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

Author(s): Wungki Park, M.D.1,2; Anup Kasi, M.D., M.P.H.3; Alexander I. Spira, M.D., Ph.D.4; Luis Paz-Ares Rodríguez, M.D., Ph.D.5; Benjamin O. Herzberg, M.D.6; Meredith S. Pelster, M.D.7; Anthony W. Tolcher, M.D.8; Yasutoshi Kuboki, M.D., Ph.D.9; Shigehisa Kitano, M.D., Ph.D.10; Hirokazu Shoji, M.D., Ph.D.11; Judy S. Wang, M.D.12; Jordan D. Berlin, M.D.13; Antoine Hollebecque, M.D.14; Patricia LoRusso, D.O.15; Christos Fountzilas, M.D.16; Philippe A. Cassier, M.D., Ph.D.17; Tomohiro Nishina, M.D., Ph.D.18; Daisuke Sakai, M.D.19; Chiaki Inagaki, M.D., Ph.D.20; Daniel Morgensztern, M.D.21; Makoto Ueno, M.D.22; Minkyu Jung, M.D., Ph.D.23; Sang-We Kim, M.D.24; Pasi A. Jänne, M.D., Ph.D.25; Antoine Italiano, M.D., Ph.D.14,26; Benoît You, M.D., Ph.D.27,28,29; T Macarulla, M.D., Ph.D.30; Hisaki Fujii, M.D., Ph.D.31; Aditya Shetty, M.D.31; Ying Lu, M.S.31; Daniel Cui, Ph.D.31; Shilpa Kadam, Ph.D.31; Stanley C. Gill, Ph.D.31; Junko Toyoshima, Ph.D.31; Takeshi Saito, Ph.D.31; Jonathan W. Goldman, M.D.32;
Source: DOI: 10.1056/NEJMoa2600752
Original Article
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45 patients with Non–Small-Cell Lung Cancer (NSCLC) who received the 600-mg dose, 36% had a partial response, the median progression-free survival (PFS) was 8.3 months, estimated 12-month overall survival was 59% 21 patients with metastatic pancreatic ductal adenocarcinoma 24% had a response, the median PFS was 3.0 months and the median overall survival was 10.3 months. Our colleague Dr. Judy Wang is one of the authors of this paper.

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 doses of 10 to 800 mg.

RESULTS

Overall, 203 patients were enrolled. Among the 76 patients who received setidegrasib 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.)

Author Affiliations

1Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York; 2David M. Rubenstein Center for Pancreatic Cancer Research, New York; 3University of Kansas Medical Center, Kansas City; 4Virginia Cancer Specialists and NEXT Oncology-Virginia, Fairfax; 5Department of Medical Oncology, Hospital Universitario 12 de Octubre, Madrid; 6Division of Hematology/Oncology, Columbia University Irving Medical Center, New York; 7Sarah Cannon Research Institute, Nashville; 8NEXT Oncology, San Antonio, TX; 9Department of Experimental Therapeutics, National Cancer Center Hospital East, Kashiwa, Japan; 10Department of Advanced Medical Development, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo; 11Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo; 12Florida Cancer Specialists/Sarah Cannon Research Institute, Sarasota; 13Division of Hematology and Oncology, Vanderbilt-Ingram Cancer Center, Nashville; 14Gustave Roussy, Villejuif, France; 15Yale School of Medicine, New Haven, CT; 16Roswell Park Comprehensive Cancer Center, Buffalo, NY; 17Department of Medical Oncology, Centre Léon Bérard, Lyon, France; 18Department of Gastrointestinal Medical Oncology, NHO Shikoku Cancer Center, Matsuyama, Japan; 19Department of Medical Oncology, Osaka International Cancer Institute, Osaka, Japan; 20Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka, Japan; 21Department of Medicine, Washington University School of Medicine, St. Louis; 22Department of Gastroenterology, Kanagawa Cancer Center, Yokohama, Japan; 23Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea; 24Asan Medical Center, Seoul, South Korea; 25Lowe Center for Thoracic Oncology, Dana–Farber Cancer Institute, Boston; 26Institut Bergonie, Bordeaux, France; 27Lyon University Hospital, Institut de Cancérologie des Hospices Civils de Lyon (IC-HCL), Lyon University, Lyon, France; 28Medical Oncology, IC-HCL, EPSILYON, Université Claude Bernard, CICLY, Lyon, France; 29Gynecology and Obstetrics, Lyon-Sud Hospital, CICLY, Lyon, France; 30Medical Oncology Department, Hospital Clinic Barcelona, Translational Oncology in Upper Gastrointestinal Cancer Group, IDIBAPS, Barcelona; 31Astellas Pharma, Northbrook, IL; 32University of California, Los Angeles, Los Angeles

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