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

Ye Wang, Deliang Huang

Show Less

¹ Department of Interventional Radiology, Guangzhou Royal Lee Oncology Hospital, 1st Ciji Road, Zhongxin Knowledge City, Huangpu District, Guangzhou, Guangdong, China,

PAR 2025 , 9(5), 1–8; https://doi.org/10.26689/par.v9i5.12116

© 2025 by the Authors. Licensee Whioce Publishing, Singapore. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )

Abstract

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.

References

Bray F, Laversanne M, Sung H, et al., 2024, Global Cancer Statistics 2022: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin, 74(3): 229–263.

Wen R, Chen Y, Long J, et al., 2023, Aggressive Progression to EGFR Tyrosine Kinase Inhibitors in Advanced NSCLC Patients: Concomitant Mutations, Prognostic Indicator and Subsequent Management. J Cancer Res Clin Oncol, 149(11): 8307–8316.

Sun D, Zhu Y, Zhu J, et al., 2020, Primary Resistance to First-Generation EGFR-TKIs Induced by MDM2 Amplification in NSCLC. Mol Med, 26(1): 66.

Wu S, Qiu Z, Shi H, et al., 2025, High-Dose Third-Generation EGFR-TKIs Combined With Intrathecal Pemetrexed in Advanced EGFR-Mutant NSCLC With Leptomeningeal Metastases Following EGFR-TKI Therapy. BMC Cancer, 25(1): 926.

Piper-Vallillo A, Rotow J, Aredo J, et al., 2022, High-Dose Osimertinib for CNS Progression in EGFR+ NSCLC: A Multi-Institutional Experience. JTO Clin Res Rep, 3(6): 100328.

Jiang T, Chen X, Ding N, et al., 2020, Osimertinib in Combination With Bevacizumab in EGFR-Mutated NSCLC With Leptomeningeal Metastases. Transl Lung Cancer Res, 9(6): 2514–2517.

Park S, Baldry R, Jung H, et al., 2024, Phase II Efficacy and Safety of 80 mg Osimertinib in Patients With Leptomeningeal Metastases Associated With Epidermal Growth Factor Receptor Mutation-Positive Non-Small Cell Lung Cancer (BLOSSOM). J Clin Oncol, 42(23): 2747–2756.

Feng S, Liu H, Yun C, et al., 2025, Application of EGFR-TKIs in Brain Tumors, a Breakthrough in Future? J Transl Med, 23(1): 449.

Qi R, Fu X, Yu Y, et al., 2023, Efficacy and Safety of Re-Challenging 160 mg Furmonertinib for Advanced NSCLC After Resistance to Third-Generation EGFR-TKIs Targeted Agents: A Real-World Study. Lung Cancer, 184: 107346.

Rodier T, Puszkiel A, Cardoso, et al., 2022, Exposure-Response Analysis of Osimertinib in Patients With Advanced Non-Small-Cell Lung Cancer. Pharmaceutics, 14(9).

Ding J, Ding X, Zeng J, et al., 2024, Furmonertinib for EGFR-Mutant Advanced Non-Small Cell Lung Cancer: A Glittering Diamond in the Rough of EGFR-TKI. Front Pharmacol, 15: 1357913.

Xu Z, Hao X, Wang Q, et al., 2023, Intracranial Efficacy and Safety of Furmonertinib 160 mg With or Without Anti-Angiogenic Agent in Advanced NSCLC Patients With BM/LM as Salvage Therapy. BMC Cancer, 23(1): 206.

Chen T, Chen J, Liu D, et al., 2023, Successful Therapy Using High-Dose Furmonertinib for Non-Small Cell Lung Cancer With Leptomeningeal Metastasis: A Case Report and Literature Review. Front Oncol, 13: 1233198.

Li K, Chen B, Wang J, et al., 2024, Long-Term Survival of a Patient With Epidermal Growth Factor Receptor (EGFR)-Mutant Non-Small Cell Lung Cancer (NSCLC) and Untreated Multiple Brain Metastases Treated With Zorifertinib: A Case Report. Thorac Cancer, 15(16): 1325–1329.

