Volume 10,Issue 5
Combined Zorifertinib and Almonertinib in EGFR-Mutant NSCLC with Leptomeningeal Metastasis: A Two-Case Report with Serial Plasma and Cerebrospinal Fluid Drug Concentration Monitoring
Background: Leptomeningeal metastasis (LM) is a devastating complication of EGFR-mutant non-small cell lung cancer (NSCLC) with a dismal prognosis. Optimal CNS-penetrating EGFR-tyrosine kinase inhibitors (TKIs) and combination strategies remain poorly defined, and real-time pharmacokinetic data in LM patients are scarce. Case presentation: We report two female patients (Z005, aged 50, EGFR exon 19 deletion; Z006, aged 62, EGFR L858R/T790M) with LM who received combination therapy with zorifertinib and almonertinib. Serial paired plasma and cerebrospinal fluid (CSF) samples were collected via the Ommaya reservoir for targeted drug concentration measurements, alongside longitudinal RANO-LM assessments. Patient Z005 demonstrated a dramatic response, with neurological score improving from 3 to 0 and MRI showing marked improvement within two months. Patient Z006 received the combination regimen for five months, after which her cerebrospinal fluid cytology turned negative and neurological symptoms resolved completely, suggesting effective disease control. Both patients tolerated the combination therapy with manageable adverse events, and at the time of last follow-up, both remained clinically stable with no evidence of disease progression. Results: CSF total concentrations of almonertinib ranged from 0.770 to 14.9 nmol/L. zorifertinib achieved substantially higher CSF penetration, with CSF total concentrations of 20.9–27.2 nmol/L and Kpuu, CSF values of 0.81–0.94, consistent with near-complete blood-brain barrier penetration. Conclusion: This report provides the detailed pharmacokinetic characterization of combined zorifertinib and almonertinib in LM patients using Ommaya reservoir-based CSF sampling. Two similar clinical outcomes suggest that combination regimens may produce favorable therapeutic effects in patients with LM, and also reflect the potential clinical value of therapeutic drug monitoring (TDM).
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