MA09.07 Genomic Landscape and Clinical Outcomes With Immune Checkpoint Inhibitors in NF1-Mutant NSCLC

NF1 encodes for neurofibromin 1, a RAS GTPase-activating protein (GAP) that regulates nucleotide cycling and when inactivated can promote aberrant signaling carcinogenesis. Deleterious mutations have been previously reported in non-small cell lung cancer (NSCLC), particularly current/former smokers, but the genomic landscape of this molecular subgroup remains incompletely characterized. Furthermore, clinical outcomes NF1-mutant (NF1-mut) NSCLC upon treatment with immune checkpoint inhibitors (ICI) remain unknown. The Foundation Medicine Inc. (FMI) dataset (FoundationCore – N=62845) was used to analyze mutations, gene co-mutations, tumor mutational burden (TMB) PD-L1 expression NF1-mut NSCLC. A proprietary, artificial intelligence-supported algorithm employed infer pathogenicity individual mutations. Clinical single-agent ICI were assessed using two publicly available cohorts: OAK/POPLAR (N=765) Rizvi (N=185). Patients known EGFR/ALK alterations excluded. PFS outcome analysis. In FMI dataset, inactivating somatic present 6.9% (2805/40388) adenocarcinomas (LUAD) 7.7% (855/11041) squamous carcinomas (LUSC). LUAD significantly enriched high TMB (TMB≥16 mutations/Mb: 31.3% NF1-wild type [NF1-wt] 14.9%; P= 8E-141) TPS≥1% (P=6E-10), both LUSC TP53 co-mutations (LUAD P=3E-79; P=1E-5). Co-alterations and/or CDKN2A/B highly prevalent (82.0%) near universal (95.4%). association between further validated (P=0.002) cohorts (P=0.008). Importantly, OAK-POPLAR cohort TMB-high patients bearing tumors treated exhibited markedly longer compared those harboring NF1-wt (cutoff TMB>=16mut/Mb: 9.63 vs 2.84 months, HR 0.55, P=0.054; cutoff TMB>=10mut/Mb: 4.14 2.53 0.69, P=0.119). This finding 8.33 3.07 0.52, P=0.070). Despite small sample size, trend NF1-mut-TMB also observed subpopulation STK11/KEAP1 (TMB>=16mut/Mb 14.36 <16mut/Mb 1.40 0.13, p=0.067). Among TMB, identify therapy. These findings highlight impact underscore context dependent effect on from immunotherapy.