The U.S. Food and Drug Administration (FDA) has granted approval of a new indication for the EGFR inhibitor cetuximab (Erbitux) in combination with encorafenib (Braftovi) for the treatment of adults with metastatic colorectal cancer and a BRAF V600E mutation, as detected by an FDA-approved test, after prior therapy.
The safety of cetuximab (400 mg/m2 initial infusion, followed by 250 mg/m2 weekly) in combination with encorafenib (300 mg once daily) was evaluated in a randomized, open-label, active-controlled trial (BEACON CRC). Eligible patients had BRAF V600E–mutant metastatic colorectal cancer, as detected by an FDA-approved test, with disease progression after one or two prior regimens. Patients were randomly assigned 1:1:1 to one of the following treatment arms: encorafenib at 300 mg orally once daily in combination with cetuximab; encorafenib at 300 mg orally once daily in combination with cetuximab and binimetinib; or irinotecan with cetuximab or FOLFIRI (leucovorin, fluorouracil, irinotecan) with cetuximab.
The major efficacy outcome measure was overall survival. Overall and progression-free survival were assessed in all randomly assigned patients; objective response rate and duration of response were assessed in the subset of the first 220 patients included in the randomized portion of the encorafenib/cetuximab and control arm of the study.
A total of 220 patients were randomly assigned to the encorafenib/cetuximab arm and 221, to the control arm. The trial was conducted at more than 200 investigational sites in North America, South America, Europe, and the Asia-Pacific region.
In BEACON CRC, cetuximab plus encorafenib yielded a median overall survival of 8.4 months (95% confidence interval [CI] = 7.5–11.0 months), compared with 5.4 months (95% CI = 4.8–6.6 months) in the control arm (irinotecan with cetuximab or FOLFIRI with cetuximab, hazard ratio [HR] = 0.60, 95% CI = 0.45–0.79, P = .0003). Additionally, cetuximab plus encorafenib yielded an objective response rate of 20% (95% CI = 13%–29%) compared with 2% (95% CI = 0%–7%) for the control arm (P < .0001), and a median progression-free survival of 4.2 months (95% CI = 3.7–5.4 months) compared with 1.5 months for the control arm (95% CI = 1.4–1.7 months; HR = 0.40, 95% CI = 0.31–0.52, P < .0001).
The most common (≥ 25%) adverse reactions in patients receiving cetuximab in combination with encorafenib were fatigue, nausea, diarrhea, dermatitis acneiform, abdominal pain, decreased appetite, arthralgia, and rash. The labeling for cetuximab includes warnings and precautions for infusion reactions, cardiopulmonary arrest, pulmonary toxicity, dermatologic toxicity, hypomagnesemia and accompanying electrolyte abnormalities, and embryofetal toxicity.