Triplet Succeeds in Colorectal Cancer

A drug triplet consisting of BRAF, MEK, and EGFR inhibitors may become the new standard of care in BRAF-mutant metastatic colorectal cancer. In the phase III BEACON CRC trial, encorafenib (Braftovi; Array Biopharma), binimetinib (Mektovi; Array BioPharma), and cetuximab (Erbitux; Eli Lilly) significantly extended overall and progression-free survival and increased response rate compared with cetuximab plus chemotherapy. The trio also appeared more effective than a doublet of encorafenib and cetuximab.

“BEACON is a practice- and perspective-changing study in the treatment of this disease,” said Alfredo Falcone, MD, of the University of Pisa in Italy, who provided outside commentary on the trial. Findings were presented at the ESMO Congress 2019, September 27–October 1, in Barcelona, Spain, and simultaneously published.

The approximately 10% of patients with metastatic colorectal cancer who have BRAF V600 mutations tend to have a poor prognosis and generally don't respond to single-agent BRAF inhibitors, likely due to feedback activation of the EGFR pathway. However, “many preclinical studies have shown that this feedback may be overcome by targeting multiple nodes in this pathway,” such as BRAF, MEK, and EGFR, said senior author Josep Tabernero, MD, PhD, director of the Vall d'Hebron Institute of Oncology in Barcelona, leading researchers to combine multiple targeted agents.

To this end, the BEACON CRC trial compared encorafenib, binimetinib, and cetuximab with encorafenib plus cetuximab and with cetuximab plus chemotherapy in 665 patients with BRAF V600E–mutant metastatic colorectal cancer. Patients had received one or two prior therapies, but had not been treated with RAF, MEK, or EGFR inhibitors.

Patients who received the drug triplet had a median overall survival (OS) of 9 months, a median progression-free survival (PFS) of 4.3 months, and an objective response rate (ORR) of 26%, compared with 8.4 months, 4.2 months, and 20% in patients who received the drug duo, and 5.4 months, 1.5 months, and 2% in patients in the control arm. Differences between the triplet and control arm and the doublet and control arm were significant. Patients who received the triplet trended toward longer OS and PFS and a higher ORR than those treated with the doublet, although the trial was not powered for this comparison.

Overall, 58% of patients receiving the triplet experienced a grade 3 or 4 adverse event, and 7% discontinued treatment, compared with 50% and 8% of patients receiving the doublet, and 61% and 11% of patients in the control arm. Patients receiving the triplet or doublet reported better quality of life than those in the control arm, and certain BRAF inhibitor–related toxicities, such as skin papilloma and musculoskeletal pain, were less common in the triplet arm, possibly due to the presence of the MEK inhibitor.

Some of these findings were previously reported at the ESMO World Congress on Gastrointestinal Cancer 2019 in Barcelona.

“The BEACON study provides a new standard of care in patients with previously treated BRAF V600E–mutant metastatic colorectal cancer,” Tabernero said. “The triplet regimen may have clinically relevant advantages over the doublet, but further follow-up will better define the relative benefits of the two regimens.”

Although the preliminary results suggest that the triplet elicits more and deeper responses than the doublet without reducing quality of life, Falcone thinks that researchers should move away from investigating this difference. Instead, he said, researchers should focus on other aspects of BRAF-mutant colorectal cancer. For example, “further studies are needed and/or are ongoing in the first line—in combination with immunotherapy; to take into account BRAF heterogeneity; to understand and overcome resistance.” –Catherine Caruso