Zorifertinib for EGFR-mutant Non-small Cell Lung Cancer after Leptomeningeal Metastasis on Double-Dose Third-generation EGFR-TKI: A Case Report and Literature Review

Background: Leptomeningeal metastasis (LM) after third-generation EGFR-TKIs resistance carries a dismal prognosis. Limited blood–brain-barrier penetration rather than secondary EGFR mutations is the dominant resistance mechanism. We report a case managed with CNS-penetrant EGFR inhibition of zorifertinib. Method: A 53-year-old, never-smoking woman with EGFR L858R-mutant stage IVb non-small-cell lung cancer (NSCLC) developed LM after progression on osimertinib 160 mg and firmonertinib 160 mg. Salvage therapy with zorifertinib (200 mg BID) plus firmonertinib (80 mg qd) was initiated. Results: Within 14 days, the coma resolved. Karnofsky Performance Status improved from 20 to 70. Serial imaging at 3 and 5 months revealed stable disease with shrinkage according to RECIST 1.1. Only grade 1–2 diarrhea, rash, and transaminitis occurred and resolved with symptomatic care. Conclusion: The combination of zorifertinib plus firmonertinib provides durable intracranial control and rapid neurological recovery after third-generation EGFR-TKI failure. Prospective validation is warranted.