Yang Z, Guo Q, Wang Y, et al., 2016, AZD3759, a BBB-Penetrating EGFR Inhibitor for the Treatment of EGFR Mutant NSCLC With CNS Metastases. Sci Transl Med, 8(368): 368ra172.

Ahn M, Kim D, Cho B, et al., 2017, Activity and Safety of AZD3759 in EGFR-Mutant Non-Small-Cell Lung Cancer With CNS Metastases (BLOOM): A Phase 1, Open-Label, Dose-Escalation and Dose-Expansion Study. Lancet Respir Med, 5(11): 891–902.

Musib L, Kowanetz M, Li Q, et al., 2023, PP01.11 Furmonertinib Is an Oral, Irreversible, Highly Brain-Penetrant Pan-EGFR Inhibitor With Activity Against Classical and Atypical EGFR Mutations. J Thorac Oncol, 18(3): e14–e15.

Zhou Q, Yu Y, Xing L, et al., 2025, First-Line Zorifertinib for EGFR-Mutant Non-Small Cell Lung Cancer With Central Nervous System Metastases: The Phase 3 EVEREST Trial. Med, 6(1): 100513.

Lee J, Ahn M, Park S, 2024, Durable Response to First-Line Treatment With AZD3759 (Zorifertinib) in a Patient With Epidermal Growth Factor Receptor Mutated Non-Small Cell Lung Cancer and Untreated Multiple Brain Metastasis. Precis Future Med, 8(1): 23–27.

Zhou X, Zeng L, Huang Z, et al., 2025, Strategies Beyond 3rd EGFR-TKI Acquired Resistance: Opportunities and Challenges. Cancer Med, 14(9): e70921.

Wilcox J, Boire A, 2023, Leveraging Molecular and Immune-Based Therapies in Leptomeningeal Metastases. CNS Drugs, 37(1): 45–67.

Yang J, Kim S, Kim D, et al., 2020, Osimertinib in Patients With Epidermal Growth Factor Receptor Mutation-Positive Non-Small-Cell Lung Cancer and Leptomeningeal Metastases: The BLOOM Study. J Clin Oncol, 38(6): 538–547.

He J, Huang Z, Han L, et al., 2021, Mechanisms and Management of 3rd-Generation EGFR-TKI Resistance in Advanced Non-Small Cell Lung Cancer (Review). Int J Oncol, 59(5).

Liu Y, Yang S, Zhao J, et al., 2021, Cell-Free DNA From Cerebrospinal Fluid Can Be Used to Detect the EGFR Mutation Status of Lung Adenocarcinoma Patients With Central Nervous System Metastasis. Transl Lung Cancer Res, 10(2): 914–925.

Zhao Y, Gao X, Han Y, et al., 2025, The Efficacy and Safety of Intrathecal Pemetrexed for Leptomeningeal Metastasis From Non-Small Cell Lung Cancer: A Single-Arm Meta-Analysis of Chinese Patients. Front Oncol, 15: 1543416.

Fan C, Jiang Z, Teng C, et al., 2024, Efficacy and Safety of Intrathecal Pemetrexed for TKI-Failed Leptomeningeal Metastases From EGFR+ NSCLC: An Expanded, Single-Arm, Phase II Clinical Trial. ESMO Open, 9(4): 102384.

Chen H, Yang S, Wang L, et al., 2025, High-Dose Furmonertinib in Patients With EGFR-Mutated NSCLC and Leptomeningeal Metastases: A Prospective Real-World Study. J Thorac Oncol, 20(1): 65–75.

Wu H, Zhang Q, Zhai W, et al., 2024, Effectiveness of High-Dose Third-Generation EGFR-Tyrosine Kinase Inhibitors in Treating EGFR-Mutated Non-Small Cell Lung Cancer Patients With Leptomeningeal Metastasis. Lung Cancer, 188: 107475.

Liu S, Dong X, Wang Z, et al., 2023, Efficacy, Safety and Dose Selection of AZD3759 in Patients With Untreated EGFR-Mutated Non-Small-Cell Lung Cancer and Central Nervous System Metastases in China (CTONG1702-Arm 8): A Multi-Center, Single-Arm, Phase 2 Trial. EClinicalMedicine, 64: 102238.

Previous article in this issue

Next article in this issue