The phase I therapeutic landscape in pancreatic ductal adenocarcinoma: Molecular profiling and emerging strategies.

Abstract

e15114 Background: Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with limited treatment options. Phase I trials explore novel therapies, yet the investigational landscape and genomic characteristics of enrolled patients (pts) remain poorly defined. We analyzed therapeutic strategies and genomic profiles of pts in early-phase trials to better inform future precision oncology approaches. Methods: This retrospective study included pts with advanced PDAC at a single center. Demographic, clinical, molecular, and outcome data were extracted from electronic health records. Tumor genomic profiling was performed using next-generation sequencing. Investigational agents were classified by mechanism of action. Response was assessed per RECIST v1.1. Overall survival (OS) was calculated from trial consent to death or last follow-up. Responses were compared using chi-square tests, and associations of OS with mechanisms and responses were evaluated using Kaplan-Meier and log-rank analyses. Results: Between Jan 2015 and Apr 2025, 617 pts with advanced PDAC enrolled in phase 1 trials. Median age was 61 years (range 22–87), 44% were female. Median prior lines of therapy were 2 (range 1–6). Genomic profiling revealed alterations of KRAS in 42% (G12D 19%, G12V 11%, G12R 8%), TP53 in 37%, and CDKN2A/B in 19%. Other actionable alterations included BRCA 1/2 mutations (10%), MTAP deletions (3%), ERBB2 amplifications (2%), and BRAF V600E mutations (0.6%). Across 236 unique agents tested, targeted therapies (TT) were 61% and immunotherapies (IO) were 33%. Monotherapy and combinations were 64% and 36%, respectively. Leading mechanisms included RAS pathway inhibition (18%), immune checkpoint modulation (16%), tumor microenvironment targeting (14%), and DNA damage response inhibition (12%). Best responses included complete response (CR, 0.2%), partial response (PR, 7.6%), stable disease (SD, 31.8%), and progressive disease (PD, 60.4%). The objective response rates (CR + PR) were highest for TT (13.9%) followed by combinations (4%), and IO (1.3%) (p < 0.001). Median OS (mOS) for the entire cohort was 5.0 mo (95% CI, 4.5–5.4). Pts receiving TT had highest mOS (5.5 mo) vs. combinations (5.1 mo), and IO (2.8 mo) (p = 0.002). Response correlated significantly with OS (CR: 49.1 mo, PR: 18.0 mo, SD: 7.6 mo, PD: 3.7 mo) (p < 0.001). KRAS alteration status was not significantly associated with OS. Conclusions: This analysis highlights a shift in PDAC phase I trials from cytotoxic therapy toward precision oncology, with targeted therapies demonstrating superior efficacy. However, the low mOS underscores refractory nature of PDAC. Our findings emphasize that comprehensive genomic profiling is essential for precision therapeutic matching and biomarker-driven trial enrollment in PDAC.