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

Dr. Anjan Patel's Thoughts

Setidegrasib represents a meaningful advance in targeting KRAS G12D–mutant tumors, demonstrating a 36% response rate with median PFS exceeding 8 months in heavily pretreated NSCLC, and a 24% response rate with ~10 month median overall survival (OS) in third line pancreatic cancer, both notable signals in populations lacking approved targeted therapies. Weekly IV administration and transient infusion reactions appear manageable. The absence of the gastrointestinal tract (GI) and dermatologic toxicities commonly seen with other KRAS inhibitors is particularly notable. It will be important to see how efficacy and convenience compare as oral G12D and pan RAS inhibitors mature and head to head data emerge.

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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