Clinical Significance of MTAP Deletions and Their Overlap With Concurrent Oncogenic Driver Alterations Including EGFR...

Methylthioadenosine phosphorylase (MTAP) deletions (dels) occur with CDKN2A dels in a subset of NSCLCs. These deletions have been associated with inferior survival in several tumor types, and they may be targetable by PRMT5 and MAT2A inhibitors through synthetic lethality. Their co-occurrence with oncogenic drivers including EGFR is underexplored.

We analyzed 4926 NSCLC tumors sequenced with MSK-IMPACT, a next-generation sequencing panel, and evaluated the incidence of MTAP dels with a copy number-based approach.

Of 4926 NSCLC tumors, 475 (10%) harbored an MTAP del. Among 258 stage IV MTAP-del NSCLC tumors, 214 (83%) also had a co-occurring oncogenic driver alteration, including 123 (48%) with EGFR mutations. Baseline MTAP del was associated with shorter time to osimertinib monotherapy discontinuation (19.0 versus 24.9 mo, hazard ratio 1.8, confidence interval 1.02-3.15, p = 0.01) but did not statistically significantly affect overall survival (38.4 versus 40.5 mo, hazard ratio 1.7, CI 0.8-3.6, p = 0.1). In patients who developed resistance to osimertinib with paired pre- and post-treatment tissue samples, acquired MTAP del was identified in nine of 69 patients (13%). A heavily pretreated patient with metastatic EGFR-mutant, MTAP-del NSCLC had a confirmed partial response to treatment with PRMT5 inhibitor monotherapy (BMS-986504).

MTAP dels frequently co-occur with oncogenic driver alterations and can develop at time of osimertinib resistance. A patient with oncogenic driver-positive, MTAP-del NSCLC had a partial response to PRMT5 inhibitor treatment. This work could inform future trials of PRMT5 and MAT2A inhibitors.