FDA Grants Priority Review to the sNDA for Encorafenib in Combination with Cetuximab

The FDA has accepted and granted priority review to the supplemental new drug application (sNDA) for encorafenib (Braftovi) in combination with cetuximab (Erbitux; Braftovi doublet) for the treatment of patients with unresectable or metastatic melanoma with a BRAF^V600E or BRAF^V600K mutation, according to Pfizer, the developer of the drug.¹

The application is based on results from the phase III BEACON CRC trial, which evaluated the efficacy and safety of encorafenib in combination with cetuximab with or without binimetinib (MEKTOVI) in patients with advanced BRAF^V600E-mutant metastatic colorectal cancer (mCRC), following 1 or 2 lines of therapy. 

Results from the trial were published in The New England Journal of Medicine (NEJM), and showed improvements in overall survival (OS) and objective response rates (ORR) for both the doublet (encorafenib and cetuximab) and triplet (encorafenib, cetuximab, and binimetinib) combination, compared to cetuximab plus irinotecan-containing regimens (control). 

“Currently there are no FDA-approved treatments specifically for patients with BRAF-mutant mCRC who have received prior treatment,” Chris Boshoff, MD, PhD, Chief Development Officer for Oncology at Pfizer Global Product Development, said in a press release. “If approved, the BRAFTOVI Doublet would become the first targeted regimen for this patient population, who typically have a poor prognosis. We also look forward to continuing to explore this targeted Doublet regimen with or without MEKTOVI in earlier lines of BRAF-mutant mCRC, including in the ongoing, phase II ANCHOR study in previously untreated patients.” 

The primary overall survival endpoint for the phase III BEACON CRC trial is a comparison of the triplet combination to the control arm. Secondary endpoints look to address efficacy of the doublet combination compared to the control arm, and the triplet combination compared to the doublet therapy. Other secondary endpoints include progression-free survival, duration of response, safety, and tolerability.

Interim analysis results showed a median OS of 9.0 months for patients treated with the triplet, compared to 5.4 moths for control (HR, 0.52; 95% CI, 0.39-0.70; P < .0001).² The triplet also demonstrated a significantly improved ORR of 26% (95% CI, 28-35) compared to 2% for control (95% CI, 0-7; P < .0001).

Improvements were also indicated for secondary efficacy endpoints. The doublet showed a statistically significant improvement in OS (median, 8.4 months vs 5.4 months; HR, 0.60; 95% CI, 0.45-0.79; P = 0.0003) compared to control. 

Both the triplet and doublet were generally well-tolerated with no unexpected toxicities. Grade 3 or higher adverse events (AEs) were seen in 58%, 50% and 61% of patients in the triplet, doublet, and control arms, respectively. The most common grade 3 or higher AEs reported in patients treated with the triplet were diarrhea (10% vs 2% in the doublet arm and 10% in the control arm), abdominal pain (6% vs 2% in the doublet arm and 5% in the control arm) and nausea (5% vs <1% in the double arm and 1% in the control arm). 

The trial is being conducted at over 200 investigational sites in North America, South America, Europe, and the Asia Pacific region. 

References:

1. U.S. FDA ACCEPTS AND GRANTS PRIORITY REVIEW TO SNDA FOR BRAFTOVI® (ENCORAFENIB) IN COMBINATION WITH ERBITUX® (CETUXIMAB) (BRAFTOVI DOUBLET) FOR THE TREATMENT OF BRAFV600E-MUTANT METASTATIC COLORECTAL CANCER AFTER PRIOR THERAPY [news release]. Published December 18, 2019. pfizer.com/news/press-release/press-release-detail/u_s_fda_accepts_and_grants_priority_review_to_snda_for_braftovi_encorafenib_in_combination_with_erbitux_cetuximab_braftovi_doublet_for_the_treatment_of_brafv600e_mutant_metastatic_colorectal_cancer_after_prior. Accessed December 18, 2019.

2. PFIZER PRESENTS INTERIM ANALYSIS RESULTS FROM PHASE 3 BEACON CRC TRIAL OF BRAFTOVI® (ENCORAFENIB), MEKTOVI® (BINIMETINIB) AND CETUXIMAB FOR THE TREATMENT OF BRAFV600E-MUTANT METASTATIC COLORECTAL CANCER. Published September 30, 2019. pfizer.com/news/press-release/press-release-detail/pfizer_presents_interim_analysis_results_from_phase_3_beacon_crc_trial_of_braftovi_encorafenib_mektovi_binimetinib_and_cetuximab_for_the_treatment_of_brafv600e_mutant_metastatic_colorectal_cancer. Accessed December 18, 2019.