Chemotherapy-free phase 1/2 trial of HRS-4642 plus adebrelimab in previously treated metastatic KRAS G12D-mutant pancreatic cancer

KRAS G12D mutations drive approximately 40% of pancreatic ductal adenocarcinoma (PDAC) cases and foster an immunosuppressive tumor microenvironment. This phase 1/2 trial (NCT06427239) evaluated HRS-4642, a selective KRAS G12D inhibitor, combined with the PD-L1 blockade adebrelimab in 48 pretreated patients with metastatic KRAS G12D-mutant PDAC. Dose escalation revealed no dose-limiting toxicities, establishing the recommended phase 2 dose (RP2D), and no treatment-related deaths occurred; hypercholesterolemia and anemia (each 50%) were the most common treatment-related adverse events. In the RP2D cohort (n = 37), the confirmed objective response rate was 43.2% (95% confidence interval [CI], 27.1-60.5), disease control rate was 81.1% (95% CI, 64.8-92.0), median duration of response was 6.9 months (95% CI, 4.8-8.6), median progression-free survival was 5.7 months (95% CI, 4.0-7.5), and median overall survival was 11.5 months (95% CI, 9.2-16.9). This chemotherapy-free regimen is tolerable and shows encouraging antitumor activity in refractory KRAS G12D-mutant PDAC, warranting further investigation.