Olomorasib Shows Promising Intracranial Activity in NSCLC Brain Metastases, Data Reveal

The treatment landscape for non–small cell lung cancer (NSCLC) harboring the challenging KRAS G12C mutation may be shifting, following the presentation of updated data on the investigational agent olomorasib. New results from the phase 1/2 LOXO-RAS-20001 study (NCT04956640), presented at the European Society of Clinical Oncology Congress 2025, highlight the potent second-generation inhibitor’s strong intracranial (IC) efficacy in patients diagnosed with active, untreated brain metastases.¹

This patient population is particularly difficult to treat, as brain metastases occur in 25% to 42% of patients with KRAS G12C-mutant NSCLC and are historically associated with a poor prognosis.²

The LOXO-RAS-20001 study specifically evaluated single-agent olomorasib (150 mg twice daily) in KRAS G12C inhibitor naïve patients with advanced NSCLC who also had measurable IC lesions at least 5 mm. As of the data cutoff on January 15, 2025, a total of 19 patients were treated with a median age of 65 years, and 15 had received prior therapy with 8 having 2 or more lines of treatment.^1,3

The results demonstrated significant clinical activity within the brain. Among the 18 efficacy-evaluable patients, the IC objective response rate (ORR) reached 44.4%. This robust response rate included 8 patients showing an objective response, including 1 complete response, 5 partial responses, and 2 unconfirmed partial responses that were pending or ongoing at the time of cutoff.¹

Furthermore, the disease control rate, which includes stable disease and objective responses, was notably high at 83.3%. Patients who responded saw a rapid effect, with the median time to IC response measured at just 2 months. The median duration of response (DOR) and median progression-free survival (PFS) were not yet reached at the time of reporting, with a median follow-up of 5.4 months for IC response.¹

The safety profile of olomorasib was consistent with previous reports. Importantly, no grade 3 or higher treatment-related adverse events (TRAEs) were observed. The most common TRAEs, reported in more than 15% of patients, were low-grade diarrhea, nausea, and fatigue.¹

These findings strongly suggest that olomorasib is demonstrating promising IC activity and disease control in this vulnerable subgroup of patients with KRAS G12C-mutant NSCLC. Researchers concluded that the positive results support the continued clinical development of olomorasib, particularly for patients presenting with brain metastases.

Moving forward, the drug’s role is being explored in earlier treatment lines and in combination with other therapies. Two global registrational studies are currently ongoing, investigating olomorasib combined with immunotherapy in both first-line metastatic NSCLC and early-stage NSCLC settings (NCT06119581 and NCT06890598).

REFERENCES

1. Schneider J, Italiano A, Hollebecque A, et al. Intracranial efficacy of olomorasib, a second-generation KRAS G12C inhibitor, in patients with KRAS G12C-mutant NSCLC who have active, untreated brain metastases. Presented at: European Society of Medical Oncology 2025 Congress. October 19, 2025.

2. Swart EM, Noordhof AL, Damhuis RAM, et al. Survival of patients with KRAS G12C mutated stage IV non-small cell lung cancer with and without brain metastases treated with immune checkpoint inhibitors. Lung Cancer. 2023;182(107290). doi:10.1016/j.lungcan.2023.107290

3. Study of LY3537982 in cancer patients with a specific genetic mutation (KRAS G12C). NCT04956640. Clinicaltrials.gov. Updated September 25, 2025. Accessed December 10, 2025. https://clinicaltrials.gov/study/NCT04956640