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

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.

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Journal
Nature Communications
Published
2026-03-12
DOI
https://doi.org/10.1038/s41467-026-69943-7
Primary Topic
Protein Kinase Regulation and GTPase Signaling
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article
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article

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

Natraj Reddy Ammakkanavar, Aaron Chen, Ji‐Youn Han, Joshua K. Sabari et al.
Nature Communications
Protein Kinase Regulation and GTPase Signaling
article

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

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

Abstract

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.

Nature Communications
Kansai Medical University (JP), Fox Chase Cancer Center (US), University Health Network (CA), Memorial Sloan Kettering Cancer Center (US), Eli Lilly (United States) (US), University of Toronto (CA), University of California, Irvine (US), Institut Gustave Roussy (FR), Princess Margaret Cancer Centre (CA), UNSW Sydney (AU), Yale University (US), NYU Langone Health (US), St Vincent's Hospital Melbourne (AU), Massachusetts General Hospital (US), Institut universitaire du cancer de Toulouse Oncopole (FR), Centre Léon Bérard (FR), South Texas Accelerated Research Therapeutics (US), National Cancer Center (KR), Virginia Cancer Specialists (US), UPMC Hillman Cancer Center (US), University of Pittsburgh Medical Center (US), Community Health Network (US), Institut de Recherche en Cancérologie de Montpellier (FR), National Cancer Center Hospital East (JP), The Kinghorn Cancer Centre (AU), Tokyo National Hospital (JP), Institut Regional du Cancer de Montpellier (FR)
Eli Lilly and Company, Memorial Sloan-Kettering Cancer Center, National Institutes of Health, National Cancer Institute
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Openalex Percentile: Top 26%
Protein Kinase Regulation and GTPase Signaling
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