The three-drug combination of encorafenib (a BRAF inhibitor), binimetinib (a MEK inhibitor), and cetuximab (an EGFR inhibitor) significantly improved overall survival in patients with BRAF-mutated metastatic colorectal cancer, according to the results of the phase III BEACON CRC clinical trial. These findings were presented by Kopetz et al at the European Society for Medical Oncology (ESMO) World Congress on Gastrointestinal Cancer 2019.1 BEACON CRC is reportedly the first phase III trial designed to test BRAF/MEK combination targeted therapies in this patient population.
Scott Kopetz, MD, PhD
“This study builds on a decade of research into the tumor biology of BRAF-mutated colorectal cancer and reflects a rational combination to address the vulnerabilities unique to this tumor,” said principal investigator Scott Kopetz, MD, PhD, Associate Professor of Gastrointestinal Medical Oncology at The University of Texas MD Anderson Cancer Center, Houston. “We are encouraged to see a meaningful improvement in outcomes with this new regimen for our patients.”
In August 2018, the U.S. Food and Drug Administration granted Breakthrough Therapy designation to encorafenib in combination with binimetinib and cetuximab for the treatment of patients with BRAF V600E–mutant metastatic colorectal cancer after failure of one to two prior lines of therapy for metastatic disease. Data from the BEACON CRC trial are being used to support regulatory approval of the triplet combination in this patient population, and BRAF inhibitor–based treatment has recently been included as a treatment option in the National Comprehensive Cancer Network© (NCCN©) Clinical Practice Guidelines in Oncology for Colon and Rectal Cancers.2,3
BEACON CRC Methods and Findings
The international study was a multi-institutional collaboration of more than 200 centers worldwide. In the open label, three-arm randomized clinical trial, 665 patients with BRAF V600E–mutant metastatic colorectal cancer that had progressed after one or two prior regimens in the metastatic setting were randomly assigned to receive encorafenib/binimetinib/cetuximab, encorafenib/cetuximab, or the investigator’s choice of irinotecan or leucovorin, fluorouracil, and irinotecan (FOLFIRI) and cetuximab.
A median overall survival of 9.0 months (95% confidence interval [CI] = 8.0–11.4 months) was reported in patients treated with the triplet regimen, compared with 5.4 months (95% CI = 4.8–6.6 months) for the control regimens (hazard ratio = 0.52, 95% CI = 0.39–0.70; P < .0001). The objective response rate for the targeted triplet therapy was 26%, compared with 2% for the controls.
The triplet combination was generally well tolerated, with no unexpected toxicities. Grade 3 or higher adverse events were seen in 58% of patients who received the triplet regimen, 50% of those in the doublet group, and 61% of those in the standard-therapy group.
“This targeted therapy combination should be a new standard of care for this patient group,” said Dr. Kopetz. “Further investigation is needed to determine if this combination may also benefit those with less advanced disease or as a first-line treatment.”
The study was not intended to compare triplet and doublet therapies, but future analyses will explore which patients are most likely to benefit from triplet vs doublet combinations. Additionally, an ongoing study (ANCHOR-CRC) is investigating the effects of triplet therapy as initial treatment of metastatic BRAF V600E–mutant colorectal cancer.
Additional Commentary
Commenting on the relevance of these new data, Andrés Cervantes, MD, PhD, of the Biomedical Research Institute INCLIVA, University of Valencia, Spain, stressed that it will be important for all patients with colorectal cancer to be tested for BRAF mutations in the light of the BEACON CRC findings. “We now have a specific treatment that can change the natural course of the disease in patients with BRAF mutations and is better than previous therapy, so it is essential that patients are routinely -tested,” he said.
Andrés Cervantes, MD, PhD
Dr. Cervantes also highlighted the chemotherapy-free nature of the targeted combination used in the study. “In many other types of cancer, particularly colorectal, it is common for biologic targeted therapies to be used in combination with chemotherapy. The fact that we can give this targeted combination without the need for chemotherapy is very good news for patients, not least because of the side effects they typically experience with chemotherapy,” he added.
“At present, targeted therapy should probably be limited to the patient group treated in the BEACON CRC trial who had disease progression after one or two previous lines of chemotherapy. However, it is important that we investigate its use in other settings where more patients with BRAF mutations may also benefit, including those with less advanced metastatic disease and possibly in the adjuvant setting after primary surgery with curative intent,” concluded Dr. Cervantes. ■
DISCLOSURE: This study was sponsored by Array Biopharma and is being conducted with support from Merck KGaA, Darmstadt, Germany (for sites outside of North America), Ono Pharmaceutical, and Pierre Fabre. For full disclosures of the study authors, visit academic.oup.com.
REFERENCES
1. Kopetz S, Grothey A, Van Cutsem E, et al: BEACON CRC: a randomized, 3-arm, phase 3 study of encorafenib and cetuximab with or without binimetinib vs. choice of either irinotecan or FOLFIRI plus cetuximab in BRAF V600E–mutant metastatic colorectal cancer. Ann Oncol 30 (suppl 4):iv137-iv151, 2019.
2. Benson AB, Venook AP, Al-Hawary MM, et al: NCCN Clinical Practice Guidelines in Oncology for Colon Cancer, version 2.2019. Available at https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf. Accessed July 11, 2019.
3. Benson AB, Venook AP, Al-Hawary MM, et al: NCCN Clinical Practice Guidelines in Oncology for Rectal Cancer, version 2.2019. Available at https://www.nccn.org/professionals/physician_gls/pdf/rectal.pdf. Accessed July 11, 2019.
