Intracranial efficacy and safety of furmonertinib 160 mg with or without anti-angiogenic agent in advanced NSCLC patients with BM/LM as salvage therapy
Ziyi Xu, Xuezhi Hao, Qi Wang, Ke Yang, Junling Li, Puyuan Xing, Ziyi Xu, Xuezhi Hao, Qi Wang, Ke Yang, Junling Li, Puyuan Xing
Abstract
Objectives: Central nervous system (CNS) metastases including brain metastases (BM) and leptomeningeal metastases (LM) are frequent in epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC), and are correlated with poor outcomes. In this study, we evaluated the efficacy of single-agent furmonertinib 160 mg or combining with anti-angiogenic agent in NSCLC patients who had developed BM/LM progression from previous tyrosine kinase inhibior (TKI) treatment.
Methods: EGFR-mutated NSCLC patients who developed BM (the BM cohort) or LM progression (the LM cohort) were included, having received furmonertinib 160 mg daily as second-line or later treatment, with or without anti-angiogenic agents. The intracranial efficacy was evaluated by intracranial progression-free survival (iPFS).
Results: Totally 12 patients in the BM cohort and 16 patients in the LM cohort were included. Almost one half of patients in the BM cohort and a majority in the LM cohort had a poor physical status, with a Eastern Cooperative Oncology Group performance status (ECOG-PS) ≥2. The administration of single-agent furmonertinib or combination treatment achieved a median iPFS of 3.6 months (95%CI 1.435-5.705) in the BM cohort, and 4.3 months (95%CI 2.094-6.486) in the LM cohort. Subgroup and univariate analysis has shown that a good ECOG-PS correlated with a favorable efficacy of furmonertinib in the BM cohort (median iPFS = 2.1 with ECOG-PS ≥ 2 vs. 14.6 months with ECOG-PS < 2, P < 0.05). Overall, any grade of adverse events (AEs) occured in 46.4% of patients (13/28). Among them, 14.3% of patients (4 of 28) had grade 3 or higher AEs, and were all under control, led to no dose reductions or suspension.
Conclusion: Single-agent furmonertinib 160 mg or in combination of anti-angiogenic agent is an optional salvage therapy for advanced NSCLC patients who developed BM/LM progression from prior EGFR-TKI treatment, with a promising efficacy and an acceptable safety profile, and is worth of further exploration.
Keywords: Anti-angiogenic agent; BM/LM; EGFR-mutated NSCLC; Furmonertinib; Salvage therapy.
Conflict of interest statement
The authors declare no competing interests.
© 2023. The Author(s).
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References
- Sung H, Ferlay J, Siegel RL, et al. Global Cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209–249. doi: 10.3322/caac.21660.
- Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004;350:2129–2139. doi: 10.1056/NEJMoa040938.
- Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med. 2010;363:1693–1703. doi: 10.1056/NEJMoa1006448.
- Maemondo M, Inoue A, Kobayashi K, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 2010;362:2380–2388. doi: 10.1056/NEJMoa0909530.
- Wu YL, Zhou C, Hu CP, et al. Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-lung 6): an open-label, randomised phase 3 trial. Lancet Oncol. 2014;15:213–222. doi: 10.1016/S1470-2045(13)70604-1.
- Soria JC, Ohe Y, Vansteenkiste J, et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung Cancer. N Engl J Med. 2018;378:113–125. doi: 10.1056/NEJMoa1713137.
- Lu S, Dong X, Jian H, et al. AENEAS: a randomized phase III trial of Aumolertinib versus Gefitinib as first-line therapy for locally advanced or metastatic non-small-cell lung Cancer with EGFR exon 19 deletion or L858R mutations. Journal of clinical oncology: official journal of the American society of. Clin Oncol. 2022;Jco2102641:3162–71.
- Mok TS, Wu YL, Ahn MJ, et al. Osimertinib or platinum-Pemetrexed in EGFR T790M-positive lung Cancer. N Engl J Med. 2017;376:629–640. doi: 10.1056/NEJMoa1612674.
