D3S-001 in advanced solid tumors with KRASG12C mutations: a phase 1 trial

D3S-001 is a next-generation KRAS-G12C inhibitor (G12Ci) designed to enhance target engagement efficiency and overcome growth factor-induced nucleotide exchange. D3S-001 was evaluated in a phase 1a dose-escalation study in patients with advanced solid tumors harboring KRASG12C mutation (N = 42) and a phase 1b expansion cohort of patients with non-small-cell lung cancer (NSCLC) whose disease progressed after prior G12Ci therapy (N = 20). The primary endpoints were safety and determination of the maximum tolerated dose. Secondary endpoints included pharmacokinetics, confirmed objective response rate (ORR) and disease control rate. D3S-001 demonstrated dose-dependent pharmacokinetics and no dose-limiting toxicities, and the maximum tolerated dose was not reached. Grade 3 treatment-related adverse events were reported in seven patients (16.7%) in the G12Ci-naive dose-escalation cohort and two patients (10.0%) in the G12Ci-pretreated NSCLC expansion cohort. There were no grade 4 or 5 treatment-related adverse events. D3S-001 600 mg was selected as the dose for further investigation based on pharmacokinetics. Confirmed ORR in the G12Ci-naive population was 73.5% overall (25 of 34), and 66.7% (14 of 21), 88.9% (8 of 9) and 75.0% (3 of 4) in patients with NSCLC, colorectal cancer and pancreatic ductal adenocarcinoma, respectively. Among patients with G12Ci-pretreated NSCLC, ORR was 30.0% (6 of 20) and disease control rate was 80.0% (16 of 20). This study demonstrates the safety and tolerability of D3S-001 monotherapy with promising antitumor activity. The phase 1b expansion phase is ongoing. ClinicalTrials.gov identifier: NCT05410145 . As presented at the 2025 AACR Annual Meeting, in an ongoing first-in-human phase 1 trial of a next-generation KRAS-G12C inhibitor in patients with solid tumors, encouraging safety and response results were observed, including in patients with non-small-cell lung cancer.