Olomorasib Combo Shows Manageable Liver Toxicity in KRAS G12C-Mutant NSCLC

In an interview at the 2026 ESMO Congress, Marcelo Vailati Negrao, assistant professor of thoracic/head and neck medical oncology at The University of Texas MD Anderson Cancer Center, in Houston, TX, discusses the hepatic safety profile of olomorasib combined with chemoimmunotherapy in patients with KRAS G12C-mutant non–small cell lung cancer (NSCLC), addressing a key challenge that has limited the development of earlier KRAS G12C inhibitor and immunotherapy combinations.

Liver toxicity has been a concern with some combinations of KRAS G12C inhibitors and immunotherapy. According to updated findings from the LOXO-RAS-20001 (NCT04956640) and SUNRAY-01 (NCT06119581) trials, however, olomorasib combined with pembrolizumab (Keytruda) and chemotherapy demonstrated a manageable hepatic safety profile in the first-line setting.

The median time to onset of grade 3 or higher hepatic adverse events was 43 days, and the median duration of these events was 4 days. Grade 3 or higher increases in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) occurred in 12% and 10% of patients. Importantly, all grade 3 or higher hepatic events resolved to grade 1 or baseline following interventions that included dose modifications, treatment interruptions, and/or corticosteroids.

No patients discontinued the study regimen because of hepatic adverse events. Investigators also reported no confirmed cases of Hy's law, a combination of liver injury and elevated bilirubin that can indicate potentially serious drug-induced liver damage.

These safety findings are relevant because treatment-related hepatotoxicity has complicated efforts to combine KRAS G12C inhibitors with immune checkpoint inhibitors. A regimen with manageable liver toxicity could support further evaluation of this approach for patients with previously untreated advanced KRAS G12C-mutant NSCLC.

Olomorasib is an investigational, selective KRAS G12C inhibitor with central nervous system activity. The phase 3 SUNRAY-01 trial is evaluating olomorasib plus pembrolizumab and chemotherapy against placebo plus pembrolizumab and chemotherapy in patients with advanced KRAS G12C-mutant NSCLC and PD-L1 expression of 1% to 100%.

The ongoing trial will help further characterize the combination's safety and efficacy as a potential first-line treatment option.