A real world analysis of secondary BRAF variations after targeted therapy resistance in driver gene positive NSCLC

Secondary BRAF variations have been identified as a mechanism of resistance to tyrosine kinase inhibitors (TKIs) in patients with driver gene-positive NSCLC. Nevertheless, there is still a lack of consensus regarding the characteristics and subsequent treatment strategies for these patients. We retrospectively reviewed the medical records of patients with driver gene-positive NSCLC who received TKIs therapy at Zhejiang Cancer Hospital between May 2016 and December 2023. The clinical and genetic characteristics of these patients were assessed, along with the impact of various treatment strategies on survival. This study enrolled 27 patients with advanced NSCLC, in whom BRAF variations occurred at a median time of 28 months after the initiation of targeted therapy. The multivariate accelerated failure time (AFT) model revealed that, compared to chemotherapy-based regimens group, the combined targeted therapy group (p < 0.001) and the combined local treatment group for oligo-progression (p < 0.001) significantly extended patient survival. In contrast, continuing the original signaling pathway's targeted monotherapy was associated with shorter survival (p = 0.034). The median global OS for each treatment group was as follows: chemotherapy-based regimens group, 45 months; combined targeted therapy group, 59 months; combined local treatment group for patients with oligo-progression, 46 months; and targeted monotherapy group, 36 months. Study results indicate that the combination targeted therapy group (including TKIs, BRAF inhibitors, and/or MEK inhibitors) and the localized treatment group are more effective than traditional chemotherapy-based regimens in improving survival. Additionally, continuing targeted monotherapy along the original signaling pathway proves less effective than chemotherapy-based regimens.