A Comprehensive Monograph on Olomorasib (LY3537982): A Second-Generation KRAS G12C Inhibitor

1.0 Executive Summary

Olomorasib (LY3537982) is an investigational, orally available, small-molecule therapeutic agent developed by Eli Lilly and Company. It is engineered as a potent, highly selective, second-generation covalent inhibitor of the Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) protein harboring the G12C mutation. This specific mutation is a key oncogenic driver in a significant subset of solid tumors, most notably non-small cell lung cancer (NSCLC) and colorectal cancer (CRC). Preclinical data established Olomorasib's superior potency and target engagement compared to first-generation KRAS G12C inhibitors. A key pharmacological feature is its ability to achieve high ($>90\%$) and sustained target occupancy at low, well-tolerated doses, which has proven critical for its clinical development.

The clinical program for Olomorasib is extensive, headlined by the foundational Phase 1/2 LOXO-RAS-20001 trial and the pivotal Phase 3 SUNRAY-01 and SUNRAY-02 studies. Clinical data have demonstrated a manageable safety profile and compelling anti-tumor activity. As a monotherapy, Olomorasib has shown efficacy in patients with NSCLC who have progressed on prior first-generation KRAS G12C inhibitors, with an objective response rate (ORR) of approximately 40%. In combination regimens, Olomorasib has produced particularly striking results. For the first-line treatment of KRAS G12C-mutant, PD-L1-high ($ \ge 50% $) NSCLC, its combination with the immune checkpoint inhibitor pembrolizumab yielded an ORR of up to 85%. This promising outcome led the U.S. Food and Drug Administration (FDA) to grant the combination Breakthrough Therapy Designation.