9095 Background: METex14 is a heterogeneous family of mutations (mt) in NSCLC that can be effectively treated with approved targeted agents. Unlike some other drivers in NSCLC, METex14 occurs in both squamous and adenocarcinoma histology and in both smokers and non-smokers. Here, we present updated results from analysis of a large dataset to characterize the mutational landscape within METex14 NSCLC. Methods: NSCLC tissue samples were analyzed with DNA-based next-generation sequencing (NGS; 592 genes, NextSeq) or whole-exome sequencing (NovaSeq), RNA-based whole transcriptome sequencing (WTS, NovaSeq), and PD-L1 immunohistochemistry (Dako 22C3) at Caris Life Sciences (Phoenix, AZ). METex14 was detected by WTS. TMB-high was defined as ≥ 10 mt/Mb. Chi-square, Fisher’s exact or Mann-Whitney U tests were used to determine statistical significance and corrected for multiple hypothesis testing (q<0.05). Immune cell estimates (quanTIseq) and pathway analysis (ssGSEA) were informed by WTS analysis. Results: A total of 711 METex14 cases were detected with 288 distinct METex14 mt. By histology, 79 (11.1%) were squamous (Sq), 478 (67.23%) were nonsquamous (nSq), and 24 (3.23%) were adenosquamous. The most common METex14 mt were D1028H (8.1%), D1028N (7.8%), c.3082+2T>C (5.0%), D1028Y (4.6%), and c.3082+1G>T (4.4%). Co-mutated TP53 was common (43.4%) but varied by specific METex14 mt, observed in 60.0% of MET c.3082+3A>G vs 16.7% of MET G344R . Co-amplified CDK4 was found in 9.3%, with 42.9% in MET c.2924-1G>A vs 6.7% in MET c.3802+1G>T (p<0.05). High TMB was seen in 9%; median TMB ranged from 2 mt/Mb in MET c.3082+2T>A to 6.5 mt/Mb in MET c.3082+2T>G (p<0.05). PD-L1 ≥ 1% was seen in 80.8% compared to 56.2% in METex14-WT(p<0.05), and median PD-L1 tumor proportion score (TPS) ranged from 0% in MET G344R to 75% in MET c.3082+2T>A (p<0.05). Co-mutations varied by histology: in Sq-NSCLC, 18.18% had TP53 mt (q<0.05), 8.97% had POT1 mt (p<0.05), 6.06% had TERT mt (p<0.05), 5.13% CASP8 mt (q<0.05), and 2.53% RNF43 mt (p<0.05), while in nSq-NSCLC, 45.51% had TP53 mt, 3.38% had POT1 mt, 0.87% had TERT mt, and 0% in CASP8 and RNF43 mt. Smoking status was available for 120 cases: 88% were smokers and 12% were nonsmokers. Wnt, Hedgehog, and Notch signaling were enriched in nSq (q<0.05) while upregulation of KRAS signaling, Epithelial-Mesenchymal Transition, and angiogenesis pathways were enriched in smokers with METext14 NSCLC (q<0.2). Higher estimates of neutrophils and lower estimates of M2 macrophages, NK cells, and CD8+ T-cells were observed in Sq-NSCLC. PD-L1, PD-1, HAVCR-2, IDO-1 and IFN-γ expression were higher in nSq than Sq-NSCLC (q<0.05). Conclusions: METex14 NSCLC is highly heterogenous, with variations in co-mutation, TMB, and PD-L1 expression. Although Sq- and nSq-NSCLC harbor METex14, the enrichment of oncogenic pathways and infiltrating immune cells differ between histology and smoking history.