The covalent KRAS-G12C inhibitors adagrasib and sotorasib are approved for patients with previously treated KRASG12C-mutant non-small-cell lung cancer (NSCLC) or colorectal cancer (CRC); however, the efficacy of these agents is limited, in large part, by suboptimal target engagement. Now, data from an ongoing single-arm phase I/II trial indicate that D3S-001 (also known as elisrasib), a next-generation KRAS-G12C inhibitor with higher potency, faster target-binding kinetics and thus reduced susceptibility to growth factor-stimulated nucleotide exchange, might have improved antitumour activity.

In phase Ia of this trial, 42 patients with previously treated advanced-stage KRASG12C-mutant NSCLC (n = 25), CRC (n = 13) or pancreatic ductal adenocarcinoma (PDAC; n = 4) received D3S-001 at various doses, with primary end points of safety, tolerability, maximum tolerated dose (MTD) and recommended phase II dose (RP2D). D3S-001 was generally well tolerated and had a safety profile similar to that of first-generation KRAS-G12C inhibitors. No dose-limiting toxicities were observed and thus the MTD was not reached. Although 7 patients (16.7%) had grade 3 treatment-related adverse events (TRAEs), these were limited to elevated serum markers or nausea; no grade 4–5 TRAEs occurred. An RP2D of 600 mg was selected on the basis of pharmacokinetics. Among 34 evaluable patients with KRAS-G12C inhibitor-naive disease, the objective response rate (ORR) was 73.5% overall, and it was 66.7%, 88.9% and 75.0% in those with NSCLC, CRC and PDAC, respectively. The disease control rate (DCR) was 97.1%, and the estimated 6-month duration of response (DOR) and progression-free survival (PFS) were 78.4% and 68.6%, respectively.