Clinical significance of MTAP deletions and their overlap with concurrent oncogenic driver alterations in non-small cell lung cancer

MTAP (methylthioadenosine phosphorylase) deletions (dels) occur with CDKN2A dels in a subset of non-small cell lung cancers (NSCLCs). These deletions have been associated with inferior survival in several tumor types. In a multicenter retrospective study, 475 of 4,926 analyzed NSCLC tumors (10%) harbored an MTAP del. Among 258 stage IV MTAP-del NSCLC tumors, 214 (83%) had a co-occurring oncogenic driver alteration, including 123 (48%) with EGFR mutations. Baseline MTAP deletion was associated with shorter time to osimertinib monotherapy discontinuation (19.0 versus 24.9 months; HR 1.8; p=0.01), but did not statistically signifcantly affect overall survival (38.4 versus 40.5 months; p=0.1). In patients who developed resistance to osimertinib with paired pre-and post-treatment tissue samples, acquired MTAP del was identified in 9 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. The authors conclude that MTAP dels frequently co-occur with oncogenic driver alterations and can develop at time of osimertinib resistance and may be targetable by PRMT5 inhibitors.