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

Yonina R Murciano-Goroff1, Antoine Hollebecque2, Rebecca S Heist3

  • 1Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. murciany@mskcc.org.

Nature Communications
|March 13, 2026
PubMed

Insights

Olomorasib, a novel KRAS G12C inhibitor, demonstrated good tolerability and promising antitumor activity in advanced solid tumors. The recommended Phase 2 dose was established, showing potential for overcoming limitations of prior KRAS G12C therapies.

Area of Science:

  • Oncology
  • Clinical Pharmacology
  • Drug Development

Background:

  • KRAS G12C mutations are common drivers in various solid tumors, including non-small cell lung cancer (NSCLC) and colorectal cancer (CRC).
  • Existing KRAS G12C inhibitors face challenges such as limited target occupancy and acquired resistance.
  • Olomorasib (LY3537982) represents a next-generation inhibitor designed for enhanced target engagement.

Purpose of the Study:

  • To evaluate the safety, tolerability, and determine the recommended Phase 2 dose (RP2D) of olomorasib in patients with advanced solid tumors harboring KRAS G12C mutations.
  • To assess the preliminary antitumor activity, including objective response rate (ORR) and progression-free survival (PFS), of olomorasib monotherapy.
  • To explore the efficacy of olomorasib in specific tumor types and in patients with brain metastases.

Main Methods:

  • A multicenter, first-in-human Phase 1 study (NCT04956640) involving dose escalation (Phase 1a) and dose expansion (Phase 1b).
  • Phase 1a enrolled 112 patients with advanced solid tumors treated with olomorasib at doses of 50, 100, 150, or 200 mg twice daily (BID) to determine the RP2D based on dose-limiting toxicities (DLTs).
  • Phase 1b enrolled 83 patients to further evaluate safety, tolerability, and antitumor activity in specific KRAS G12C-mutant tumor types.

Main Results:

  • No DLTs were observed in Phase 1a, and 150 mg BID was selected as the RP2D.
  • Olomorasib was well tolerated, with most treatment-related adverse events (TRAEs) being Grade 1-2; no Grade 4/5 TRAEs occurred.
  • Among 168 efficacy-evaluable patients, higher ORR and median PFS were observed in non-CRC solid tumors compared to CRC, including in NSCLC patients previously treated with a KRAS G12C inhibitor. Intracranial responses were noted in patients with untreated brain metastases.

Conclusions:

  • Olomorasib is a well-tolerated, next-generation KRAS G12C inhibitor with promising antitumor activity in advanced solid tumors.
  • The RP2D of 150 mg BID supports further clinical investigation of olomorasib.
  • Olomorasib shows potential to overcome limitations of earlier KRAS G12C inhibitors and warrants investigation in combination therapies.

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