Triplet therapy could benefit patients with BRAF-mutant metastatic colorectal cancer

Results presented today at the ESMO Congress 2019, Barcelona 27 September - 01 October, during the second Proffered Paper Session on Gastrointestinal tumors (colorectal) by VHIO's Director, Josep Tabernero, show that the triplet combination of the BRAF inhibitor, encorafenib, MEK inhibitor, binimetinib, and EGFR inhibitor, cetuximab, not only significantly improves overall survival but also increases objective response rates compared with standard of care in patients with BRAF V600E-mutant metastatic colorectal cancer.

This phase III multicenter study, also counting on the expertise of VHIO co-author Elena Élez, Medical Oncologist and Clinical Investigator of our Gastrointestinal & Endocrine Tumors Group (led by Teresa Macarulla and directed by Josep Tabernero), published in parallel as an Original Article in The New England Journal of Medicine.

Inhibition of BRAF, a gene that produces the B-RAF protein implicated in sending signals in cells and cell growth, has shown promise in improving survival of patients across certain tumor types including melanoma. BRAF blockade as monotherapy has not proven effective in the treatment of colorectal cancer.

BRAF inhibition alone in colorectal cancer has limited activity because of pathway reactivation through epidermal growth factor receptor signaling. This does not occur in melanoma, for example.

Preclinical models of BRAF V600E-mutant colorectal cancer have shown that BRAF inhibition leads to the rapid activation of EGFR. Treatment with BRAF inhibitors as monotherapy does not sufficiently block pathway signaling, which explains the resistance of most colon cancers despite the presence of the BRAF V600E mutation."

Josep Tabernero, ESMO and ESMO Congress President, Corresponding and Senior Author of this study

This present BEACON CRC randomized, open-label, 3-arm phase III study evaluated the combination of encorafenib plus cetuximab with or without binimetinib towards improving outcomes for this particular patient population. "Our study included patients with BRAF V600E-mutant metastatic colorectal cancer who had had disease progression after one or two previous regimens", noted co-author Elena Élez.

She added, "This BRAF mutation occurs in around 8-12% of colorectal cancer patients with a poor prognosis. While the number of patients who could benefit from this triple combination might be relatively few, we must continue to identify this sub-population baring this mutation, and seek to improve outcomes for these patients."

655 patients were enrolled and randomly assigned to receive triplet therapy with encorafenib, binimetinib and cetuximab, doublet therapy with encorafenib and cetuximab, or the investigators' choice of either cetuximab and irinotecan or cetuximab and FOLFIRI (folinic acid, fluorouracil, and irinotecan).

Results showed significant clinical benefits with median overall survival of 9.0 months in the triplet group, 8.4 months in the doublet, and 5.4 months in the control arm. Regarding response rates, the researchers confirmed 26% in the triplet and 2% in the control. Importantly, tolerability of this novel combination was favorable.

"Our findings point to a potential paradigm shift in the treatment of this disease, and certainly warrant further investigation to better define the benefits of both the triplet and doublet combinations," concluded Josep.