WCLC 2025 - Posters & ePosters-P3.14.22 Outcomes to Systemic Standard-Of-Care Therapies in Patients With MTAP-Deleted Advanced Non-Small Cell Lung Cancer

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This study investigates clinical outcomes of systemic standard-of-care therapies in advanced non-small cell lung cancer (NSCLC) patients with methylthioadenosine phosphorylase gene deletions (MTAPdel) compared to MTAP wild type (MTAPwt). MTAP, located at chromosome 9p21.3 and involved in the methionine salvage pathway, is deleted in about 13% of NSCLC cases, and its loss is synthetically lethal with PRMT5 inhibition. PRMT5-MTA cooperative inhibitors are in clinical trials for MTAPdel cancers.<br /><br />The authors retrospectively analyzed 1,690 advanced NSCLC patients with known MTAP status, receiving standard therapies including platinum doublet chemotherapy plus anti-PD-(L)1 immunotherapy, anti-PD-(L)1 monotherapy, and docetaxel-based chemotherapy. After strict tumor purity and genomic criteria, 346 MTAPwt and 93 MTAPdel patients were selected for outcome comparison. Baseline characteristics were mostly similar except that MTAPdel patients had less smoking history, lower tumor mutation burden (TMB), higher rates of stage IV diagnosis and brain metastases, and frequent co-deletion of CDKN2A and CDKN2B genes. EGFR mutations were strongly associated with MTAP deletion.<br /><br />Clinical outcomes showed that MTAPdel patients had significantly shorter progression-free survival (PFS) on anti-PD-(L)1 containing regimens—both platinum doublet plus anti-PD-(L)1 and anti-PD-(L)1 monotherapy—compared to MTAPwt patients. Median PFS on platinum doublet plus anti-PD-(L)1 was 4.2 months for MTAPdel versus 6.1 months for MTAPwt (P=0.025), and on anti-PD-(L)1 monotherapy, 1.4 vs. 4.4 months (P=0.022). However, overall survival (OS) did not differ significantly between MTAPdel and MTAPwt across treatment modalities. There were no PFS or OS differences with platinum doublet therapy alone or docetaxel chemotherapy.<br /><br />In summary, MTAP deletion in advanced NSCLC correlates with distinct clinical and molecular features and predicts poorer PFS to immunotherapy-based regimens but not to chemotherapy alone. These findings support further exploration of MTAP as a biomarker and the development of targeted therapies for MTAPdel NSCLC.

Asset Subtitle

Julian Huang

Meta Tag

Speaker Julian Huang

Topic Mesothelioma, Thymoma, and Other Thoracic Tumors

Keywords

MTAP deletion

non-small cell lung cancer

NSCLC

progression-free survival

immunotherapy

platinum doublet chemotherapy

anti-PD-(L)1 therapy

PRMT5 inhibition

methylthioadenosine phosphorylase

EGFR mutations