Olomorasib Plus Pembrolizumab Earns Breakthrough Therapy Designation in Untreated KRAS G12C–Mutated NSCLC

Olomorasib has received breakthrough therapy designation from the FDA in combination with pembrolizumab (Keytruda) for the frontline treatment of patients with unresectable advanced or metastatic non–small cell lung cancer (NSCLC) harboring a KRAS G12C mutation and a PD-L1 expression level of at least 50%, as determined by FDA approved tests.1

The designation is based on findings from the phase 1/2 LOXO-RAS-20001 trial (NCT04956640) and the dose optimization portion of the phase 3 SUNRAY-01 trial (NCT06119581). Updated findings from an integrated analysis of the 2 studies will be presented at the IASLC 2025 World Conference on Lung Cancer (WCLC).

Prior data from LOXO-RAS-20001 presented during the 2025 ASCO Annual Meeting demonstrated that efficacy-evaluable patients (n = 46) who received olomorasib plus pembrolizumab experienced an overall response rate (ORR) of 74% (95% CI, 59.8%-85.7%) regardless of PD-L1 expression.2 The disease control rate (DCR) was 91% (95% CI, 79.2%-97.6%) and the median duration of response (DOR) was not evaluable (NE; 95% CI, 10.5-NE). The median progression-free survival (PFS) was NE (95% CI, 12.0-NE); the 6- and 12-month PFS rates were 80.2% (95% CI, 64.1%-89.6%) and 66.7% (95% CI, 40.9%-83.2%).

"The breakthrough therapy designation recognizes the potential for olomorasib to be a meaningful treatment advance and highlights the continued unmet need for improved options for patients with KRAS G12C-mutant NSCLC, particularly in the first-line setting in combination with standard-of-care [SOC] immunotherapy," David Hyman, MD, chief medical officer of Eli Lilly and Company, stated in a news release.1 "We look forward to presenting updated data from the olomorasib development program in significantly more patients and with longer follow-up at WCLC and continuing to investigate olomorasib in combination with immunotherapy-based regimens in a variety of treatment settings across the phase 3 SUNRAY-01 and SUNRAY-02 [NCT06890598] studies."

Part G of LOXO-RAS-20001 enrolled patients with treatment-naive NSCLC who received no prior therapy for metastatic disease.2 Notably, all PD-L1 expression levels were permitted. Up to 1 cycle of SOC therapy was allowed prior to enrollment, defined as a single 21-day cycle of pembrolizumab at 200 mg. Patients were stratified by PD-L1 status (0%-49% vs ≥ 50%).

Patients were randomly assigned 1:1 to receive olomorasib at 50 mg or 100 mg twice daily. All patients received pembrolizumab at 200 mg every 3 weeks.

The key objectives of the study included safety and tolerability, determining the maximum tolerated and recommended phase 2 doses, pharmacokinetic measures, and ORR, DCR, PFS, and DOR, all per RECIST 1.1 criteria.

Additional findings from LOXO-RAS-20001 revealed that efficacy-evaluable patients with a PD-L1 expression level of at least 50% (n = 20) achieved an ORR of 90% (95% CI, 68.3%-98.8%) and a DCR of 95% (95% CI, 75.1%-99.9%). The median DOR and PFS were NE (95% CI, 10.5-NE) and NE (95% CI, 12.0-NE), respectively. The 6- and 12-month PFS rates were 89.7% (95% CI, 64.8%-97.3%) and 59.8% (95% CI, 8.2%-90.0%), respectively.

In terms of safety, any-grade treatment-emergent adverse effects (TEAEs) were reported in 93.8% of the safety population (n = 48). The most common any-grade TEAEs included diarrhea (41.7%), increased alanine aminotransferase (ALT) levels (33.3%), and increased aspartate aminotransferase (AST) levels (29.2%).

Any-grade treatment-related adverse effects (TRAEs) were reported in 89.6% of patients. The most common any-grade TRAEs were diarrhea (35.4%), increased ALT levels (29.2%), and increased AST levels (29.2%). Dose reductions of olomorasib due to TRAEs were reported in 23% of patients and 4% of patients had to discontinue treatment due to TRAEs.

References

1. Lilly's olomorasib receives U.S. FDA's Breakthrough Therapy designation for the treatment of certain newly diagnosed metastatic KRAS G12C-mutant lung cancers. News release. Eli Lilly and Company. September 4, 2025. Accessed September 4, 2025. https://investor.lilly.com/news-releases/news-release-details/lillys-olomorasib-receives-us-fdas-breakthrough-therapy
2. Dragnev K, Murciano-Goroff Y, Ammakkanavar N, et al. Safety and efficacy of olomorasib + immunotherapy in first-line treatment of patients with KRAS G12C-mutant advanced NSCLC: update from the LOXO-RAS-20001 trial. J Clin Oncol. 2025;43(suppl 16):8519. doi:10.1200/JCO.2025.43.16_suppl.8519