Genomic Landscape and Clinical Impact of MTAP Loss in Driver-Positive NSCLC: Insights From a Large-Scale Real-World Chinese Cohort.

MTAP loss is a frequent genomic event in NSCLC, yet its clinical and therapeutic implications in oncogene-driven disease remain incompletely understood. We analyzed genomic profiles of 6492 Chinese patients with NSCLC from a real-world database and evaluated survival outcomes in 173 treatment-naïve, driver-positive patients receiving first-line targeted therapies. Associations of MTAP loss with clinicopathologic characteristics, co-mutations, and outcomes were assessed, with particular attention to its interplay with CDKN2A loss. MTAP loss was identified in 10.4% of the overall cohort and was enriched in advanced stage and tumors harboring oncogenic drivers, including EGFR mutations, ALK fusions, and amplifications of MET and ERBB2. Co-deletion with CDKN2A was highly prevalent in MTAP-loss tumors (92.3%). Structurally, MTAP loss was predominantly complete (87.8%), with the remaining cases mainly comprising partial losses involving exon 8 (10.6%). A high concordance (92.1%) was observed between next-generation sequencing and immunohistochemistry for the identification of MTAP loss. In driver-positive patients, MTAP loss was associated with a lower response rate and shorter progression-free survival and overall survival, especially in EGFR-mutant patients treated with third-generation EGFR-tyrosine kinase inhibitors. Combined MTAP/CDKN2A analysis revealed a prognostic gradient, with dual loss conferring the worst outcomes and remaining an independent predictor in multivariable models. MTAP loss defines a distinct molecular subset of NSCLC and serves as a robust adverse prognostic biomarker in EGFR-mutant disease treated with targeted therapies. These findings support integrating MTAP status into risk stratification and exploring combination strategies that incorporate PRMT5 or MAT2A inhibition.