Pfizer's combination therapy BRAFTOVI (encorafenib) plus MEKTOVI (binimetinib) has demonstrated unprecedented long-term survival outcomes in patients with BRAF V600E-mutant metastatic non-small cell lung cancer (mNSCLC), according to updated results from the Phase 2 PHAROS trial presented at the 2025 European Society for Medical Oncology Congress and published simultaneously in the Journal of Clinical Oncology.
Landmark Survival Results
In treatment-naïve patients, the median overall survival reached 47.6 months (95% confidence interval, 31.3, not estimable) after a median follow-up of 52.3 months. Previously treated patients achieved a median overall survival of 22.7 months (95% CI, 14.1, 32.6) following a median follow-up of 48.2 months.
The four-year overall survival rates were 49% (95% CI, 35, 62) for treatment-naïve patients and 31% (95% CI, 16, 47) for previously treated patients, representing what investigators describe as the longest survival observed in people with treatment-naïve metastatic NSCLC harboring a BRAF V600E mutation.
"The PHAROS trial results set a new standard for NSCLC patients with the BRAF V600E mutation, with survival outcomes nearing four years—the longest survival we've seen in people with treatment-naïve metastatic NSCLC who harbor a BRAF V600E mutation," said Melissa Johnson, M.D., Director of Lung Cancer Research at Sarah Cannon Research Institute and PHAROS investigator.
Clinical Trial Design and Efficacy
The PHAROS trial (NCT03915951) is an open-label, multicenter, single-arm study examining the BRAFTOVI plus MEKTOVI combination in both treatment-naïve and previously treated patients with BRAF V600E-mutant metastatic NSCLC. The combination was approved by the U.S. Food and Drug Administration in October 2023 and by the European Commission in August 2024 based on initial efficacy results.
The objective response rate, which served as the primary endpoint, was 75% (95% CI: 62, 85) for treatment-naïve patients (n=59) and 46% (95% CI: 30, 63) for previously treated patients (n=39).
Safety Profile Remains Consistent
The safety profile of BRAFTOVI plus MEKTOVI remained consistent with previous findings. The most common treatment-related adverse events occurring in 30% or more of patients were nausea (52%), diarrhea (44%), fatigue (33%), and vomiting (30%).
Serious adverse reactions occurred in 38% of patients receiving the combination therapy. The most frequent serious adverse reactions (≥2% of patients) included hemorrhage (6%), diarrhea (4.1%), anemia (3.1%), dyspnea (3.1%), pneumonia (3.1%), arrhythmia (2%), device-related infection (2%), edema (2%), myocardial infarction (2%), and pleural effusion (2%). Fatal adverse reactions occurred in 2% of patients, including intracranial hemorrhage (1%) and myocardial infarction (1%).
Addressing an Unmet Medical Need
BRAF V600E mutations occur in approximately 2% of NSCLC cases but represent about half of all BRAF-mutant metastatic NSCLC. Prior to the development of targeted treatments, patients with BRAF V600E-mutant metastatic NSCLC had poor outcomes with standard chemotherapy.
"These long-term survival results reinforce Pfizer's unwavering commitment to improving outcomes in lung cancer," said Jeff Legos, Chief Oncology Officer, Pfizer. "The findings provide hope for treatment-naïve BRAF V600E mNSCLC patients and their families and underscore the importance of advancing therapies that can provide a sustained impact for patients."
Mechanism of Action and Market Access
BRAFTOVI is an oral small molecule kinase inhibitor that targets BRAF V600E, while MEKTOVI is an oral small molecule MEK inhibitor. Both drugs target key proteins in the MAPK signaling pathway (RAS-RAF-MEK-ERK), where inappropriate activation has been shown to occur in certain cancers, including melanoma, colorectal cancer, and NSCLC.
Pfizer holds exclusive rights to BRAFTOVI plus MEKTOVI in the U.S., Canada, Latin America, Middle East, and Africa. Ono Pharmaceutical Co., Ltd. has exclusive rights in Japan and South Korea, Medison has exclusive rights in Israel, and Pierre Fabre Laboratories has exclusive rights in all other countries, including Europe and Asia (excluding Japan and South Korea).
Clinical Context
Lung cancer remains the leading cause of cancer-related deaths worldwide, with NSCLC accounting for approximately 80-85% of all lung cancers. Despite advances in precision medicine, unmet needs persist for advanced disease. Approximately one in six patients with advanced NSCLC have no biomarker testing results prior to first-line treatment, and among tested patients, many do not receive targeted therapy or have limited options available.
