In a phase I trial reported in The New England Journal of Medicine, Park et al identified the toxicity profile and preliminary antitumor activity of setidegrasib, a first-in-class KRAS G12D–targeted protein degrader, in patients with previously treated advanced non–small cell lung cancer (NSCLC) or pancreatic ductal carcinoma harboring the KRAS p.G12D variant.
As stated by the investigators, “The KRAS p.G12D variant occurs in 5% of patients with … 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.”
Study Details
In the international study, 203 patients with advanced NSCLC, pancreatic ductal carcinoma, or other solid tumors harboring KRAS p.G12D variants were enrolled between June 2022 and April 2025 and received setidegrasib once weekly at 10 to 800 mg.
Key Findings
In the dose-escalation phase, dose-limiting toxic effects occurred in 3 (2%) of 123 patients. The maximum tolerated dose was not reached. The selected phase II dose was setidegrasib at 600 mg once weekly.
Among the 76 patients who received setidegrasib at 600 mg, treatment-related adverse events of any grade occurred in 93%, most commonly transient infusion-related reactions (80%) and nausea (30%). Treatment-related adverse events of grade 3 or higher occurred in 9% of patients, including increased alanine aminotransferase (3%) and neutropenia (3%). Treatment-related adverse events led to discontinuation of treatment in two patients.
Among the 45 patients with NSCLC who received 600 mg, 36% (95% confidence interval [CI] = 22%–51%) had objective responses (all partial). Responses were ongoing at 6 months in 76% of responders. Median progression-free survival was 8.3 months (95% CI = 4.1 months to could not be estimated). Estimated 12-month overall survival was 59% (95% CI = 40%–74%). Among 32 patients who received setidegrasib at 600 mg as second- or third-line treatment, the objective response rate was 38%, and median progression-free survival was 11.2 months (95% CI = 5.6 months to could not be estimated).
Efficacy in pancreatic ductal adenocarcinoma was assessed in the 21 patients who received setidegrasib at 600 mg as second-line (n =7) or third-line (14 patients) treatment. The objective response rate was 24% (95% CI = 8%–47%), median progression-free survival was 3.0 months (95% CI = 1.4–6.9 months), and median overall survival was 10.3 months (95% CI = 4.2–13.0 months).
The investigators concluded: “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.”
Wungki Park MD, of Memorial Sloan Kettering Cancer Center, and Jonathan W. Goldman, MD, of University of California, Los Angeles, are the corresponding authors for the New England Journal of Medicine article.
DISCLOSURE: The study was funded by Astellas Pharma. For full disclosures of the study authors, visit nejm.org.
