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<p>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&#xa0;195 patients are reported: Phase 1a dose escalation (<i>n</i> = 112) assessed olomorasib monotherapy at 50, 100, 150 or 200 mg BID across <i>KRAS</i> 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 (<i>n</i> = 83) was to evaluate the safety and tolerability of olomorasib in specific <i>KRAS</i> 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&#xa0;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.</p>

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Pan-tumor activity of olomorasib, a next-generation KRAS G12C inhibitor in KRAS G12C-mutant advanced solid tumors: a first-in-human study

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年3月12日

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  • Yonina R. Murciano-Goroff,
  • Antoine Hollebecque,
  • Rebecca S. Heist,
  • Philippe A. Cassier,
  • Ji-Youn Han,
  • So Yeon Kim,
  • Joshua K. Sabari,
  • Diego Tosi,
  • Adrian Sacher,
  • Timothy F. Burns,
  • Toshio Shimizu,
  • Natraj Reddy Ammakkanavar,
  • Alexander Spira,
  • Carlos Gomez-Roca,
  • Amita Patnaik,
  • Rasha Cosman,
  • J. Nicholas Bodor,
  • Misako Nagasaka,
  • Arthur Xintian You,
  • Samuel C. McNeely,
  • Raimund Peter,
  • Aaron Fink,
  • Aaron Chen,
  • Geoffrey R. Oxnard,
  • Melinda D. Willard,
  • Yasutoshi Kuboki,
  • Takafumi Koyama

摘要

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.