First-line immunotherapy with or without chemotherapy versus BRAF plus MEK inhibitors for patients with BRAFV600E-mutated metastatic non-small cell lung cancer: The FRONT-BRAF study
Recommended Citation
Di Federico A, Wang K, Chen MF, Barsouk A, Pagliaro A, Chen LN, Ogliari F, Stockhammer P, Thawani R, Raslan S, Gariazzo E, Fusco F, Hambelton G, Citarella F, Meyer D, Corassa M, Langer CJ, Offin M, Negrao MV, Ricciuti B. First-line immunotherapy with or without chemotherapy versus BRAF plus MEK inhibitors for patients with BRAFV600E-mutated metastatic non-small cell lung cancer: The FRONT-BRAF study. J Clin Oncol 2025; 43(16 Suppl).
Document Type
Conference Proceeding
Publication Date
5-28-2025
Publication Title
J Clin Oncol
Abstract
Background: Patients (pts) with BRAFV600E mutated non-small cell lung cancer (NSCLC) can be effectively treated with BRAF and MEK inhibitors (BRAFi+MEKi) or with immune checkpoint inhibitors ± chemotherapy (ICI±CT). Which one should be prioritized as initial systemic treatment in this population remains unclear. Methods: Clinicopathologic data were collected from pts with metastatic BRAFV600E mutated NSCLC treated with 1st line ICI6CT or BRAFi+MEKi between 2015 and 2024 at 17 centers across the United States, Europe, and Brazil. Results: Of 284 patients, 88 received ICI6CT and 196 received BRAFi+MEKi. Compared to pts treated with BRAFi+MEKi, pts receiving ICI6CT were more likely to have a history of smoking (83% vs. 61%, P<0.001) and a higher median PD-L1 tumor proportion score (TPS) (68% vs 30%, P<0.001). ICI6CT, compared to BRAFi+MEKi, was associated with a lower objective response rate (ORR, 49% vs 63%, P=0.03), similar median progression-free survival [mPFS, 9.6 vs.12.2 months (mo.), HR 1.13, P=0.43], but significantly improved median overall survival (mOS, 40.9 vs 25.1 mo., HR 0.69, P=0.039), even after adjusting in a multivariable model (HR 0.66, P=0.02). Consistent results were observed in a propensity score-matched cohort (1:1 ratio, N=75 pts per treatment group), where ICI6CT, compared to BRAFi+MEKi, was associated with improved mOS (40.9 vs 22.7 mo., HR 0.63, P=0.04), but similar ORR and mPFS. In key subgroup analyses, ICI6CT, compared to BRAFi+MEKi, was associated with longer mOS in pts with a history of tobacco smoking (HR 0.60, P=0.01), PD-L1 TPS ≥1% (HR 0.66, P=0.039), and without brain metastases (HR 0.66, P=0.045). A shorter mPFS was noted in pts without tobacco smoking history (HR 1.94, P=0.03). In evaluating genomic correlates of treatment efficacy, pts with TP53 co-mutations (N=107) had worse outcomes compared to pts with wild-type TP53 (N=121) when treated with BRAFi+MEKi, including shorter mPFS (HR 1.67, P=0.01) andmOS(HR 1.77, P=0.01), but not with ICI6CT. Notably, pts with TP53 co-mutations had longer mOS with ICI6CT compared to BRAFi+MEKi (48.4 vs 18.8 mo., HR 0.46, P=0.005). In contrast, pts with IDH1 co-mutations (N=9) had worse outcomes compared to pts with wild-type IDH1(N=188) when treated with ICI6CT, including shorter mPFS (HR 4.04, P=0.03) and mOS (HR 6.12, P=0.007), as well as shorter mPFS with BRAFi+MEKi (HR 2.73, P=0.03). Safety of BRAFi+MEKi was comparable whether administered as 1st line or as 2nd line therapy following ICI±CT, with similar rates of adverse events of any grade (71% vs 76%, P=0.58) and grade ≥3 (22% vs 23%, P=0.92). Conclusions: Initial therapy with ICI±CT, compared to BRAFi+MEKi, showed a lower ORR, similar PFS, but superior OS, particularly among specific subgroups of pts. A prospective evaluation of the optimal 1st-line therapy for this population is warranted.
Volume
43
Issue
16 Suppl
