Setidegrasib in Advanced Non-Small-Cell Lung Cancer and Pancreatic Cancer.
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Park Wungki, Kasi Anup, Spira Alexander I, Paz-Ares Rodríguez Luis, Herzberg Benjamin O, Pelster Meredith S, Tolcher Anthony W, Kuboki Yasutoshi, Kitano Shigehisa, Shoji Hirokazu, Wang Judy S, Berlin Jordan D, Hollebecque Antoine, LoRusso Patricia, Fountzilas Christos, Cassier Philippe A, Nishina Tomohiro, Sakai Daisuke, Inagaki Chiaki, Morgensztern Daniel, Ueno Makoto, Jung Minkyu, Kim Sang-We, Jänne Pasi A, Italiano Antoine, You Benoît, Macarulla T, Fujii Hisaki, Shetty Aditya, Lu Ying, Cui Daniel, Kadam Shilpa, Gill Stanley C, Toyoshima Junko, Saito Takeshi, Goldman Jonathan W
Аннотация
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.).