Encorafenib Now Approved for BRAF-Positive Colorectal Cancer

The targeted agent encorafenib (Braftovi, Array BioPharma, now part of Pfizer) has been approved by the US Food and Drug Administration (FDA) for use in BRAF-positive colorectal cancer (CRC) and offers a subgroup of patients with CRC a chemotherapy-free treatment option.

Encorafenib is already approved for use in BRAF-positive metastatic melanoma.

The new approval is for the use of encorafenib in combination with another targeted agent, cetuximab (Erbitux, Lilly), a monoclonal antibody directed against EGFR, for the treatment of patients with metastatic CRC with a BRAF V600E mutation, as detected by an FDA-approved test, whose disease has progressed with previous therapy.

"BRAF mutations are estimated to occur in up to 15% of people with metastatic colorectal cancer and represent a poor prognosis for these patients," said Scott Kopetz, MD, PhD, FACP, associate professor of gastrointestinal medical oncology at the University of Texas MD Anderson Cancer Center, Houston.

"As the first and only targeted regimen for people with BRAF V600E–mutant metastatic CRC who have received prior therapy, encorafenib in combination with cetuximab is a much-needed new treatment option for these patients," he said in a press statement.

The approval is based on results from the BEACON trial, which were initially reported last year from the World Conference on Gastrointestinal Cancer (WCGC). The results were subsequently published in the New England Journal of Medicine (NEJM) and were reported by Medscape Medical News at that time.

At the WCGC, principal investigator Scott Kopetz, MD, PhD, from the University of Texas MD Anderson Cancer Center, commented that he was "pleased to report that really this is the first evidence of a survival benefit with a chemotherapy-free targeted therapy regimen in a prospective biomarker-defined subgroup, in this case BRAF V600E mutations in colorectal cancer.

"On the basis of this, we think it really defines a new standard of care," he added.

The BEACON results were described as practice changing in a Medscape video commentary by David Kerr, MD, professor of cancer medicine at the Oxford Cancer Center, United Kingdom.

However, the BEACON trial was fiercely criticized by Vinay Prasad, MD, MPH, hematologist/oncologist and assistant professor of medicine at Oregon Health and Science University in Portland, in his podcast Plenary Session.

Doublet vs Triplet Combo

When the BEACON results were first reported, it was a triplet combination that was being discussed as the new standard of care for this subgroup of patients with CRC. That triplet therapy consisted of encorafenib, cetuximab, and the MEK inhibitor binimetinib (Mektovi, Array BioPharma).

The new approval is for the doublet of encorafenib plus cetuximab.

Both the triplet and the doublet were tested in the BEACON trial, and both therapies were superior to the control arm of chemotherapy.

Lead author of the NEJM BEACON article, Josep Tabernero, MD, PhD, medical oncologist and director, Vall d'Hebron Institute of Oncology, Barcelona, Spain, told Medscape Medical News: "While this study was not designed to compare the triplet and doublet therapies, the doublet regimen might be sufficient for some patients."

Evidently, the FDA thought so, because it approved the doublet but not the triplet combination.

Details of the BEACON Study Results

BEACON was an open-label phase 3 trial that involved 665 patients with BRAF V600E–mutated metastatic CRC whose disease had progressed after one or two prior regimens.

The trial had three treatment arms. One group of patients received triplet therapy with three targeted agents ― encorafenib, binimetinib, and cetuximab.

Another group received doublet targeted therapy with encorafenib and cetuximab.

A third (control) group received standard chemotherapy (physician choice of cetuximab and irinotecan or cetuximab and FOLFIRI [folinic acid, fluorouracil, and irinotecan]).

The median overall survival (OS) was 9.0 months in the triplet-therapy group and 5.4 months in the control (chemo) group (hazard ratio [HR] for death, 0.52; 95% confidence interval [CI], 0.39 – 0.70; P < .001).

The median OS in the doublet-therapy group was 8.4 months (HR for death vs control, 0.60; 95% CI, 0.45 – 0.79; P < .001).

The objective response rate was 26% (95% CI, 18 – 35) in the triplet-therapy group vs 2% (95% CI, 0 – 7) in the control group (P < .001). It was 20% in the doublet-therapy group, which was also significantly higher than in the control group (P < .001).

Adverse events of grade 3 or higher occurred in 58% of patients in the triplet-therapy group, 50% in the doublet-therapy group, and 61% in the control group.

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