Intracranial efficacy of olomorasib, a second-generation KRAS G12C inhibitor, in patients with KRAS G12C-mutant NSCLC who have active, untreated brain metastases

Background: Olomorasib, a potent and highly selective second-generation inhibitor of GDP-bound KRAS G12C has demonstrated preliminary intracranial (IC) activity in patients (pts) with brain metastases (mets). Brain mets are associated with poor prognosis and occur in 25-42% of pts with KRAS G12C-mutant NSCLC. Here we present updated results on the IC efficacy of olomorasib in pts with KRAS G12C-mutant NSCLC with active, untreated brain mets from the phase 1/2 LOXO-RAS-20001 (NCT04956640) study. Methods : ECOG 0-1 and KRAS G12C inhibitor-naïve pts with advanced NSCLC positive for KRAS G12C (tissue or plasma) with active, untreated brain mets received single agent olomorasib (150 mg BID). Safety was assessed in all treated pts. IC response by modified RECIST v1.1 in≥1 measurable (≥5 mm) IC lesion was evaluated in pts with at least one post-baseline response assessment or who discontinued treatment before the first assessment. Results : As of 15 January 2025, 19 pts (median age 65 yrs, range 42-80) were treated. 15 pts had prior systemic therapy – 13 pts in the metastatic setting; 8 pts had≥2 lines of therapy. Median number of IC target lesions was 1 (range, 1-3). Safety was consistent with previous reports of olomorasib. The most common TRAEs (>15%) were low-grade diarrhea, fatigue and nausea; no grade≥3 TRAEs were observed. Among the 18 efficacy-evaluable pts, IC objective response rate was 44.4% (8/18 pts; 95% CI: 21.5-69.2; 1 CR, 5 PR, 2 uPR pending/ongoing) and disease control rate was 83.3% (15/18 pts; 95% CI, 58.6-96.4; 7 SD). Median time to IC response was 2.0 months (range 1.3-3.9) and median duration of response and progression-free survival were not yet reached (5.4 months median follow-up for IC response; 95% CI, 2.79-NE). Conclusion: Olomorasib continues to demonstrate promising IC activity and disease control in pts with KRAS G12C-mutant NSCLC and active, untreated brain mets. These results support continued clinical development of olomorasib in pts with KRAS G12C-mutant NSCLC including in pts with brain mets. Two global registrational studies investigating olomorasib in combination with immunotherapy in first-line metastatic and early-stage NSCLC are ongoing (NCT06119581 and NCT06890598). Publication History Article published online: 04 March 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany