Leptomeningeal metastases from non-small cell lung cancer: state of the art and recent advances

Abstract

Patients with leptomeningeal metastases (LM) from non-small cell lung cancer (NSCLC) have a poor outcome with survival of less than 1 year regardless of advancements in treatment strategy. In the past, some randomized clinical trials have been conducted with heterogeneous inclusion criteria, diagnostic parameters, response evaluation and primary endpoints. Efforts to develop a standardized magnetic resonance imaging (MRI) assessment and liquid biopsy techniques to monitor disease evolution in plasma or cerebrospinal fluid (CSF) are underway. This review aims to cover the main clinical and diagnostic challenges of LM from NSCLC, in particular the role of MRI, CSF cytology and liquid biopsy for the diagnosis and monitoring of the disease, as well as the most recent clinical trials on targeted therapies. Targeted therapy, such as epidermal growth factor receptor tyrosine kinase inhibitors and anaplastic lymphoma kinase rearranged inhibitors, represent a feasible treatment with encouraging results in terms of disease control and survival. For ineligible patients, immune checkpoint inhibitors could represent a therapeutic option with acceptable tolerance, although clinical trials focused on LM from NSCLC are lacking and represent a research focus for the future.

Keywords

Anaplastic lymphoma kinase inhibitors / epidermal growth factor receptor tyrosine kinase inhibitors / clinical trials / immunotherapy / leptomeningeal metastases / liquid biopsy

References

[1] Le Rhun E,Chamberlain MC.Carcinomatous meningitis: leptomeningeal metastases in solid tumors..Surg Neurol Int2013;4:S265-88 PMCID:PMC3656567

[2] Le Rhun E.Leptomeningeal metastases of solid cancer..Curr Opin Neurol2016;29:797-805

[3] Pan Z,He H,Wang Y.Leptomeningeal metastasis from solid tumors: clinical features and its diagnostic implication,.Sci Rep2018;8:10445 PMCID:PMC6041294

[4] Remon J,Besse B.Leptomeningeal carcinomatosis in non-small cell lung cancer patients: A continuing challenge in the personalized treatment era..Cancer Treat Rev2017;53:128-37

[5] Lee Y,Kim HT,Lee GK.Impact of EGFR tyrosine kinase inhibitors versus chemotherapy on the development of leptomeningeal metastasis in never smokers with advanced adenocarcinoma of the lung..J Neurooncol2013;115:95-101

[6] Gainor JF,Logan J,Shaw AT.The central nervous system as a sanctuary site in ALK-positive non-small-cell lung cancer..J Thorac Oncol2013;8:1570-3

[7] van Tellingen O,de Gooijer MC,Wurdinger T.Overcoming the blood-brain tumor barrier for effective glioblastoma treatment..Drug Resist Updat2015;19:1-12

[8] Obermeier B,Ransohoff RM.Development, maintenance and disruption of the blood-brain barrier..Nat Med2013;19:1584-96 PMCID:PMC4080800

[9] Pardridge WM.Drug transport across the blood-brain barrier..J Cereb Blood Flow Metab2012;32:1959-72 PMCID:PMC3494002

[10] Abbott NJ,Dolman DE,Begley DJ.Structure and function of the blood-brain barrier..Neurobiol Dis2010;37:13-25

[11] Pardridge WM.The blood-brain barrier: bottleneck in brain drug development..NeuroRx2005;2:3-14 PMCID:PMC539316

[12] Liu Y.Characteristics and significance of the pre-metastatic niche..Cancer Cell2016;30:668-81

[13] Sprowls SA,Bumgarner JR,Lateef SS.Improving CNS delivery to brain metastases by blood-tumor barrier disruption..Trends Cancer2019;5:495-505 PMCID:PMC6703178

[14] Ota K,Harada T,Kitazaki T.Phase II study of erlotinib in advanced non-small cell lung cancer patients with leptomeningeal metastasis (LOGIK1101)..J Thorac Oncol2017;12:S271-2

