Treatment sequences in BRAF-V600-mutated non-small cell lung cancer: First-line targeted therapy versus first-line (chemo-) immunotherapy.

Background: Targeted treatment of patients with metastatic BRAF-V600-mutated non-small-cell lung cancer (NSCLC) using BRAF/MEK-inhibitors is effective but limited by acquired resistance. Patients with BRAF-mutant NSCLC may derive long-lasting benefit from immune checkpoint inhibition with PD-1/-L1 antibodies (IO). While IO is the preferred first-line therapy in BRAF-mutated melanoma, the optimal treatment sequence in BRAF-mutated NSCLC is not defined.

Methods: Retrospective study of the clinical outcome of patients with metastatic BRAF-V600-mutated NSCLC diagnosed in the German national Network Genomic Medicine Lung Cancer (nNGM).

Results: We identified 205 patients with BRAF-V600-mutated NSCLC. 175 patients received first-line therapy with dabrafenib/trametinib (DAB/TRM, 65.1%), IO alone (19.4%), or chemo-IO (15.4%). Overall survival (OS) and time-to-treatment failure of first-line therapy (TTF) was identical for patients receiving first-line DAB/TRM (median OS 28.0 months) or chemo/IO (27.8 months, HR 1.1, p=0.68). Female patients had superior OS (HR 0.65, p=0.049, confirmed in multivariate model), which was mainly driven by superior OS of female versus male patients receiving first-line DAB/TRM (OS HR 0.53, p=0.015). There was no gender difference in survival of patients receiving IO-based first-line treatment (OS HR 1.02). Surprisingly, high PD-L1 status (TPS ≥50%) associated with shortened time-to-treatment failure in first-line (HR 1.83, p=0.002, confirmed in multivariate models adjusting for gender; OS with non-significant trend, HR 1.4), regardless of whether the first-line regimen was IO-based or targeted therapy.

Conclusions: Targeted or IO-based first-line treatment of BRAF-V600-mutated NSCLC have similar survival outcomes. Gender and PD-L1 status may support decision making at the individual patient level.