Related Experiment Video
Updated: Jul 7, 2026
Ultra-Fast Amplicon-Based Next-Generation Sequencing in Non-Squamous Non-Small Cell Lung Cancer
Published on: September 8, 2023
Presenting features and outcomes to standard systemic therapies in patients with MTAP-deleted advanced non-small cell
Julian Huang1, Mihaela Aldea2, Kathryn W Miller3
1Brigham and Women's Hospital Boston, MA United States.
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.
Insights
Methylthioadenosine phosphorylase deletion (MTAPdel) in non-small cell lung cancer (NSCLC) is linked to aggressive disease and poorer outcomes with anti-PD-(L)1 therapies. New treatments are needed for MTAPdel NSCLC patients.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- Methylthioadenosine phosphorylase (MTAP) deletion occurs in 13% of non-small cell lung cancer (NSCLC) cases.
- MTAP-deleted (MTAPdel) NSCLC exhibits vulnerability to protein arginine methyltransferase 5 inhibitors.
- Clinical outcomes for MTAPdel NSCLC remain inadequately characterized.
Purpose of the Study:
- To characterize the clinical outcomes of advanced MTAPdel NSCLC.
- To compare baseline characteristics and treatment efficacy between MTAPdel and MTAPwt NSCLC cohorts.
- To identify potential therapeutic strategies for MTAPdel NSCLC.
Main Methods:
- Retrospective study of advanced NSCLC patients (MTAPdel and MTAPwt) undergoing NGS.
- Systemic therapy data included platinum doublet + anti-PD-(L)1, anti-PD-(L)1 monotherapy, and docetaxel.
- Comparison of baseline characteristics, progression-free survival (PFS), and overall survival (OS) between cohorts.
Main Results:
- MTAPdel NSCLC cohort (n=93) showed more female patients, less smoking history, more stage IV disease, lower PD-L1 TPS, and lower tumor mutational burden compared to MTAPwt (n=307).
- MTAPdel NSCLC patients experienced shorter PFS on anti-PD-(L)1 monotherapy (HR 1.70) and platinum doublet + anti-PD-(L)1 therapy (HR 1.89).
- Overall survival was similar between MTAPdel and MTAPwt NSCLC cohorts across different treatment regimens.
Conclusions:
- MTAPdel NSCLC presents with more aggressive disease features and is associated with PD-L1 TPS <1%.
- Patients with MTAPdel NSCLC demonstrate inferior outcomes when treated with anti-PD-(L)1-based therapies.
- Development of effective therapies targeting MTAPdel NSCLC is crucial.