[15] Tamiya A,Nishihara T,Nakao K.Efficacy and cerebrospinal fluid concentration of afatinib in NSCLC patients with EGFR mutation developing leptomeningeal carcinomatosis..J Thorac Oncol2017;12:S273

[16] Yang JC,Kim D,Lee JS.Osimertinib for patients (pts) with leptomeningeal metastases (LM) from EGFR-mutant non-small cell lung cancer (NSCLC): updated results from the BLOOM study..Proc Am Soc Clin Oncol2017;35:2020(abstr)

[17] Nanjo S,Okuda C,Okada H.Standard-dose osimertinib for refractory leptomeningeal metastases in T790M-positive EGFR-mutant non-small cell lung..Br J Cancer2018;118:32-7 PMCID:PMC5765232

[18] Ahn M,Kim TM,Ratnayake J.Phase I study of AZD3759, a CNS penetrable EGFR inhibitor, for the treatment of non-small-cell lung cancer (NSCLC) with brain metastasis (BM) and leptomeningeal metastasis (LM)..Proc Am Soc Clin Oncol2016;34:9003(abstr)

[19] Costa DB,Pandya SS,Shen Z.CSF concentration of the anaplastic lymphoma kinase inhibitor crizotinib..J Clin Oncol2011;29:e443-5

[20] Zhang I,Palmer JD,Lu B.Targeting brain metastases in ALK-rearranged non-small-cell lung cancer..Lancet Oncol2015;16:e510-21

[21] Sakamoto H,Hiroshima S,Kobayashi T.CH5424802, a selective ALK inhibitor capable of blocking the resistant gatekeeper mutant..Cancer Cell2011;19:679-90

[22] Kodama T,Takanashi K,Kondoh O.Antitumor activity of the selective ALK inhibitor alectinib in models of intracranial metastases..Cancer Chemother Pharmacol2014;74:1023-8

[23] Solomon B,Felip E,Philip L.Safety and efficacy of lorlatinib (PF-06463922) from the dose-escalation component of a study in patients with advanced ALK+ or ROS1+ non-small cell lung cancer (NSCLC)..Proc Am Soc Clin Oncol2016;34:9009(abstr)

[24] Demeule M,Jodoin J,Dagenais C.Drug transport to the brain: key roles for the efflux pump P-glycoprotein in the blood-brain barrier..Vascul Pharmacol2002;38:339-48

[25] Cheng H.Leptomeningeal metastases in non-small-cell lung cancer..Lancet Oncol2018;19:e43-55

[26] Chamberlain MC,Gadi VK,Chow LQM.Systemic therapy of brain metastases: non-small cell lung cancer, breast cancer, and melanoma..Neuro Oncol2017;19:1-24 PMCID:PMC5193029

[27] Pardridge WM.CSF, blood-brain barrier, and brain drug delivery..Expert Opin Drug Deliv2016;13:963-75

[28] Kummar S,Kinders R,Gutierrez ME.Phase 0 clinical trials: conceptions and misconceptions..Cancer J2008;14:133-7 PMCID:PMC7185299

[29] Arbour KC,Riely GJ,Beal K.Twice weekly pulse and daily continuous-dose erlotinib as initial treatment for patients with epidermal growth factor receptor-mutant lung cancers and brain metastases..Cancer2018;124:105-9 PMCID:PMC5735028

[30] Clarke JL,Wu N,Lassman AB.High dose weekly erlotinib achieves therapeutic concentrations in CSF and is effective in leptomeningeal metastases from epidermal growth factor receptor mutant lung cancer..J Neurooncol2010;99:283-6 PMCID:PMC3973736

[31] Grommes C,Kris MG,Pao W.“Pulsatile” high-dose weekly erlotinib for CNS metastases from EGFR mutant non-small cell lung cancer..Neuro Oncol2011;13:1364-9 PMCID:PMC3223088