- Lu S, Wang Q, Zhang G, et al. Efficacy of Aumolertinib (HS-10296) in patients with advanced EGFR T790M+ NSCLC: updated post-National Medical Products Administration Approval Results from the APOLLO Registrational trial. J Thoracic Oncol. 2022;17:411–422. doi: 10.1016/j.jtho.2021.10.024.
- Kobayashi S, Boggon TJ, Dayaram T, et al. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med. 2005;352:786–792. doi: 10.1056/NEJMoa044238.
- Ernani V, Stinchcombe TE. Management of Brain Metastases in non-small-cell lung Cancer. J Oncol Pract. 2019;15:563–570. doi: 10.1200/JOP.19.00357.
- Lee J, Ahn MJ. Brain metastases in patients with oncogenic-driven non-small cell lung cancer: pros and cons for early radiotherapy. Cancer Treat Rev. 2021;100:102291. doi: 10.1016/j.ctrv.2021.102291.
- Li YS, Jiang BY, Yang JJ, et al. Leptomeningeal metastases in patients with NSCLC with EGFR mutations. J Thoracic Oncol. 2016;11:1962–1969. doi: 10.1016/j.jtho.2016.06.029.
- Umemura S, Tsubouchi K, Yoshioka H, et al. Clinical outcome in patients with leptomeningeal metastasis from non-small cell lung cancer: Okayama lung Cancer study group. Lung Cancer (Amsterdam, Netherlands) 2012;77:134–139. doi: 10.1016/j.lungcan.2012.03.002.
- Xu Y, Hu M, Zhang M, et al. Prospective study revealed prognostic significance of responses in leptomeningeal metastasis and clinical value of cerebrospinal fluid-based liquid biopsy. Lung Cancer (Amsterdam, Netherlands) 2018;125:142–149. doi: 10.1016/j.lungcan.2018.08.017.
- Park S, Lee MH, Seong M, et al. A phase II, multicenter, two cohort study of 160 mg osimertinib in EGFR T790M-positive non-small-cell lung cancer patients with brain metastases or leptomeningeal disease who progressed on prior EGFR TKI therapy. Ann Oncol. 2020;31:1397–1404. doi: 10.1016/j.annonc.2020.06.017.
- Yang JCH, Kim SW, Kim DW, et al. Osimertinib in patients with epidermal growth factor receptor mutation-positive non-small-cell lung Cancer and leptomeningeal metastases: the BLOOM study. J Clin Oncol. 2020;38:538–547. doi: 10.1200/JCO.19.00457.
- Shi Y, Zhang S, Hu X, et al. Safety, clinical activity, and pharmacokinetics of Alflutinib (AST2818) in patients with advanced NSCLC with EGFR T790M mutation. J Thoracic Oncol. 2020;15:1015–1026. doi: 10.1016/j.jtho.2020.01.010.
- Shi Y, Hu X, Zhang S, et al. Efficacy, safety, and genetic analysis of furmonertinib (AST2818) in patients with EGFR T790M mutated non-small-cell lung cancer: a phase 2b, multicentre, single-arm, open-label study. Lancet Respir Med. 2021;9:829–839. doi: 10.1016/S2213-2600(20)30455-0.
- Shi Y, Chen G, Wang X, Liu Y, Wu L, Hao Y, et al. Furmonertinib (AST2818) versus gefitinib as first-line therapy for Chinese patients with locally advanced or metastatic EGFR mutation-positive non-small-cell lung cancer (FURLONG): a multicentre, double-blind, randomised phase 3 study. Lancet Respir Med. 2022;10(11):1019–1028. doi: 10.1016/S2213-2600(22)00168-0.
- Borgelt B, Gelber R, Kramer S, et al. The palliation of brain metastases: final results of the first two studies by the radiation therapy oncology group. Int J Radiat Oncol Biol Phys. 1980;6:1–9. doi: 10.1016/0360-3016(80)90195-9.
- Bernardo G, Cuzzoni Q, Strada MR, et al. First-line chemotherapy with vinorelbine, gemcitabine, and carboplatin in the treatment of brain metastases from non-small-cell lung cancer: a phase II study. Cancer Investig. 2002;20:293–302. doi: 10.1081/CNV-120001173.
