Scott Kopetz, MD, PhD

For patients with previously treated metastatic colorectal cancer harboring BRAF V600E mutations, the phase III BEACON-CRC study showed the benefit for combining two or three targeted agents vs the standard of care.¹ The study has now also shown a benefit for the triplet and doublet in maintaining quality of life during treatment, the lead investigator Scott Kopetz, MD, PhD, of The University Texas MD Anderson Cancer Center, reported at the 2020 Gastrointestinal Cancers Symposium.²

BEACON-CRC evaluated a triplet encompassing BRAF, MEK, and EGFR inhibition, as well as BRAF plus EGFR inhibition, in patients with BRAF V600E–mutant metastatic colorectal cancer. In the study, 444 patients were randomly assigned to one of three treatments: (1) a doublet that included the BRAF inhibitor encorafenib plus the EGFR inhibitor cetuximab; (2) a targeted triplet containing encorafenib, cetuximab, and the MEK inhibitor binimetinib; (3) standard treatment with cetuximab plus either FOLFIRI (fluorouracil, leucovorin, irinotecan) or irinotecan.

“Encorafenib plus cetuximab, with or without binimetinib, demonstrated longer maintenance of quality of life based on patient-reported assessments, over the current standard of care, in patients with BRAF V600E–mutated metastatic colorectal cancer,” Dr. Kopetz reported.

Updated Survival Data

As previously reported, both the triplet and doublet regimens significantly improved overall survival and response rates relative to the standard of care in a patient population with historically dismal outcomes. The study was not powered, however, to formally compare the results of the triplet with those of the doublet.

“We also wanted to take the opportunity at this meeting to provide an update on the overall survival,” Dr. Kopetz said. The cutoff for the new data was November 2019, with a median follow-up of almost 13 months. In the previous report, based on a data cutoff of February 2019, the median overall survival was 9.0 months with the triplet, compared with 5.4 months with the standard of care (hazard ratio = 0.52; P < .0001) and 8.4 months with the doublet (hazard ratio = 0.60; P = .0003).

“Encouragingly, we see that the overall survival for the doublet improved by almost a month with the additional mature follow-up, with a final median of 9.3 months for the triplet and 9.3 months for the doublet vs 5.9 months for the control,” he reported.

The U.S. Food and Drug Administration has granted Priority Review designation to a supplemental new drug application for the doublet—the combination of encorafenib and cetuximab—as a treatment for patients with advanced BRAF V600E–mutant metastatic colorectal cancer who have received up to two prior lines of therapy. The decision was made not to submit binimetinib for consideration in this disease setting, stated Dr. Kopetz.

Quality of Life Better Maintained

“The overall summary of safety and relative dose intensity were maintained across the arms, and grade 3 or 4 adverse events and serious adverse events were comparable across the three arms,” Dr. Kopetz said. “But we recognize that safety doesn’t always capture the patient experience, and that’s the rationale for incorporating quality-of-life metrics into the study. This is an important component that helps to understand the patient experience and complements the clinical efficacy endpoints.”

The survival benefit achieved with the doublet and triplet regimens was mirrored in the quality-of-life outcomes. These assessments, which were secondary endpoints in the trial, included the European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire (EORTC QLQ C30), Functional Assessment of Cancer Therapy–Colorectal (FACT-C), EuroQol-5D-5L Visual Analogue Scale, and Patient Global Impression of Change. The primary assessment for the quality-of-life variables was the time to definitive 10% deterioration in quality of life between the arms. Patients were queried at baseline, day 1 of every treatment cycle, at the end of treatment, as well as at the 30-day follow-up visit.

The time to a 10% deterioration of quality of life among patients on the doublet and triplet arms was about 2 months longer than patients on the control arm. On the Patient Global Impression of Change scale, more than 20% of the double and triplet arms said they were “very much improved,” compared with 10% of the control arm.

“The perception of change in symptoms was improved in the majority of patients in the doublet and triplet arms,” Dr. Kopetz noted. “And, there was no discernible difference in the quality of life between the doublet and triplet regimens across the four instruments.” 

DISCLOSURE: The BEACON-CRC study was supported by Pfizer. Dr. Kopetz owns stock or other ownership interests in MolecularMatch and Navire; has served as a consultant or advisor to Amal Therapeutics, Amgen, AstraZeneca/MedImmune, Bayer Health, Biocartis, Boehringer Ingelheim, Boston Biomedical, EMD Serono, Genentech, Holy Stone, Karyopharm Therapeutics, Lilly, Merck, Navire Pharma, Novartis, Pierre Fabre, Redx Pharma, Roche, and Symphogen; and has received institutional research funding from Amgen, Array BioPharma, Biocartis, EMD Serono, Genentech/Roche, Guardant Health, Lilly, MedImmune, Novartis, and Sanofi.

REFERENCES

1. 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.

2. Kopetz S, Grothey A, Van Cutsem E, et al: Encorafenib plus cetuximab with or without binimetinib for BRAF V600E-mutant metastatic colorectal cancer: Quality-of-life results from a randomized, three-arm, phase III study vs the choice of either irinotecan or FOLFIRI plus cetuximab (BEACON CRC). 2020 Gastrointestinal Cancers Symposium. Abstract 8. Presented January 25, 2020.