[32] Wang S,Xie Z,Luo W.Pulsatile crizotinib treatment for brain metastasis in a patient with non-small-cell lung cancer..J Clin Pharm Ther2017;42:627-30

[33] Pellerino A,Rudà R.Neoplastic meningitis in solid tumors: from diagnosis to personalized treatments..Ther Adv Neurol Disord2018;11:1756286418759618 PMCID:PMC5844521

[34] Roelz R,Jabbarli R,Hippchen B.Surgical ventricular entry is a key risk factor for leptomeningeal metastasis of high grade gliomas..Sci Rep2015;5:17758 PMCID:PMC4669436

[35] Ahn JH,Kim S,Gwak HS.Risk for leptomeningeal seeding after resection for brain metastases: implication of tumor location with mode of resection..J Neurosurg2012;116:984-93

[36] Ojerholm E,Thawani JP,Alonso-Basanta M.Stereotactic radiosurgery to the resection bed for intracranial metastases and risk of leptomeningeal carcinomatosis..J Neurosurg2014;121:75-83

[37] Mahajan A,McAleer MF,Li J.Post-operative stereotactic radiosurgery versus observation for completely resected brain metastases: a single-centre, randomised, controlled, phase 3 trial..Lancet Oncol2017;18:1040-8 PMCID:PMC5560102

[38] Foreman PM,Singh KP,Guthrie B.Postoperative radiosurgery for the treatment of metastatic brain tumor: Evaluation of local failure and leptomeningeal disease..J Clin Neurosci2018;49:48-55 PMCID:PMC5805568

[39] Boire A,Shieh J,Pentsova E.Complement component 3 adapts the cerebrospinal fluid for leptomeningeal metastasis..Cell2017;168:1101-13.e13 PMCID:PMC5405733

[40] Conrad C,Miller MA,Strik H.Profiling of metalloprotease activities in cerebrospinal fluids of patients with neoplastic meningitis..Fluid Barriers CNS2017;14:22 PMCID:PMC5556623

[41] Brastianos PK,Santagata S,Taylor-Weiner A.Genomic characterization of brain metastases reveals branched evolution and potential therapeutic targets..Cancer Discov2015;5:1164-77 PMCID:PMC4916970

[42] Shih DJH,Bihun I,Gill CM.Genomic characterization of human brain metastases identifies drivers of metastatic lung adenocarcinoma..Nat Genet2020;52:371-7 PMCID:PMC7136154

[43] Nanjo S,Wang W,Yamada T.MET copy number gain is associated with gefitinib resistance in leptomeningeal carcinomatosis of EGFR-mutant lung cancer cells..Mol Cancer Ther2017;16:506-15

[44] Balak MN,Riely GJ,Li AR.Novel D761Y and common secondary T790M mutations in epidermal growth factor receptor-mutant lung adenocarcinomas with acquired resistance to kinase inhibitors..Clin Cancer Res2006;12:6494-501

[45] Ohara S,Gunji I,Tanaka Y.Brain metastasis effectively treated with erlotinib following the acquisition of resistance to gefitinib: a case report..J Med Case Rep2014;8:64 PMCID:PMC3943274

[46] Fan Y,Zhu X,Xu Y.Exploration of the underlying mechanisms of leptomeningeal metastasis in NSCLC patients through NGS of cerebrospinal fluid..J Thorac Oncol2017;12:S271

[47] Jiang BY,Chuai S.NGS to reveal heterogeneity between cerebrospinal fluid and plasma ctDNA among non-small cell lung cancer patients with leptomeningeal carcinomatosis..Proc Am Soc Clin Oncol2017;35:9022

[48] Oxnard GR,Sima CS,Chmielecki J.Acquired resistance to EGFR tyrosine kinase inhibitors in EGFR-mutant lung cancer: distinct natural history of patients with tumor harboring the T790M mutation..Clin Cancer Res2011;17:1616-22 PMCID:PMC3060283

