Clinical and molecular presentation of KRAS G12D-mutated pancreatic ductal adenocarcinoma in real-world settings.

738 Background: Pancreatic ductal adenocarcinoma (PDAC) remains a devastating diagnosis with an overall 5-year survival rate of ~10%. Therapies targeting KRAS G12D, a prevalent molecular driver of PDAC, represent an active area of investigation with many agents currently in clinical development. This study characterizes the real-world clinico-genomic landscape of patients with KRAS G12D-mutated PDAC to inform ongoing therapeutic development and clinical trial design. Methods: We conducted a retrospective, records-based analysis of 2,805 patients with PDAC from across 299 community-based oncology clinics. All patients had broad-panel next generation sequencing (NGS) from commercial vendors performed as standard of care. Patients were stratified into KRAS WT (26%), KRAS G12D (31%), and KRAS non-G12D (43%) cohorts according to NGS results and assessed for co-mutations, overall survival, and time to chemotherapy failure. Results: The KRAS G12D and KRAS non-G12D cohorts exhibited similar mutational landscapes with frequent alterations in TP53, CDKN2A, and SMAD4 ( > 20% frequency occurrence) and infrequent actionable co-mutations (i.e. ATM, MTAP, BRCA1/2, PIK3CA, and MYC; < 5% frequency occurrence). KRAS G12D exhibited significantly decreased overall survival compared to KRAS WT (m (95% CI); 32.4 months (27.6-37.6 months) [ KRAS WT ], 20.1 months (17.0-22.7 months) [ KRAS G12D ], 21.7 months (20.0-25.0 months) [ KRAS non-G12D ]; Cox model p-value < 0.001) as well as significantly shortened time to chemotherapy failure compared to both KRAS non-G12D and KRAS WT (m (95% CI); 10.8 months (9.6-11.6 months) [ KRAS WT ], 7.8 months (7.3-8.7 months) [ KRAS G12D ], 9.8 months (8.8-11.1 months) [ KRAS non-G12D ]; Cox model p-value < 0.01). Within the KRAS G12D cohort, no co-mutations were significantly associated with overall survival. Conclusions: This study demonstrates the acute need for KRAS G12D-targeted agents in the clinic, as patients with KRAS G12D-driven PDAC experience particularly poor patient outcomes and lack alternative molecular targets.