First-in-class KRAS G12D–targeted protein degrader active against lung, pancreatic cancers

The first-in-class KRAS G12D–targeted protein degrader setidegrasib has demonstrated antitumour activity in patients with previously treated advanced non–small-cell lung cancer (NSCLC) or pancreatic ductal adenocarcinoma harbouring the KRAS G12D mutation, according to a phase I study.

The trial involved 203 patients, of which 59 had NSCLC, 124 had pancreatic ductal adenocarcinoma, and 20 had other solid tumours. These patients received setidegrasib, administered intravenously once a week at doses of 10 to 800 mg.

In the trial, researchers evaluated the drug’s safety profile, with dose-limiting toxic effects and adverse events (AEs) set as the primary endpoints, and determined the phase II dose. Setidegrasib at 600 mg was selected as the recommended phase II dose based on safety analyses and pharmacokinetics.

A total of 76 patients (median age 66 years, 54 percent female, 57 percent White) received the recommended setidegrasib dose. Of these, 45 had NSCLC and 31 had pancreatic ductal adenocarcinoma, with a median of two lines of previous anticancer therapy.

All patients experienced AEs during treatment, with 42 percent having AEs of grade 3 or higher. Treatment-related AEs occurred in 93 percent of patients, with the most common being transient infusion-related reactions (80 percent) and nausea (30 percent). Only two patients discontinued treatment due to AEs.

In the NSCLC group, 36 percent of patients had an objective response over a median follow-up of 9.7 months. The median progression-free survival (PFS) was 8.3 months, and the estimated 12-month overall survival (OS) was 59 percent.

In the metastatic pancreatic ductal adenocarcinoma, 24 percent of patients had an objective response over a median follow-up of 15.2 months. The median PFS was 3 months, and the median OS was 10.3 months.