Targeted Triplet Therapy Improved Overall Survival in BRAF-Mutated Colorectal Cancer

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For patients with metastatic colorectal cancer harboring BRAF V600E mutations, three drugs seem to be better than two, the most recent analysis of the phase III BEACON CRC study has shown.1 The results, presented at the 2019 European Society for Medical Oncology (ESMO) Congress, were concurrently published in The New EnglandJournal of Medicine.2

“BEACON opens a new era in the treatment of metastatic colorectal cancer, with a targeted approach in a molecularly selected population,” said the study’s invited discussant, Alfredo Falcone, MD, of the University of Pisa, Italy. In Dr. Falcone’s opinion, and that of other colorectal cancer experts at the meeting, the findings elevate the targeted triplet as the new standard of care in this previously treated BRAF-mutated population.

Triplet vs Doublet in BEACON CRC

In the randomized phase III trial, 444 patients received targeted treatment with a doublet or a triplet. The doublet contained the BRAF inhibitor encorafenib plus the EGFR inhibitor cetuximab; the triplet contained the same drugs plus the MEK inhibitor binimetinib. Another 221 patients served as the control arm, receiving cetuximab plus either FOLFIRI (fluorouracil, leucovorin, irinotecan) or irinotecan.

The comparison of the triplet and doublet regimens was presented at the ESMO Congress 2019 by Josep Tabernero, MD, of Vall d’Hebron Institute of Oncology in Barcelona. Dr. Tabernero is also President of ESMO. “The data suggest that the triplet offers improved efficacy, with some additional manageable toxicity and no relative impact on maintenance of quality of life, compared with the doublet,” Dr. Tabernero said.

Outcomes Better With Triplet

The updated analysis showed, for the first time, that a regimen of three targeted agents improves overall survival in patients with mutations in BRAF V600E who experienced disease progression after first-line therapy. Both the triplet and the doublet significantly improved overall survival and response rates relative to the standard of care (ie, control arm) in a patient population “with historically dismal outcomes,” acknowledged Dr. Tabernero. The study was not powered, however, to formally compare the results of the triplet with the doublet combination.

At a median follow-up of 7.8 months, analyzing all randomly assigned patients, the triplet and the doublet, respectively, yielded median overall survival times of 9.0 months and 8.4 months (hazard ratio [HR] = 0.79; 95% confidence interval = 0.59–1.06). At a median follow-up of 12.5 months, in an analysis of the first 331 randomly assigned patients, the median overall survival was 9.5 months and 8.3 months, respectively (HR = 0.74; 95% CI = 0.53–1.04).

Compared with the control arm, the median progression-free survival and overall survival were calculated for the triplet and the doublet regimens, with the following findings:

  • Triplet vs control: Median progression-free survival, 4.3 months vs 1.5 months (HR = 0.38; P < .0001). Median overall survival, 9.0 months vs 5.4 months (HR = 0.52; P < .0001)
  • Doublet vs control: Median progression-free survival, 4.2 months vs 1.5 months (HR = 0.40; P < .0001). Median overall survival 8.4 months vs 5.4 months (HR = 0.60; P = .0003).

The objective response rates with the triplet, doublet, and control arms were 26%, 20%, and 2% (P < .0001 for both experimental arms vs controls), Dr. Tabernero reported. The median duration of treatment exposure was 21 weeks with the triplet, 19 weeks with the doublet, and 7 weeks with the control therapy. Grade 3 or 4 adverse events for these three respective arms occurred in 58%, 50%, and 61%, with discontinuation of all drugs observed in 7%, 8%, and 11%.

The addition of the MEK inhibitor ameliorated some encorafenib-related toxicities and modestly increased the incidence of diarrhea and anemia. Time to 10% deterioration in health-related quality-of-life parameters was about 5 months in both targeted treatment arms, compared with about 2 months in the control arm.

“The safety and tolerability profile of both combinations allow maintenance of high-dose intensity for most patients and are consistent with the known profiles of the component agents,” said Dr. Tabernero. “The data suggest the triplet regimen may have clinically relevant advantages over the doublet.”

Although further follow-up will better define the relative benefits of the two regimens, Dr. Tabernero concluded: “The BEACON CRC study results provide a new standard of care in patients with previously treated BRAF V600E–mutant metastatic colorectal cancer.” 

DISCLOSURE: Dr. Falcone has served as an advisor or consultant for Bayer, Bristol-Myers Squibb, Lilly, Merck, Pierre-Fabre, Roche, and Servier. Dr. Tabernero has served as an advisor or consultant for Bayer, Boehringer Ingelheim, Eli Lilly, MSD, Merck Serono, Novartis, Sanofi, Taiho Pharmaceutical, Merrimack, Peptomyc, Rafael Pharmaceuticals, Symphogen, Chugai Pharma, Ipsen, Merus, Pfizer, Seattle Genetics, Array BioPharma, AstraZeneca, BeiGene, Genentech, Genmab, Halozyme, Imugene Limited, Inflection Biosciences Limited, Kura, Menarini Group, Molecular Partners, Pharmacyclics, ProteoDesign SL, Roche, Servier, VCN Biosciences, Biocartis, Foundation Medicine, HalioDX SAS, and Roche Diagnostics.


1. Tabernero J, Grothey Z, Van Cutsem E, et al: Encorafenib plus cetuximab with or without binimetinib for BRAF V600–mutant metastatic colorectal cancer: Expanded results from a randomized, 3-arm, phase III study vs the choice of either irinotecan or FOLFIRI plus cetuximab (BEACON CRC). ESMO Congress 2019. Abstract LBA32. Presented September 30, 2019.

2. Kopetz S, Grothey A, Yaeger R, et al: Encorafenib, binimetinib, and cetuximab in BRAF V600E-mutated colorectal cancer. N Engl J Med 381:1632-1643, 2019.

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