Multinational phase 1 trial of setidegrasib in advanced non-small cell lung cancer and pancreatic cancer

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 (PDAC), occurring in 40% of patients. No targeted therapies directed against this variant are currently approved for clinical use. Setidgrasib is a first-in-class KRAS G12D-targeted protein degrader. A phase 1 trial at 28 centers in five countries evaluated setidegrasib in patients with previously treated advanced solid tumors harboring KRAS p.G12D variants. Primary objectives were to evaluate safety and to determine the recommended phase 2 dose (RP2D). A total of 203 patients were enrolled and received seticegrasib intravenously once weekly at doses of 10 to 800 mg. Among the 76 patients who received setidegrasib at a dose of 600 mg, which was ultimately selected as RP2D, adverse events occurred in all patients, with events of grade 3 or higher in 42%; treatment-related adverse events occurred in 93%, and adverse events leading to discontinuation in two patients. Among the patients with advanced NSCLC who received the RP2D, 36% (95% CI 22-51) had a partial response, with median progression-free survival (PFS) 8.3 months (4.1-NE) and estimated 12-months overall survival (OS) rate 59% (40-74). Among the patients with advanced PDAC who received the RP2D, 24% (95% CI 8-47) had a response, with a median PFS of 3.0 months (1.4-6.9) and median OS 10.3 months (4.2-13.0). The authors conclude that 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 PDAC.