Background: NF1 is a tumor suppressor gene that regulates the RAS-MAPK and mTOR pathways. Co-mutations previously observed with NF1-mutations (mt) include TP53, KRAS, EGFR and rarely HER2, STK11, and PIK3CA mutations. We report a comprehensive molecular characterization with clinical outcomes analyses for NF1-mt non-small cell lung cancer (NSCLC). Methods: Next-generation sequencing (NGS) of DNA (592-gene or whole exome) and RNA (whole transcriptome) was performed for NSCLC patient (pt) samples (n = 10,310) submitted to a CLIA-certified laboratory (Caris Life Sciences, Phoenix, AZ).. RAS-MAPK and PI3K-AKT-MTOR signaling were assessed by transcriptional signatures of pathway activation (MAPK pathway Activation Score [MPAS], Wagle, 2018; and GSEA Hallmarks collection, respectively)., PD-L1 by immunohistochemistry (IHC, positive: TPS ≥1%), high tumor mutational burden (TMB) defined as ≥10 mut/Mb, and deficient mismatch repair/high microsatellite instability (dMMR/MSI-High) was assessed by IHC/NGS. Overall survival (OS) was obtained from insurance claims. Statistical significance was determined using Chi-square & Wilcoxon rank sum tests. P-value adjust for multiple hypothesis testing (Benjamini-Hochberg). Results:NF1-mt were identified in 1,045 NSCLC samples (10.1%). Concurrent KRAS,EGFR, ERBB2, BRAF or MET alterations are noted in Table 1, with no ROS1, RET or ALK fusions identified. Compared to NF1-wt, NF1-mt NSCLC was associated with increased RAS-MAPK expression (3.0-fold, P < 0.0001), while PI3K-AKT-MTOR-signaling was not significantly increased (2.1-fold, P = 0.12). Rates of TMB-High (51.7% vs 32.5%, P < 0.0001), PD-L1+ (69.1% vs 58.8%, P = 0.06), and dMMR/MSI-High (1.7 vs 0.7%, P < 0.05) were higher in NF1-mt samples. OS and duration on treatment from the start of Pembrolizumab (HR: 1.0 and 1.0, respectively) or other IOs (HR: 0.9 and 1.0, respectively) were not significantly different between NF1-mt and NF1-wt patients, However, among NF1-mt samples, high TMB and TP53-wt were associated with better OS (HR 0.6, P < 0.05 each). Conclusions:NF1-mt patients rarely harbored actionable NSCLC driver co-alterations. NF1-mt cases showed increased activation of RAS-MAPK axis, which may represent a potential pathway to target with MEK inhibitors. NF1-mt are responsive to immunotherapy and better outcomes are seen with high TMB and absence of TP53 mutations. Further work is warranted to determine the influence of actionable drivers on targeted therapy outcomes in NF1-mt NSCLC.