Highlights
- Encorafenib plus binimetinib yields high confirmed objective response rates (75% in treatment-naïve; 46% in previously treated) in BRAF V600E-mutant metastatic NSCLC.
- Updated median overall survival (mOS) reaches 47.6 months in treatment-naïve patients, representing the longest mOS reported with targeted therapy in this population.
- The combination’s safety profile is consistent, with manageable adverse events predominantly comprising gastrointestinal symptoms and fatigue.
- Durable responses and prolonged progression-free survival (PFS) underscore the efficacy of dual BRAF/MEK inhibition, supporting its FDA-approved use in this subset of NSCLC patients.
Background
Non-small cell lung cancer (NSCLC) remains a leading cause of cancer mortality worldwide. Within this heterogeneous disease, BRAF V600E mutations occur in approximately 1–2% of metastatic cases, driving constitutive MAPK pathway activation and oncogenesis. Historically, treatment options for BRAF-mutant NSCLC were limited, with chemotherapy and immunotherapy showing variable efficacy. The advent of targeted therapies against BRAF and downstream MEK kinases has transformed management paradigms, inspired by successes in melanoma. Encorafenib (a BRAF inhibitor) combined with binimetinib (a MEK inhibitor) offers a rational therapeutic strategy to overcome resistance mechanisms and improve clinical outcomes. The Phase II PHAROS study was designed to evaluate this regimen’s efficacy and safety in patients with BRAF V600E-mutant metastatic NSCLC, both treatment-naïve and previously treated, addressing a significant unmet need in precision oncology.
Key Content
Study Design and Patient Population
The PHAROS trial (NCT03915951) is a multicenter, open-label, single-arm Phase II study enrolling 98 patients diagnosed with BRAF V600E-mutant metastatic NSCLC. Among these, 59 were treatment-naïve, and 39 had received prior systemic therapy. Patients received oral encorafenib 450 mg once daily plus binimetinib 45 mg twice daily in continuous 28-day cycles. The primary endpoint was the confirmed objective response rate (ORR) evaluated by independent radiology review (IRR). Secondary endpoints included duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), time to response, and safety assessments.
Efficacy Outcomes and Updated Survival Analyses
Initial results reported an ORR of 75% (95% CI, 62–85) in treatment-naïve patients and 46% (95% CI, 30–63) in previously treated patients, demonstrating significant tumor shrinkage and disease control. Median DOR was not estimable in treatment-naïve patients (95% CI, 23.1 months to NE), compared to 16.7 months in previously treated patients. Median PFS was not estimable for treatment-naïve patients (95% CI, 15.7 months to NE), and 9.3 months for previously treated patients.
With extended follow-up (median OS follow-up 52.3 months for treatment-naïve; 48.2 months for previously treated), updated analyses revealed median OS of 47.6 months (95% CI, 31.3 to NE) for treatment-naïve patients and 22.7 months (95% CI, 14.1 to 32.6) for previously treated patients. Four-year OS probabilities were 49% for treatment-naïve and 31% for previously treated groups, respectively. The median duration of treatment extended to 16.3 months and 5.5 months in treatment-naïve and previously treated, highlighting sustained clinical benefit. Notably, over half of the treatment-naïve patients received subsequent systemic anticancer therapy, reflecting integrated multi-line management.
Safety and Tolerability
The safety profile of encorafenib plus binimetinib was consistent with prior reports and class effects of BRAF and MEK inhibitors. The most frequent treatment-related adverse events (TRAEs) included nausea (52%), diarrhea (44%), fatigue (33%), and vomiting (30%). Dose reductions due to TRAEs occurred in 26% of patients, and permanent discontinuations were necessary in 16%. One grade 5 treatment-related intracranial hemorrhage was reported. These findings underscore the importance of proactive management of gastrointestinal toxicities and patient monitoring.
Mechanistic Rationale and Translational Insights
BRAF V600E mutations lead to constitutive activation of the MAPK signaling cascade, promoting cellular proliferation and survival. Monotherapies targeting BRAF often induce rapid feedback activation of MEK and ERK, resulting in secondary resistance. Combined BRAF and MEK inhibition effectively suppresses pathway reactivation, improving response durability. Encorafenib’s pharmacodynamics, characterized by prolonged target inhibition and sustained therapeutic levels, combined with binimetinib’s complementary MEK blockade, enhance pathway suppression and tumor control. These mechanistic insights justify the combination approach and potential for overcoming resistance observed with single-agent BRAF inhibitors.
Expert Commentary
The PHAROS study marks a significant advancement in the personalized treatment of BRAF V600E-mutant metastatic NSCLC. Achieving an ORR of 75% in treatment-naïve patients and a median OS approaching four years is unprecedented for targeted therapies in this NSCLC subset, often characterized by aggressive clinical behavior and limited therapeutic options.
These results align with findings from earlier melanoma studies, reinforcing the therapeutic paradigm of combined BRAF and MEK inhibition. However, the single-arm design necessitates cautious interpretation; randomized trials comparing encorafenib plus binimetinib with standard chemotherapy or immunotherapy are warranted to define definitive comparative efficacy.
The safety profile, although manageable, requires vigilance for gastrointestinal and dermatologic adverse events, and rare but serious toxicities. Future research should explore biomarkers predictive of response and resistance mechanisms to optimize patient selection and sequence therapies.
Clinical guidelines, including NCCN and ESMO, are increasingly incorporating BRAF/MEK inhibitors in management algorithms for this molecularly defined NSCLC subset. The encouraging durability of responses observed in PHAROS supports this trend and may inform frontline therapeutic decisions, particularly for patients ineligible or refractory to immunotherapy.
Conclusion
The Phase II PHAROS study provides robust evidence supporting the clinical benefit of encorafenib plus binimetinib in BRAF V600E-mutant metastatic NSCLC. The combination achieves meaningful ORRs, durable responses, and unprecedented survival outcomes in a population with a historically poor prognosis. Safety data affirm a manageable profile consistent with class effects. These findings exemplify the value of molecularly targeted therapy in precision oncology and underscore the necessity for ongoing trials to further optimize treatment strategies and improve patient outcomes in this rare molecular subgroup.
References
- Johnson ML, Smit EF, Felip E, Ramalingam SS, Ahn MJ, Tsao A, et al. 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. J Clin Oncol. 2025 Dec 10;43(35):3706-3713. doi:10.1200/JCO-25-02023. PMID:41109959.
- Riely GJ, Ahn MJ, Clarke JM, Dagogo-Jack I, Esper R, Felip E, et al. Updated Efficacy and Safety From the Phase 2 PHAROS Study of Encorafenib Plus Binimetinib in Patients With BRAF V600E-Mutant Metastatic NSCLC–A Brief Report. J Thorac Oncol. 2025 Oct;20(10):1538-1547. doi:10.1016/j.jtho.2025.05.023. PMID:40480428.
- Riely GJ, Smit EF, Ahn MJ, Felip E, Ramalingam SS, Tsao A, et al. Phase II, Open-Label Study of Encorafenib Plus Binimetinib in Patients With BRAFV600-Mutant Metastatic Non-Small-Cell Lung Cancer. J Clin Oncol. 2023 Jul 20;41(21):3700-3711. doi:10.1200/JCO.23.00774. PMID:37270692.
