Genomic landscape of MTAP deletions and association with EGFR alterations in NSCLC.
Authors: Thummalapalli Rohit , Muldoon Daniel , Febres-Aldana Christopher A. , Falcon Christina J. , Pupo Amanda , Bandlamudi Chaitanya , Berger Michael F. , Yu Helena Alexandra , Riely Gregory J. , Ladanyi Marc , Arbour Kathryn C. 
Published: June 2024

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Background: Genomic loss of 9p21, containing methylthioadenosine phosphorylase ( MTAP) and CDKN2A/B,is frequently observed across cancers, including non-small cell lung cancer (NSCLC). With the clinical development of multiple classes of agents aimed at achieving synthetic lethality in the context of MTAP deletions (del) across solid tumors, including novel PRMT5 and MAT2A inhibitors, there is a need to understand the genomic landscape and outcomes of patients with NSCLC and MTAP del. Methods: All NSCLC samples sequenced with MSK-IMPACT v7, a DNA-based NGS panel with coverage for 505 genes including MTAP and CDKN2A/B were queried. MTAP-del and CDKN2A-del were defined by significantly low read counts in coverage-based copy number analyses. Analyses of enrichment in co-altered genes between MTAP-del and MTAP-intact tumors were completed using Fisher tests with multiple test correction. For subsequent analyses, samples profiled with earlier MSK-IMPACT versions not covering MTAP were manually reviewed for 9p21 status. Results: Of 3010 NSCLC samples sequenced, 246 (8.2%) had MTAP del; of these, 243/246 (99%) had concurrent CDKN2A del. Among MTAP-del compared to MTAP-intact tumors, EGFR ( Q = 0.01) and SMARCA2 ( Q < 0.01) alterations were more frequent, while KRAS ( Q = 0.05) and RB1 ( Q = 0.02) alterations were less frequent. Patients (pts) with MTAP-del tumors were more likely to be Asian ( P < 0.01) and never smokers ( P < 0.01). We next identified 193 pts with stage IV MTAP-del lung adenocarcinoma (LUAD). Among these pts, 121/193 (63%) had concurrent oncogenic driver alterations with approved first-line targeted therapies, including 46% with EGFR sensitizing alterations (26% EGFR exon 19 del, 17% EGFR L858R). Among pts with advanced EGFR exon 19 del or L858Rlung cancer treated with 1L osimertinib (osi), MTAP-del was not associated with significant differences in time to discontinuation (TTD) of osi (median TTD 19 months vs 24 months for MTAP-intact, HR = 1.2, P = 0.57). We then identified 69 pts with paired NGS available pre- and post-progression on osi who were MTAP-intact at baseline. Acquired MTAP del was found in 10/69 (14%) of these pts at progression on osi, which was more frequent than any previously characterized osi acquired resistance (AR) mechanism (SCLC transformation: 13%, EGFR amplification [amp]: 10%, MET amp: 10%, EGFR C797S: 7%). In 4 of these pts, acquired MTAP del was seen in the absence of other AR mechanisms, while in 6 pts, acquired MTAP del was seen alongside an additional mechanism ( EGFR amp: 2, EGFR C797S: 1, EGFR L718Q: 1, SCLC transformation: 1, MET amp: 1). Conclusions: Among pts with advanced LUAD, MTAP deletions are enriched in tumors with targetable driver alterations, particularly in EGFR, and are frequently observed at acquired resistance to osimertinib. Demonstration of activity of novel agents targeting MTAP deficiency could be of significant benefit to pts with EGFR-and other oncogene-driven lung cancers.