Clinical and molecular landscape of MTAP-deleted thoracic tumors across Western and Asian cohorts: Implications for synthetic lethal targeting.

Abstract

e20713 Background: Methylthioadenosine phosphorylase (MTAP) deletion creates a synthetic lethal vulnerability to protein arginine methyltransferase 5 (PRMT5) and methionine adenosyltransferase 2A (MAT2A) inhibition. While early-phase trials targeting this pathway are ongoing, the clinicogenomic context of MTAP-deleted tumors remains incompletely characterized across diverse populations, despite its importance for optimizing patient selection and combination strategies. We utilized large-scale data to characterize MTAP deficiency in US and Japanese cohorts. Methods: We retrospectively analyzed genomic profiling data from two independent nationwide cohorts: AACR Project GENIE (United States; evaluable n = 11,091) and the Center for Cancer Genomics and Advanced Therapeutics (C-CAT; Japan; evaluable n = 4,851). MTAP copy number alterations were assessed in lung, pleural, and thymic tumors. Analyses included histology-specific prevalence, co-mutation patterns with CDKN2A/B and other genes, associations with clinically actionable drivers, tumor mutational burden (TMB), and overall survival stratified by molecular subgroup. Results: In lung cancer, MTAP deletion occurred at comparable frequencies between adenocarcinoma and squamous cell carcinoma within each cohort (GENIE: 8.1% vs 9.8%; C-CAT: 19.6% vs 16.5%) but was rare in small cell lung cancer (GENIE: 1.0%; C-CAT: 1.9%). In thymic tumors, MTAP deletion was observed predominantly in thymic carcinoma (9.7%; 25.6%) and was uncommon in thymoma (0%; 3.2%). MTAP deletion was strongly associated with CDKN2A/B deletions and was rare in their absence. MTAP deletion frequently co-existed with actionable driver alterations, including EGFR mutations, ALK fusions, and ERBB2 alterations. A robust inverse association with RB1 mutations was observed in both cohorts. While MTAP deletion appeared associated with lower TMB (p < 0.01) and shorter overall survival in EGFR-mutated lung cancer (HR 1.73 [1.24-2.41], p < 0.01), these associations were largely attributable to enrichment of oncogenic drivers and concurrent CDKN2A loss, respectively. Conclusions: MTAP-deleted thoracic tumors exhibit reproducible clinical and molecular features across Western and Asian populations, characterized by frequent co-occurrence with actionable drivers and mutual exclusivity with RB1 alterations. Careful consideration of co-existing driver alterations and CDKN2A status is essential for interpreting prognosis and immunotherapy-related biomarkers. Our findings support the rational, globally applicable development of PRMT5/MAT2A-targeted synthetic lethal strategies in thoracic malignancies, particularly in combination with molecular targeted agents.