First-line immunotherapy with or without chemotherapy versus BRAF plus MEK inhibitors for patients with BRAF ^V600E -mutated metastatic non-small cell lung cancer: The FRONT-BRAF study.

Abstract

8574 Background: Patients (pts) with BRAF V600E 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 BRAF V600E mutated NSCLC treated with 1 st line ICI±CT or BRAFi+MEKi between 2015 and 2024 at 17 centers across the United States, Europe, and Brazil. Results: Of 284 patients, 88 received ICI±CT and 196 received BRAFi+MEKi. Compared to pts treated with BRAFi+MEKi, pts receiving ICI±CT 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). ICI±CT, 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 ICI±CT, 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, ICI±CT, 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) and mOS (HR 1.77, P =0.01), but not with ICI±CT. Notably, pts with TP53 co-mutations had longer mOS with ICI±CT 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 ICI±CT, 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 1 st line or as 2 nd 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.