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The impact of first-generation covalent KRAS G12C inhibitors has been reduced due to the development of drug resistance, tolerability and challenges combining with immunotherapy. We designed olomorasib, a next-generation GDP-binding KRAS G12C inhibitor, for nanomolar potency as well as selectivity over wild-type inhibition. In both in vitro and in vivo models of KRAS G12C -mutant cancers, olomorasib reduces RAS activity and pERK levels, leading to substantial and significant tumor growth inhibition. Additionally, olomorasib combined with immune checkpoint inhibitors demonstrates greater anti-tumor activity compared to monotherapy. Furthermore, we demonstrate that olomorasib binds tightly to KRAS G12C even in the presence of clinically relevant second site mutations, a known mechanism of resistance and limitation to currently approved KRAS G12C inhibitors. These findings suggest that olomorasib could be effective for patients with KRAS G12C mutant cancers either as monotherapy or in combination with immunotherapy. Olomorasib monotherapy and combination treatments are currently being investigated clinically. The success of KRAS G12C mutation specific inhibitors in patients with KRAS-driven tumours is limited by the emergence of acquired resistance. Here, the authors characterise olomorasib, a next-generation covalent KRAS G12C-mutant inhibitor, demonstrating efficacy in the presence of clinically relevant resistance mutations in preclinical KRAS-driven cancer models.

The impact of first-generation covalent KRAS inhibitors has been reduced due to the development of drug resistance, tolerability and challenges combining with immunotherapy. We designed olomorasib, a next-generation GDP-binding KRAS inhibitor, for nanomolar potency as well as selectivity over wild-type inhibition. In both in vitro and in vivo models of KRAS -mutant cancers, olomorasib reduces RAS activity and pERK levels, leading to substantial and significant tumor growth inhibition. Additionally, olomorasib combined with immune checkpoint inhibitors demonstrates greater anti-tumor activity compared to monotherapy. Furthermore, we demonstrate that olomorasib binds tightly to KRAS even in the presence of clinically relevant second site mutations, a known mechanism of resistance and limitation to currently approved KRAS inhibitors. These findings suggest that olomorasib could be effective for patients with KRAS mutant cancers either as monotherapy or in combination with immunotherapy. Olomorasib monotherapy and combination treatments are currently being investigated clinically.