Pan-tumor activity of olomorasib, a next-generation KRAS G12C inhibitor in KRAS G12C-mutant advanced solid tumors: a first-in-human study
Published report from the trial registered as NCT04956640, in Nature Communications (2026), chosen as the most cited paper whose own text cites the registry id.
Overview
This multicenter, first-in-human Phase 1 study (NCT04956640) evaluated olomorasib (LY3537982), a next-generation KRAS G12C inhibitor designed to enhance target occupancy at low absolute exposures. In total, data from 195 patients are reported: Phase 1a dose escalation (n = 112) assessed olomorasib monotherapy at 50, 100, 150 or 200 mg BID across KRAS G12C-mutant advanced solid tumors; the primary objective was to determine the recommended Phase 2 dose (RP2D) based on dose-limiting toxicities (DLTs). No DLTs occurred, and 150 mg BID was selected as the RP2D. The primary objective for the Phase 1b dose expansion (n = 83) was to evaluate the safety and tolerability of olomorasib in specific KRAS G12C-mutant tumor types. Olomorasib was well tolerated, with predominantly grade 1-2 treatment-related adverse events (TRAEs) and infrequent grade 3 TRAEs; no grade 4/5 TRAEs occurred. Secondary objectives evaluated the antitumor activity of olomorasib. Among 168 efficacy-evaluable patients, the ORR and median PFS were both higher in non-CRC solid tumors compared to CRC, including in patients with NSCLC who previously received a KRAS G12C inhibitor. Intracranial responses were observed in patients with untreated, active brain metastases. This may support the potential of next-generation KRAS G12C inhibitors to overcome limitations of earlier agents and justify further investigation of combination therapy.
Indexed on Europe PMC as PubMed record 41820335 (DOI 10.1038/s41467-026-69943-7). Its abstract cites the registry id NCT04956640, which is how it was matched to this trial; no figure has been checked by an editor.
This is the paper Europe PMC returns for registry id NCT04956640 with the most citations, so it is the natural first reading for anyone following the trial. Read the abstract above alongside the trial page and the registry entry; the record was linked automatically and its figures have not been checked by hand.
- Matched to the trial by the registry id cited in the Europe PMC record; the summary reproduces the record's abstract and no figure has been verified against the full paper.