Clinical relevance of MTAP deletion in pancreatic ductal adenocarcinoma: a real-world US patient cohort study

MTAP deletion is a common mutation in pancreatic ductal adenocarcinoma (PDAC). With the emergence of MTA-cooperative PRMT5 inhibitors, real-world evidence from representative patient populations is needed to understand the clinical relevance of MTAP deletion and inform future treatment decisions. This retrospective cohort study describes clinical and molecular characteristics, treatment patterns, and survival of PDAC patients in the US by MTAP status. Patients in the Flatiron Health Foundation Medicine Clinico-Genomic Database with diagnosis of PDAC January 1, 2011–June 30, 2024, and Next-Generation Sequencing of tumor were observed longitudinally for treatments and outcomes through December 31, 2024. Kaplan-Meier methods were used to estimate overall survival (OS) and time to next treatment (TTNT) by line of therapy (LOT) in patients with metastatic disease. Of 2,694 patients included, 823 (30.5%) had MTAP -deleted tumors. 61% of MTAP -deleted and 55% of MTAP -wildtype patients had metastatic disease at diagnosis. Among metastatic patients, ~ 73% received ≥ 1 LOT, usually FOLFIRINOX (39% MTAP -deleted, 39% MTAP- wildtype) or gemcitabine + nab-paclitaxel (GNP) (37% MTAP -deleted, 38% MTAP -wildtype). GNP was the most common regimen used in 2 L (40% MTAP -deleted, 44% MTAP -wildtype). Few patients received targeted therapies. CDKN2A was deleted in 100% of MTAP -deleted and 18% of MTAP -wildtype patients. KRAS mutation was highly prevalent among MTAP -deleted (94.5%) and MTAP -wildtype (91.8%) patients with G12X variants accounting for 85% of KRAS mutations. Median OS (months) from 1 L was 6.4 (95% confidence interval [CI] 5.7–7.0) in MTAP -deleted and 7.3 (95% CI 6.7–7.8) in MTAP -wildtype patients. Median TTNT was 3.8 (95% CI 3.3–4.2) in MTAP -deleted and 4.4 (95% CI 4.1–4.8) in MTAP -wildtype. In stratified analyses, patients with MTAP -wildtype/ KRAS -wildtype tumors had the longest median OS (10.3, 95% CI 8.0–12.8). A pattern of lower OS among the MTAP -deleted was consistently observed across patient subgroups. These findings demonstrate high unmet need in MTAP -deleted PDAC. Emerging MTA-cooperative PRMT5 inhibitors along with pan-(K)RAS inhibitors may expand treatment options for molecularly-selected patients with PDAC. High prevalence of KRAS co-mutation in MTAP -deleted tumors supports further evaluation of novel combination strategies. Estimates of lower OS in selected MTAP -deleted subgroups warrant further investigation.