Pan-tumor activity of olomorasib, a next-generation KRAS G12C inhibitor in KRAS G12C-mutant advanced solid tumors: a first-in-human study
- 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
2026-03-12
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.