Leptomeningeal metastasis (LM) is a severe complication of epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC), associated with limited treatment options and poor prognosis. Osimertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI), has demonstrated central nervous system (CNS) efficacy, while ramucirumab, a VEGFR-2 inhibitor, may enhance drug penetration and therapeutic response. The combination has not been reported in LM. We report two patients with EGFR-mutant NSCLC who developed LM and received osimertinib (80 mg/day) plus ramucirumab (10 mg/kg every 3 weeks). A 79-year-old man with an EGFR exon 21 L858R mutation presented with progressive neurological symptoms and MRI-confirmed LM. Combination therapy led to marked clinical improvement, resolution of leptomeningeal enhancement, and stable disease for over 12 months, with only mild hypertension and rash. A 74-year-old woman with an EGFR exon 19 deletion and LM involving the brainstem also demonstrated significant neurological recovery, including regaining oral intake, radiologic regression of LM lesions, and durable control for more than one year. Adverse events were limited to mild dermatologic toxicity. Although osimertinib has established activity in LM, outcomes remain suboptimal. Data from systemic disease suggest that combining EGFR and VEGF inhibition may further enhance efficacy, but LM-specific evidence has been lacking. These two cases highlight the potential of osimertinib plus ramucirumab as a safe and effective therapeutic approach in EGFR-mutant NSCLC with LM, providing durable neurologic and radiologic responses. Further prospective studies are warranted to validate these findings and better define the role of this regimen in LM management.
Tsai et al. (2026) studied this question.