FDA Accepts sNDAs for Encorafenib Combo in BRAF V600E+ Metastatic NSCLC

The FDA has accepted supplemental new drug applications (sNDAs) for encorafenib (Braftovi) plus binimetinib (Mektovi) for the treatment of patients with metastatic non–small cell lung cancer (NSCLC) harboring a BRAF V600E mutation detected via an FDA-approved test, according to a press release from Pfizer.¹

"Through our comprehensive development program, the [encorafenib] and [binimetinib] combination has shown the potential to help more patients, such as those living with BRAF V600E–mutant [NSCLC],” according to the manufacturers of encorafenib and binimetinib.

The Prescription Drug User Fee Act date for a decision on these applications has been set for the fourth quarter of 2023.

Supporting data for these applications came from the phase 2 PHAROS trial (NCT03915951), in which investigators assessed the efficacy, safety, and tolerability of encorafenib and binimetinib in those with BRAF V600E-mutant metastatic NSCLC. In the trial, the regimen met the primary end point of objective response rate.

Investigators will present detailed results from the PHAROS trial at a future scientific congress.

“Through our comprehensive development program, the [encorafenib] and [binimetinib] combination has shown the potential to help more patients, such as those living with BRAF V600E–mutant [NSCLC],” Chris Boshoff, MD, PhD, chief development officer of Oncology and Rare Disease at Pfizer Global Product Development, said in the press release. “These sNDAs build on Pfizer’s long heritage of meeting the diverse needs of [patients] with NSCLC, and we look forward to working with the FDA on their review of these applications.”

Encorafenib and binimetinib, respectively, are oral small molecule BRAF kinase and MEK inhibitors that target key proteins in the MAPK signaling pathway. Investigators believe that inappropriate activation of this pathway is known to occur in several cancers including NSCLC.

The open-label, multi-center, non-randomized phase 2 PHAROS study evaluated encorafenib and binimetinib combination therapy in 98 patients with BRAF V600E–mutant metastatic NSCLC. Investigators conducted the trial across 5 treatment sites in Italy, 2 sites in the Netherlands, 3 sites in South Korea, 4 sites in Spain, and 39 sites in the United States.

Patients received 450 mg of encorafenib capsules once daily plus 45 mg of binimetinib tablets twice daily every 28-day cycle.

Secondary end points of the PHAROS trial included duration of response, disease control rate, progression-free survival, overall survival, adverse effects, and time to tumor response.

Patients 18 years or older who had a histologically confirmed diagnosis of stage IV NSCLC and presence of a BRAF V600E mutation in lung cancer tissue as determined by a local laboratory assay were eligible for enrollment on the trial. Additional inclusion criteria included having measurable disease per RECIST v1.1 criteria, an ECOG performance status of 0 or 1, adequate bone marrow function, and adequate hepatic and renal function.

Patients who had disease harboring an EGFR mutation, ALK fusion, or ROS1 rearrangement were not eligible for enrollment. Patients were also unsuitable for enrollment if they had received more than 1 prior line of systemic therapy in the advanced or metastatic setting, previous treatment with a BRAF inhibitor, had impaired cardiovascular function, or concurrent neuromuscular disorder associated with the potential of elevated creatine phosphokinase. Symptomatic brain metastasis or any other active central nervous system metastases were also grounds for exclusion.

The FDA previously approved encorafenib plus cetuximab (Erbitux) for adult patients with BRAF V600E–mutant metastatic colorectal cancer (CRC) as detected by an FDA-approved test in April 2020.² The approval was supported by data from the phase 3 BEACON CRC study (NCT02928224). Moreover, the FDA expanded the label for cetuximab injections and encorafenib for patients with BRAF V600E–mutant metastatic CRC in September 2021.³

References

1. FDA accepts Pfizer’s supplemental new drug applications for Braftovi + Mektovi. News release. Pfizer. April 4, 2023. Accessed April 5, 2023. bit.ly/40KoC2S
2. FDA approves encorafenib in combination with cetuximab for metastatic colorectal cancer with a BRAF V600E mutation. News release. FDA. April 9, 2020. Accessed April 5, 2023. bit.ly/3MoxWp3
3. FDA expands Lilly's ERBITUX® (cetuximab) label with combination of BRAFTOVI® (encorafenib) for the treatment of BRAF V600E mutation-positive metastatic colorectal cancer (CRC) after prior therapy. News release. Eli Lilly. September 28, 2021. Accessed April 5, 2023. https://bit.ly/3ied9nV