Dr Negrao on Olomorasib Plus Chemoimmunotherapy in KRAS G12C–Mutant NSCLC

“[The] combination of olomorasib and chemoimmunotherapy in the first-line setting continues to show promising efficacy and durable responses.”

Marcelo V. Negrao, MD, an associate professor in the Department of Thoracic/Head and Neck Medical Oncology at The University of Texas MD Anderson Cancer Center, discussed updated efficacy and safety findings from an integrated analysis of the phase 1/2 LOXO-RAS-20001 trial (NCT04956640) and the safety lead-in of the phase 3 SUNRAY-01 trial (NCT06119581) evaluating olomorasib plus pembrolizumab (Keytruda), pemetrexed, and platinum chemotherapy in patients with previously untreated KRAS G12C–mutant non–small cell lung cancer, as well as how these data inform the ongoing SUNRAY-01 trial.

At the 2026 ESMO Congress, Negrao presented updated data from 77 patients with advanced KRAS G12C–mutant non–small cell lung cancer (NSCLC) who received the investigational KRAS G12C inhibitor olomorasib plus chemoimmunotherapy as first-line treatment. The analysis pooled 37 patients from LOXO-RAS-20001 and 40 patients from the SUNRAY-01 safety lead-in. The results captured an additional 9 months of follow-up, bringing the median follow-up to 18.7 months (IQR, 16.8-20.3).

Responses remained durable with longer follow-up. The confirmed objective response rate was 62%, and the disease control rate was 90%. The median duration of response was 14.5 months (95% CI, 8.5-not evaluable [NE]), and the median progression-free survival was 11.6 months (95% CI, 9.5-21.5).

Durable responses were also observed across PD-L1 expression levels. In patients with PD-L1 expression below 1%, the median duration of response (DOR) was 10.5 months (95% CI, 5.4-NE) and the median progression-free survival (PFS) was 9.7 months (95% CI, 5.9-15.9). In those with PD-L1 expression of 1% to 49%, the median DOR was not reached and the median PFS was 12.1 months (95% CI, 5.9-NE); neither end point was evaluable in patients with PD-L1 expression of at least 50%. Confirmed objective response rates were 54%, 68%, and 67% in the PD-L1 below 1%, 1% to 49%, and at least 50% subgroups, respectively.

With respect to safety, liver toxicity has limited the development of some KRAS G12C inhibitor–immunotherapy combinations, and no targeted first-line regimen is approved for this population. Negrao called the hepatic toxicity profile of olomorasib plus chemoimmunotherapy very manageable. The median time to onset of grade 3 or higher hepatic events was 43 days (range, 13-145), and the median duration was 4 days (range, 1-37). All these events resolved to grade 1 or baseline with dose modifications and/or corticosteroids, no patients discontinued the regimen because of hepatic events, and there were no confirmed cases of Hy’s law. Across all treatment-related adverse effects, olomorasib dose reductions occurred in 19.5% of patients, and 7.8% permanently discontinued the regimen.

The FDA granted olomorasib breakthrough therapy designation in September 2025, in combination with pembrolizumab, for the first-line treatment of patients with KRAS G12C–mutant NSCLC with PD-L1 expression of at least 50%. Olomorasib is not approved by any regulatory authority.

Part B of SUNRAY-01, which compares chemoimmunotherapy plus olomorasib vs placebo plus chemoimmunotherapy in the first-line setting regardless of PD-L1 expression, has completed enrollment, and results are expected in the first half of 2027. Negrao noted that these will be the first randomized data presented for a KRAS G12C inhibitor in the first-line setting.