Chemotherapy-Free Treatment Targeting KRAS G12D in Pancreatic Cancer Shows 43% Response Rate

A chemotherapy-free clinical trial in patients with KRAS G12D-mutated pancreatic cancer found an objective response rate of 43.2%.

According to a study published on the 16th in the international journal Cancer Cell, a team led by professors Yu Xianjun, Xu Jin and Shi Si of Fudan University reported phase 1/2 clinical trial results for the combination of HRS-4642, a selective KRAS G12D inhibitor, and adebrelimab, an anti-PD-L1 antibody.

KRAS G12D mutations drive about 40% of pancreatic ductal adenocarcinomas (PDAC) and create an immunosuppressive tumor microenvironment. PDAC has a very poor prognosis, with median overall survival (OS) of less than 12 months in patients with metastatic disease.

This trial (NCT06427239) enrolled 48 patients with metastatic KRAS G12D-mutated PDAC who had received prior treatment. No dose-limiting toxicities or treatment-related deaths occurred during dose escalation.

Among the 37 patients who received the recommended phase 2 dose (RP2D), the confirmed objective response rate was 43.2%, and the disease control rate was 81.1%. Median duration of response was 6.9 months, median progression-free survival was 5.7 months, and median overall survival was 11.5 months.

The most common treatment-related adverse events were hypercholesterolemia and anemia, each occurring in 50% of patients. The research team said the chemotherapy-free regimen was tolerable and showed encouraging antitumor activity in refractory KRAS G12D-mutated PDAC, and noted that further research is needed.

Meanwhile, no therapy targeting KRAS G12D alone has yet received clinical approval. The pan-RAS inhibitor daraxonrasib recorded median overall survival of 13.2 months in second-line metastatic PDAC, but is known to have substantial toxicities, including rash, stomatitis and diarrhea.