Setidegrasib in Advanced Non-Small-Cell Lung Cancer and Pancreatic Cancer

Clinical Snapshot

Key Findings

• P Value: Not reported for efficacy endpoints (phase 1 study)

• Effect Size: NSCLC: 36% partial response rate; Pancreatic cancer: 24% response rate

• Primary Outcome: Safety profile: 100% experienced adverse events, 42% grade 3+ at 600mg dose

• Nnt Or Sensitivity: Number needed to treat: approximately 3 for NSCLC response, 4 for pancreatic cancer response

• Confidence Interval: NSCLC response: 95% CI 22-51%; Pancreatic response: 95% CI 8-47%

Clinical Application

Requires weekly intravenous administration and specialized oncology centers; infusion-related reaction management protocols needed Would require TGA approval and PBS listing; KRAS testing already available through public pathology; fits within existing precision oncology framework Patients with advanced NSCLC or pancreatic ductal adenocarcinoma harboring KRAS G12D mutations who have failed standard therapies

Abstract

BACKGROUND: 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. METHODS: We 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. RESULTS: 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). CONCLUSIONS: 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. (Funded by Astellas Pharma; ClinicalTrials.gov number, NCT05382559.).

References

1. 1.Park, W., Kasi, A., Spira, A. I., Paz-Ares Rodríguez, L., Herzberg, B. O., Pelster, M. S., Tolcher, A. W., Kuboki, Y., Kitano, S., Shoji, H., Wang, J. S., Berlin, J. D., Hollebecque, A., LoRusso, P., Fountzilas, C., Cassier, P. A., Nishina, T., Sakai, D., Inagaki, C., Morgensztern, D., Ueno, M., Jung, M., Kim, S.-W., Jänne, P. A., Italiano, A., You, B., Macarulla, T., Fujii, H., Shetty, A., Lu, Y., Cui, D., Kadam, S., Gill, S. C., Toyoshima, J., Saito, T., & Goldman, J. W. (2026). Setidegrasib in advanced non-small-cell lung cancer and pancreatic cancer. *New England Journal of Medicine*. https://doi.org/10.1056/NEJMoa2600752