Retrospective study of presenting features and outcomes to standard systemic therapies in MTAP-deleted advanced NSCLC

Methylthioadenosine phosphorylase (MTAP) is deleted in 13% of NSCLC, and MTAP two-copy deleted (MTAPdel) cancer cells are vulnerable to protein arginine methyltransferase 5 inhibitors. Outcomes for MTAPdel NSCLC are poorly characterized. A retrospective study at Dana-Farber Cancer Institute (Boston, MA) evaluated presenting features and outcomes in MTAPdel advanced NSCLC. The study included 307 patients with MTAP wild-type (wt) and 93 patient with MTAPdel disease. Compared to the MTAPwt cohort, the MTAPdel cohort had more female patients (65.6% versus 51.5%; p=0.018), less smoking history (>30 pack-years 33.3% versus 49.0%; p=0.008), more stage IV disease at diagnosis (78% versus 60.9%; p=0.002), lower PD-L1 TPS (TPS <1% 37.9% versus 24.3%; p=0.017), and lower tumor mutational burden (median 7.6 versus 9.9 mut/Mb; p=0.012). Patients with MTAPdel versus MTAPwt had shorter progression-free survival on anti-PD-(L)1 monotherapy (HR 1.70; p=0.040) and platinum doublet plus anti-PD-(L)1 therapy (HR 1,89; p=0.006) when controlling for histology, age, smoking pack-years), PD-L1 TPS, targetable co-mutations, and treatment line. OS was similar between MTAPdel and MTAPwt cohorts across regimens. The authors conclude that MTAPdel NSCLC has more features of aggressive disease, including CNS metastasis, and associates with PD-L1 TPS <1%. Compared to patients with MTAPwt NSCLC, patients with MTAPdel NSCLC have worse outcomes to anti-PD-(L)1-based therapies.