Central nervous system metastases affect approximately 40% of patients with KRAS G12C-positive non-small cell lung cancer, presenting significant management challenges that highlight the limitations of current targeted therapies. Unlike patients with EGFR- and ALK-positive tumors who benefit from highly CNS-penetrant targeted agents, KRAS G12C patients have limited systemic options with proven intracranial activity.
Limited Systemic Treatment Options for Brain Metastases
KRAS G12C inhibitors show approximately 40% to 43% intracranial response rates in untreated brain metastases. However, these response rates remain below 50%, necessitating careful patient monitoring and readiness for local ablative therapy. Immunotherapy and chemoimmunotherapy combinations demonstrate modest CNS response rates, further limiting systemic treatment options for these patients.
When systemic options are exhausted after platinum-based chemotherapy and immunotherapy, stereotactic radiosurgery often becomes the preferred approach for CNS lesions. For asymptomatic, small CNS metastases (≤5 mm without edema), systemic therapy initiation with close monitoring represents a reasonable approach.
Surveillance Strategies and Clinical Management
Surveillance strategies for CNS metastases vary among practitioners, with baseline MRI universally recommended but routine follow-up imaging practices differing. Some oncologists perform periodic surveillance scans for high-risk patients, while others monitor symptomatically. The lack of robust CNS activity from systemic agents emphasizes the importance of early detection and prompt local therapy intervention when CNS progression occurs.
KRAS G12C Treatment Landscape
KRAS mutations represent approximately 30% of NSCLC cases, with KRAS G12C comprising 12% to 14% of all non-small cell lung cancer diagnoses. Treatment decisions for KRAS G12C-positive patients depend heavily on PD-L1 expression levels, with single-agent immunotherapy recommended for patients with PD-L1 expression ≥50%, while combination immunotherapy plus chemotherapy is preferred for those with PD-L1 <50%.
Comutations, particularly STK11/LKB1, may influence treatment selection toward dual checkpoint blockade strategies. The discussion emphasizes the critical importance of comprehensive next-generation sequencing for all NSCLC patients to enable proper biomarker testing and targeted therapy matching, as patients cannot access potentially lifesaving targeted treatments without adequate molecular profiling.
The evolving landscape of KRAS G12C targeted therapy represents a significant advancement in precision oncology for lung cancer patients, with current treatment algorithms integrating biomarker testing results with patient characteristics to optimize therapeutic outcomes.
