Oncology research and treatment · 2026
KRAS Inhibition in Non-Small Cell Lung Cancer with Central Nervous System Involvement: Current Evidence and Future Directions.
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Pereira Rafael Alvim, Oliveira Christian, Tumelero Milena, Fernandes Humberto, Lenz Gabriel
Аннотация
BACKGROUND: KRAS mutations, particularly G12C, frequently cause non-small cell lung cancer (NSCLC). Due to the protective nature of the blood-brain barrier and the paucity of clinical data specifically about CNS involvement, brain metastases - which occur in up to 40% of patients with advanced KRAS-mutant NSCLC - present unique therapeutic challenges.
SUMMARY: The changing role of KRAS-targeted treatments in NSCLC with metastases to the central nervous system (CNS) is examined in this review. It highlights new clinical findings on KRAS G12C inhibitors, including sotorasib and adagrasib, and discusses the challenges in delivering medications across the blood-brain barrier. Along with outlining important resistance mechanisms, such as bypass signaling pathways, secondary KRAS mutations, and SHP2-mediated feedback, the review also examines new combination strategies that utilize SHP2 inhibitors, immunotherapy, and radiation.
KEY MESSAGES: Even with recent progress in treatment, brain metastases continue to pose a significant challenge in managing KRAS-mutant NSCLC. Among currently available agents, adagrasib has shown encouraging intracranial activity and CNS penetration, and rational combination strategies are being explored to overcome resistance. Ongoing research should prioritize CNS-specific endpoints and integrated treatment approaches tailored to patients with brain involvement.
SUMMARY: The changing role of KRAS-targeted treatments in NSCLC with metastases to the central nervous system (CNS) is examined in this review. It highlights new clinical findings on KRAS G12C inhibitors, including sotorasib and adagrasib, and discusses the challenges in delivering medications across the blood-brain barrier. Along with outlining important resistance mechanisms, such as bypass signaling pathways, secondary KRAS mutations, and SHP2-mediated feedback, the review also examines new combination strategies that utilize SHP2 inhibitors, immunotherapy, and radiation.
KEY MESSAGES: Even with recent progress in treatment, brain metastases continue to pose a significant challenge in managing KRAS-mutant NSCLC. Among currently available agents, adagrasib has shown encouraging intracranial activity and CNS penetration, and rational combination strategies are being explored to overcome resistance. Ongoing research should prioritize CNS-specific endpoints and integrated treatment approaches tailored to patients with brain involvement.