Abstract
BACKGROUND: Non-small-cell lung cancer patients with BRAF(V600E) mutations benefit from targeted and (chemo-)immune therapy. However, treatment of BRAF(non-V600E) mutations poses substantial challenges due to biological heterogeneity, different clinicogenomic features and limited therapy outcome data. MATERIALS AND METHODS: We conducted a retrospective analysis of BRAF(non-V600E) mutation patients in the national Network Genomic Medicine Lung Cancer, assessing treatment outcomes upon targeted and (chemo-)immune therapy. Additionally, we evaluated mitogen-activated protein kinase (MEK)/extracellular-signal-regulated kinase (ERK) activation potential of selected, previously not characterized mutations in vitro. RESULTS: Fifty-three patients with 11 different BRAF(non-V600E) mutations undergoing targeted and/or (chemo-)immune therapy were identified. Patients with class I mutations achieved the longest progression-free survival (PFS) under targeted therapy [median PFS (mPFS) 9.8 months], whereas chemotherapy and chemoimmunotherapy led to an mPFS of 35 and 27 months, respectively. In patients with class II mutations, targeted therapy led to an mPFS of 6.3 months while chemotherapy, chemoimmunotherapy and immunotherapy resulted in an mPFS of 3.5, 3.7 and 3.6 months, respectively. Preclinical characterization demonstrated MEK phosphorylation potential and hence actionability of BRAF class II mutations G469A, G469R, G469V and BRAF K601. Patients exhibiting class III mutations did not respond to targeted therapy (mPFS 2.6 months), but showed responses to chemotherapy (mPFS 4.2 months), chemoimmunotherapy (mPFS 10.9 months) and immunotherapy (mPFS 7 months). CONCLUSIONS: Patients with activating BRAF(non-V600E) mutations respond to BRAF/MEK inhibitor or (chemo-)immunotherapy, while those with non-activating mutations do not benefit from targeted therapy, but may benefit from (chemo-)immune therapy. Correlating preclinical activation assays with clinical outcomes can guide treatment decisions for patients with BRAF(non-V600E) mutations, facilitating personalized treatment approaches.