensive data from the largest randomized study in BRAF V600E-mutated colorectal cancer.
Given the retrospective nature of this research, the predictability of these markers will need to be further evaluated and validated prospectively.
“To optimize therapy, we must continue to decipher the evolutionary dynamics of disease, molecular determinants of response and the mechanisms of acquired drug resistance. These efforts will help to accelerate the development of new therapeutic strategies aimed at improving survival and quality of life in patients with previously treated metastatic colorectal cancer,” concluded Josep Tabernero.
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References
- Kopetz S, Grothey A, Yaeger R, Van Cutsem E, Desai J, Yoshino T, Wasan H, Ciardiello F, Loupakis F, Hong YS, Steeghs N, Guren TK, Arkenau HT, Garcia-Alfonso P, Pfeiffer P, Orlov S, Lonardi S, Elez E, Kim TW, Schellens JHM, Guo C, Krishnan A, Dekervel J, Morris V, Calvo Ferrandiz A, Tarpgaard LS, Braun M, Gollerkeri A, Keir C, Maharry K, Pickard M, Christy-Bittel J, Anderson L, Sandor V, Tabernero J. Encorafenib, Binimetinib, and Cetuximab in BRAFV600E-Mutated Colorectal Cancer. N Engl J Med. 2019 Oct 24;381(17):1632-1643.
- Tabernero J, Grothey A, Van Cutsem E, Yaeger R, Wasan H, Yoshino T, Desai J, Ciardiello F, Loupakis F, Hong YS, Steeghs N, Guren TK, Arkenau HT, Garcia-Alfonso P, Elez E, Gollerkeri A, Maharry K, Christy-Bittel J, Kopetz S. Encorafenib Plus Cetuximab as a New Standard of Care for Previously Treated BRAFV600E-Mutant Metastatic Colorectal Cancer: Updated Survival Results and Subgroup Analyses from the BEACON Study. J Clin Oncol. 2021 Feb 1;39(4):273-284.
