Encorafenib (Braftovi) combined with binimetinib (Mektovi) has shown promising anti-tumor activity in patients with treatment-naïve BRAF V600E-mutant advanced non-small cell lung cancer (NSCLC). These findings were presented at the 2024 ESMO Congress from the phase 2 ENCO-BRAF study (NCT04526782).
The study's results indicate a potential new treatment avenue for this specific NSCLC subgroup. The investigator-assessed overall response rate (ORR) was 65.6% (95% CI, 53.7%-77.5%) in cohort A, comprising 61 previously untreated patients. Specifically, 40 patients experienced partial responses.
Efficacy and Outcomes
The ENCO-BRAF trial was designed to test the hypothesis that the overall response rate would exceed 60% in treatment-naïve patients. According to Dr. David Planchard, a thoracic oncologist at Gustave Roussy, 64 patients were included in the first-line treatment analysis by the March 2024 data cutoff.
The median duration of response (DOR) was 13 months (95% CI, 9.1 months-not reached), and the disease control rate (DCR) was 85.2% (95% CI, 76.3%-94.1%). The median progression-free survival (PFS) was 10.9 months (95% CI, 6.4-16.7 months), while the median overall survival (OS) was not reached (95% CI, 20.7-NR).
Study Design and Patient Population
This ongoing phase 2, open-label, single-arm study enrolled patients with BRAF V600E-mutant NSCLC who received 450 mg of encorafenib once daily along with 45 mg of binimetinib twice daily. Cohort A consisted of previously untreated patients, while cohort B included patients pretreated with one prior line of therapy.
Key inclusion criteria were an age of 18 years or older, a WHO performance status of 0 or 1, confirmed BRAF V600E mutation, and no prior anti-BRAF cancer therapy. Stable central nervous system metastases were permitted. Between March 2021 and September 2023, 64 patients were enrolled in cohort A across 24 centers in France. The median age was 70.7 years, with 17.2% having baseline brain metastases, 46.9% being male, and 35.9% being never smokers.
The primary endpoint was the investigator-assessed confirmed ORR per RECIST v1.1, evaluated every 8 weeks for the first 12 months and then every 12 weeks thereafter. Secondary endpoints included DOR, DCR, PFS, OS, and safety.
Safety Profile
The most common treatment-related adverse events (TRAEs) were fatigue (42.2%), nausea (32.8%), and diarrhea (31.3%). Overall, 92.2% of patients experienced any grade TRAEs, with 50.0% experiencing grade 3 or higher TRAEs. Dose interruptions for encorafenib and binimetinib occurred in 32.8% and 35.9% of patients, respectively. Permanent discontinuation due to TRAEs occurred in 9.4% of patients, and death occurred in 3.1%, with one case attributed to treatment-related dyspnea.
Implications and Future Directions
According to Dr. Planchard, the ENCO-BRAF trial, along with the PHAROS trial, suggests that encorafenib plus binimetinib could be a valuable new option for patients with BRAF V600E-mutant advanced NSCLC. The study is still enrolling patients for cohort B to assess the efficacy in second-line treatment.
