Presenting features and outcomes to standard systemic therapies in patients with MTAP-deleted advanced non-small cell lung cancer

PURPOSE: 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 being examined in trials. Outcomes for MTAPdel NSCLC are poorly characterized. EXPERIMENTAL DESIGN: Patients with advanced MTAPdel and MTAPwt NSCLC who underwent large panel, tissue-based, NGS at a single center and received systemic therapy and from 10/2016-3/2024, were included in this retrospective study. Treatments of interest included platinum doublet + anti-PD-(L)1 therapy, anti-PD-(L)1 monotherapy, and docetaxel-based chemotherapy. Baseline characteristics, PFS, and OS were compared between cohorts. RESULTS: Compared to the MTAPwt cohort (n=307), the MTAPdel cohort (n=93) had more female patients (65.6% vs. 51.5%, p=0.018), less of a smoking history (33.3% vs. 49.0% >30 pack-years, p=0.008), more stage IV disease at diagnosis (78.8% vs. 60.9%, p=0.002), lower PD-L1 TPS (37.9% vs. 24.3% TPS <1%, p=0.017), and lower tumor mutational burden (median 7.6 vs. 9.9 mutations/Mb, p=0.012). Patients with MTAPdel (vs. MTAPwt) NSCLC had shorter PFS on anti-PD-(L)1 monotherapy (HR 1.70 [95% CI 1.02-2.82], p=0.040) and platinum doublet + anti-PD-(L)1 therapy (HR 1.89 [95% CI 1.20-2.97], 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. CONCLUSIONS: 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. Effective therapies targeting MTAPdel NSCLC are needed.