- Heon S, Yeap BY, Lindeman NI, et al. The impact of initial gefitinib or erlotinib versus chemotherapy on central nervous system progression in advanced non-small cell lung cancer with EGFR mutations. Clin Cancer Res. 2012;18:4406–4414. doi: 10.1158/1078-0432.CCR-12-0357.
- de Vries NA, Buckle T, Zhao J, Beijnen JH, Schellens JH, van Tellingen O. Restricted brain penetration of the tyrosine kinase inhibitor erlotinib due to the drug transporters P-gp and BCRP. Investig New Drugs. 2012;30:443–449. doi: 10.1007/s10637-010-9569-1.
- Ballard P, Yates JW, Yang Z, et al. Preclinical comparison of Osimertinib with other EGFR-TKIs in EGFR-mutant NSCLC brain metastases models, and early evidence of clinical brain metastases activity. Clin Cancer Res. 2016;22:5130–5140. doi: 10.1158/1078-0432.CCR-16-0399.
- Zhang Y, Zhang Y, Niu W, et al. Experimental study of Almonertinib crossing the blood-brain barrier in EGFR-mutant NSCLC brain metastasis and spinal cord metastasis models. Front Pharmacol. 2021;12:750031. doi: 10.3389/fphar.2021.750031.
- Shi Y, Chen G, Wang X, Liu Y, Wu L, Hao Y, et al. Central nervous system efficacy of furmonertinib (AST2818) versus gefitinib as first-line treatment for EGFR-mutated NSCLC: results from the FURLONG study. J Thorac Oncol. 2022:S1556-0864(22)01496-4. 10.1016/j.jtho.2022.07.1143. Epub ahead of print.
- Shi Y, Hu X, Liao W, et al. P76. 65 CNS efficacy of AST2818 in patients with T790M-positive advanced NSCLC: data from a phase I-II dose-expansion study. J Thorac Oncol. 2021;16:S616. doi: 10.1016/j.jtho.2021.01.1122.
- Zeng Y, Yu D, Tian W, Wu F. Resistance mechanisms to osimertinib and emerging therapeutic strategies in nonsmall cell lung cancer. Curr Opin Oncol. 2022;34:54–65. doi: 10.1097/CCO.0000000000000805.
- Blasi M, Kazdal D, Thomas M, et al. Combination of Crizotinib and Osimertinib in T790M+ EGFR-mutant non-small cell lung Cancer with emerging MET amplification post-Osimertinib progression in a 10-year survivor: a case report. Case Rep Oncol. 2021;14:477–482. doi: 10.1159/000513904.
- Gan J, Huang Y, Liao J, Pang L, Fang W. HER2 amplification in advanced NSCLC patients after progression on EGFR-TKI and clinical response to EGFR-TKI plus Pyrotinib combination therapy. OncoTargets Therapy. 2021;14:5297–5307. doi: 10.2147/OTT.S335217.
- Douillard JY, Ostoros G, Cobo M, et al. Gefitinib treatment in EGFR mutated caucasian NSCLC: circulating-free tumor DNA as a surrogate for determination of EGFR status. J Thoracic Oncol. 2014;9:1345–1353. doi: 10.1097/JTO.0000000000000263.
- Garcia-Murillas I, Chopra N, Comino-Méndez I, et al. Assessment of molecular relapse detection in early-stage breast Cancer. JAMA Oncol. 2019;5:1473–1478. doi: 10.1001/jamaoncol.2019.1838.
- Escudero L, Martínez-Ricarte F, Seoane J. Cerebrospinal fluid circulating tumour DNA as a liquid biopsy for central nervous system malignancies. Curr Opin Neurol. 2020;33:736–741. doi: 10.1097/WCO.0000000000000869.
- Cheng D, Tang S, Li D, et al. Successful salvage therapy using high-dose furmonertinib (AST2818) for non-small-cell lung cancer after Osimertinib resistance: a case report. Anti-Cancer Drugs. 2022;33:768–772. doi: 10.1097/CAD.0000000000001368.
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