Clinicogenomic features of non-small cell lung cancer patients with <i>BRAF</i> non-V600mutations.

e20519 Background: BRAF non-V600 alterations are uncommon in non-small cell lung cancer (NSCLC). Little is known about the clinical, genomic characteristics or preferred therapy for this population . We evaluated clinicogenomic features and outcomes in a real-world cohort of BRAF non -V600 NSCLC. Methods: Patients with BRAF non-V600 NSCLC undergoing CLIA next generation sequencing (NGS) at Indiana University between 2019 and 2024 were included and classified into class 2, class 3, and unclassified categories. Demographics and clinical outcomes were collected retrospectively. Kaplan-Meier method was used to assess progression free survival (PFS) and overall survival (OS). Results: Of the 738 patients with available NGS, 31 (4.2%) had pathogenic BRAF non-V600 mutations. Twelve (38.7%) had BRAF class 2, 16 (51.6%) had class 3, and 3 (9.7%) had unclassified mutations. The median age was 63 years and 51.6% was male. Most patients were White (n=28; 90%), smokers (n=27; 87%), with a median 40 pack-year history. The most common histology was adenocarcinoma (n=28; 90%). Metastatic disease was common (n=26; 83.8%), frequently seen at diagnosis (n=23; 88.5%), and commonly affected the brain (n=8; 30.8%). Detailed immune feature and genomic landscape were summarized in the table. Overall, median tumor mutation burden (TMB) was 9.5 mut/Mb and 70% had PD-L1 ≥1%. Twenty patients (64.5%) underwent systemic therapy for metastatic disease, with first-line treatments including immunotherapy-based regimens (n=14; 70%), targeted therapy (n=2; 10%), chemotherapy +/- antiangiogenic agent (n=4; 20%). Median PFS was 4.5 months, no statistical difference observed between treatment types. Five patients received BRAF targeted therapy (trametinib +/- dabrafenib) throughout their treatment, with a near complete response obtained in one BRAF class 3 case. In patients with metastatic disease, median OS was 19.7 months and 2-year OS was 31.6%. When stratified by unclassified BRAF , class 2, and class 3, median OS was 13.8, 9.7, and 23.4 months (p=0.49), with a 2-year OS of 0%, 22.5% and 44.1% (p=0.49), respectively. Conclusions: Here, we found that BRAF non-V600 NSCLC is more common in patients with smoking history, with the majority having positive PD-L1 and moderate to high TMB levels. The disease presents with early metastasis, particularly to the brain. Despite the trend toward better survival in BRAF class 3, the overall prognosis remains poor, underscoring urgent need for novel therapies. BRAF classificationImmune feature Class 2(n=12) Class 3(n=16) Unclassified(n=3) Median TMB (mut/Mb) 7.5 12.5 n/a Positive PD-L1 (≥1%) 11 (91.7%) 8 (53.3%)* 1 (33.3%) Common concurrent alterations KRAS 3 (25%) 5 (31.3%) 0 (0%) EGFR/HER2/MET 3 (25%) 3 (18.8%) 1 (33.3%) KEAP1/STK11 4 (33.3%) 11 (68.8%) 1 (33.3%) PIK3CA/PTEN/TSC1 2 (16.7%) 1 (6.3%) 1 (33.3%) MTAP 2 (16.7%) 1 (6.3%) 0 (0%) TP53 8 (66.7%) 14 (87.5%) 3 (100%) *15 patients had available PD-L1.