SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 13% of all new cancers and 21% of all cancer deaths. The American Cancer Society estimates that for 2025, about 226,650 new cases of lung cancer will be diagnosed and 124,730 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers and Adenocarcinoma is now the most frequent histologic subtype of lung cancer.
BRAF V600E mutations occur in approximately 1% to 2% of patients with NSCLC and define a biologically distinct subset for which targeted therapy has become a cornerstone of treatment. Dual inhibition of the MAPK pathway with BRAF and MEK inhibitors is currently recommended by clinical guidelines as the preferred first-line approach for patients with BRAF V600E–mutant metastatic NSCLC (mNSCLC), with immunotherapy and chemotherapy-based regimens serving as alternative options.
The Phase II PHAROS study (NCT03915951) is an ongoing, open-label, single-arm, multicenter trial designed to evaluate the efficacy and safety of Encorafenib (BRAFTOVI®) in combination with Binimetinib (MEKTOVI®) in patients with BRAF V600E–mutant mNSCLC. Eligible patients included both treatment-naïve individuals and those with prior systemic therapy for metastatic disease. All patients received oral Encorafenib 450 mg once daily plus oral Binimetinib 45 mg twice daily, administered in continuous 28-day cycles until disease progression, unacceptable toxicity, or treatment discontinuation.
The Primary endpoint of PHAROS was Objective Response Rate (ORR) as assessed by Independent Radiology Review (IRR), with separate analyses prespecified for treatment-naïve and previously treated cohorts. Key Secondary endpoints included Duration of Response (DOR), Progression-Free Survival (PFS), Overall Survival (OS), Disease Control Rate, Safety, and Tolerability. Exploratory analyses evaluated efficacy across clinically relevant subgroups, including smoking history.
A total of 98 patients were enrolled and treated, including 59 treatment-naïve and 39 previously treated patients. At the March 14, 2025 data cutoff, a small proportion of patients in both cohorts remained on active treatment, reflecting durable disease control in a subset of patients. Median treatment duration was substantially longer in the frontline cohort compared with previously treated patients, with more than 40% of treatment-naïve patients receiving therapy for longer than two years.
PHAROS met its Primary endpoint in both cohorts.
In treatment-naïve patients, the confirmed ORR by IRR was 75%, with responses demonstrating marked durability. Median Duration of Response was 40.0 months, and median PFS reached 30.4 months. After a median follow-up of more than four years for overall survival, median OS was 47.6 months, with an estimated 4-year OS rate of 49%, underscoring the potential for prolonged survival with frontline targeted therapy.
In the previously treated cohort, Encorafenib plus Binimetinib also demonstrated clinically meaningful activity. The ORR was 49%, with a median Duration of Response of 16.7 months. Median PFS was 9.3 months, and median OS was 22.7 months after nearly four years of follow-up. The estimated 4-year OS rate in this cohort was 31%.
Post hoc subgroup analyses suggested that clinical benefit was generally consistent across baseline characteristics. Notably, both PFS and OS were numerically longer in patients without a smoking history compared with those with a history of smoking, a finding that may be related to pharmacokinetic effects on Binimetinib exposure and warrants further investigation.
The safety profile observed with extended follow-up was consistent with prior analyses and with known toxicities associated with BRAF and MEK inhibition. Most treatment-related adverse events were low grade and manageable, with gastrointestinal symptoms, fatigue, and nausea among the most frequently reported. Rates of dose modification and discontinuation were similar across treatment lines, and no new safety signals emerged with longer-term exposure.
Although cross-trial comparisons should be interpreted cautiously, the Overall Survival outcomes observed in PHAROS compare favorably with historical data for targeted therapy in this population. Given that a significant proportion of patients with metastatic NSCLC may not receive subsequent lines of therapy, these findings emphasize the importance of selecting the most effective treatment upfront.
In conclusion, updated results from the PHAROS study demonstrate durable responses and sustained long-term survival with Encorafenib plus Binimetinib in patients with BRAF V600E–mutant mNSCLC. The depth and durability of benefit, particularly in treatment-naïve patients, further support this combination as a preferred first-line targeted therapy option and reinforce its role in the evolving treatment landscape for this molecularly defined NSCLC subgroup.
Updated Overall Survival Analysis From the Phase II PHAROS Study of Encorafenib Plus Binimetinib in Patients With BRAF V600E-Mutant Metastatic Non–Small Cell Lung Cancer. Johnson ML, Smit EF, Felip E, et al. J Clin Oncol. 2025;43:3706-3713
