Setidegrasib Shows Promise for KRAS G12D–Mutated lung and pancreatic Cancers: NEJM
Setidegrasib, an emerging targeted therapy, has shown promising efficacy in a phase I trial involving patients with previously treated advanced pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC) harboring KRAS G12D mutations—a subgroup for which no FDA-approved targeted treatments currently exist. The drug was generally well tolerated, with most adverse events limited to mild, transient infusion-related reactions and gastrointestinal symptoms such as nausea and vomiting, highlighting its potential as a novel therapeutic option in this unmet clinical space.
The KRAS p.G12D variant occurs in 5% of patients with non–small-cell lung cancer (NSCLC) and is the most common substitution variant in pancreatic ductal adenocarcinoma, occurring in 40% of patients, but no targeted therapies directed against this variant are currently approved for clinical use. Setidegrasib (ASP3082) is a first-in-class KRAS G12D–targeted protein degrader.
They conducted this phase 1 study to evaluate the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of setidegrasib in patients with previously treated advanced solid tumors harboring KRAS p.G12D variants. The primary objectives were to evaluate the safety profile, as indicated by dose-limiting toxic effects and adverse events (the primary end points), and to determine the phase 2 dose. Setidegrasib was administered intravenously once weekly at doses of 10 to 800 mg.
Overall, 203 patients were enrolled. Among the 76 patients who received setidegrasib at a dose of 600 mg, which was ultimately selected as the phase 2 dose, adverse events occurred during treatment in all the patients, with events of grade 3 or higher in 42%. Treatment-related adverse events occurred in 93% of the patients; the most common were transient infusion-related reactions (in 80%) and nausea (in 30%). Adverse events led to discontinuation in 2 patients. Among the 45 patients with NSCLC who received the 600-mg dose, 36% (95% confidence interval [CI], 22 to 51) had a partial response, the median progression-free survival was 8.3 months (95% CI, 4.1 to could not be estimated), and the estimated 12-month overall survival was 59% (95% CI, 40 to 74). Among the 21 patients with metastatic pancreatic ductal adenocarcinoma who received the 600-mg dose as second- or third-line treatment (of whom 67% received setidegrasib as third-line treatment), 24% (95% CI, 8 to 47) had a response, the median progression-free survival was 3.0 months (95% CI, 1.4 to 6.9), and the median overall survival was 10.3 months (95% CI, 4.2 to 13.0).
Setidegrasib was associated with antitumor activity and a low incidence of treatment discontinuation due to adverse events in patients with previously treated advanced KRAS p.G12D–mutated NSCLC or pancreatic ductal adenocarcinoma.
Reference:
Park, W., Kasi, A., Spira, A. I., Paz-Ares Rodríguez, L., Herzberg, B. O., Pelster, M. S., Tolcher, A. W., Goldman, J. W., et al. (2026). Setidegrasib in advanced non–small-cell lung cancer and pancreatic cancer. New England Journal of Medicine. https://doi.org/10.1056/NEJMoa2600752
Keywords:
Setidegrasib, Shows, Promise, KRAS, G12D–Mutated, lung, pancreatic, Cancers, NEJM, Park, W., Kasi, A., Spira, A. I., Paz-Ares Rodríguez, L., Herzberg, B. O., Pelster, M. S, Tolcher, A. W., Goldman, J. W, New England Journal of Medicine.
