Wungki Park, Anup Kumar Kasi, Alexander I. Spira, Luis Paz-Ares Rodríguez, Benjamin O. Herzberg, Meredith S. Pelster, Anthony W. Tolcher, Y. Kuboki, Shigehisa Kitano, H. Shoji, J. Wang, Jordan Berlin, A. Hollebecque, Patricia LoRusso, C. Fountzilas, Philippe A. Cassier, Tomohiro Nishina, Daisuke Sakai, Chiaki Inagaki, Daniel Morgensztern, Makoto Ueno, M.K. Jung, Sang-We Kim, Pasi A. Jänne, Antoine Italiano, Benoît You, T Macarulla, Hisaki Fujii, Aditya Shetty, Ying Lu, Daniel Cui, Shilpa Kadam, Stanley C. Gill, Junko Toyoshima, Takeshi Saito, Jonathan W. Goldman
BACKGROUND: 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: 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: p.G12D-mutated NSCLC or pancreatic ductal adenocarcinoma. (Funded by Astellas Pharma; ClinicalTrials.gov number, NCT05382559.).