This phase 1 study demonstrated that setidegrasib, a first-in-class selective KRAS G12D-targeted protein degrader, has antitumor activity in patients with previously treated advanced NSCLC and pancreatic ductal adenocarcinoma. At the recommended 600 mg dose given intravenously weekly, the drug showed manageable safety with mainly low-grade infusion-related reactions and few discontinuations, supporting further clinical development.
Study
|
Phase 1, open-label, international, multicenter study [NCT05382559] |
| Advanced solid tumors harboring KRAS G12D mutation, previously treated, including NSCLC and pancreatic ductal adenocarcinoma |
| Setidegrasib administered intravenously once weekly at doses of 10 to 800 mg; dose-escalation and dose-expansion cohorts; recommended phase 2 dose was 600 mg
|
Efficacy
|
in NSCLC (16/45), 24% in pancreatic Ca (5/21) |
| NSCLC: |
| ORR: 36%, mPFS: 8.3 mos, 1yr-OS: 59% |
| Pancreatic cancer: |
| ORR: 24%, mPFS 3.0 mos, mOS 10.3 mos
|
Safety
|
Grade >=3 AE: ALT increased (3%), neutropenia (3%), cholangitis (1%) |
| Treatment-related grade >=3 AE (all patients): 9% |
| Most common treatment-related AE: infusion-related reactions (80%, all grade 1-2), nausea (30%) |
| Infusion-related reactions led to temporary interruption in 63% but no discontinuations |
| Discontinuations due to AEs: 3%
|
N Engl J Med 2026; Published online March 25, 2026
Park W, Kasi A, Spira AI Setidegrasib in Advanced Non–Small-Cell Lung Cancer and Pancreatic Cancer
http://doi.org/10.1056/NEJMoa2600752
Reviewed by Ulas D. Bayraktar, MD on Apr 9, 2026
