Multinational phase 1 trial of D3S-001 in advanced solid tumors with KRAS-G12C mutations

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 KRAS-G12C mutation and a phase 1b expansion cohort of patients with NSCLC whose disease progressed after prior G12Ci therapy. D3S-001 demonstrated dose-dependent pharmacokinetics without dose-limiting toxicities; there were no grade 4 or 5 treatment-related adverse events. D3S-001 600 mg once daily was selected as the dose for further investigation based on pharmacokinetics. Confirmed ORR in the G12Ci-naïve population was 74% overall, and 67%, 89%, and 75% in patients with NSCLC, CRC, and PDAC, respectively. In the G12Ci-pretreated NSCLC cohort, ORR was 30% and DCR was 80%. The authors conclude that this study demonstrates the safety and tolerability of D3S-001 monotherapy with promising antitumor activity.