[49] Lombardi G,Farina P,Manara R.Neoplastic meningitis from solid tumors: new diagnostic and therapeutic approaches..Oncologist2011;16:1175-88 PMCID:PMC3228160

[50] Nayak L,Brandes AA,Galanis E.The neurologic assessment in neuro-oncology (NANO) scale: a tool to assess neurologic function for integration into the response assessment in neuro-oncology (RANO) criteria..Neuro Oncol2017;19:625-35 PMCID:PMC5464449

[51] Mason W.NANO, a practical scale for neurologic assessments in patients with brain tumors?.Neuro Oncol2017;19:603-4 PMCID:PMC5464456

[52] Chamberlain M,Brandsma D,Rudà R.Leptomeningeal metastases: a RANO proposal for response criteria..Neuro Oncol2017;19:484-92 PMCID:PMC5464328

[53] Chamberlain M,Raizer J,Brandsma D.Leptomeningeal metastasis: a response assessment in neuro-oncology critical review of endpoints and response criteria of published randomized clinical trials..Neuro Oncol2014;16:1176-85 PMCID:PMC4136900

[54] Singh SK,Ginsber LE.MR imaging of leptomeningeal metastases: comparison of three sequences..AJNR Am J Neuroradiol2002;23:817-21

[55] Chamberlain MC.Comprehensive neuraxis imaging in leptomeningeal metastasis: a retrospective case series..CNS Oncol2013;2:121-8 PMCID:PMC6169472

[56] Le Rhun E,Boulanger T,Brandsma D.The RANO leptomeningeal metastasis group proposal to assess response to treatment: lack of feasibility and clinical utility and a revised proposal..Neuro Oncol2019;21:648-58 PMCID:PMC6502503

[57] Le Rhun E,Brandsma D,de Azambuja H.EANO-ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up of patients with leptomeningeal metastasis from solid tumours..Ann Oncol2017;28:iv84-99

[58] Hyun JW,Joung A,Kim SH.Leptomeningeal metastasis: clinical experience of 519 cases..Eur J Cancer2016;56:107-14

[59] Freilich RJ,DeAngelis LM.Neuroimaging and cerebrospinal fluid cytology in the diagnosis of leptomeningeal metastasis..Ann Neurol1995;38:51-7

[60] Komori T.Leptomeningeal carcinomatosis and intramedullary spinal cord metastases from lung cancer: detection with FDG positron emission tomography..Clin Nucl Med2001;26:905-7

[61] Lee SJ,Nam DH,Han JH.Leptomeningeal carcinomatosis in non-small-cell lung cancer patients: impact on survival and correlated prognostic factors..J Thorac Oncol2013;8:185-91

[62] Boire A,Brastianos PK,Ahluwalia M.Liquid biopsy in central nervous system metastases: a RANO review and proposals for clinical applications..Neuro Oncol2019;21:571-84 PMCID:PMC6502489

[63] van Bussel MTJ,Milojkovic Kerklaan B,Sikorska K.Circulating epithelial tumor cell analysis in CSF in patients with leptomeningeal metastases..Neurology2020;94:e521-8

[64] Jiang BY,Guo WB,Chen ZH.Detection of driver and resistance mutations in leptomeningeal metastases of NSCLC by next-generation sequencing of cerebrospinal fluid circulating tumor cells..Clin Cancer Res2017;23:5480-8

[65] Nayak L,Gonzalez-Espinoza R,Panageas K.Rare cell capture technology for the diagnosis of leptomeningeal metastasis in solid tumors..Neurology2013;80:1598-605 PMCID:PMC3662321

[66] Tu Q,Le Rhun E,Wittwer B.CellSearch technology applied to the detection and quantification of tumor cells in CSF of patients with lung cancer leptomeningeal metastasis..Lung Cancer2015;90:352-7

[67] Sasaki S,Ko R,Namba Y.Diagnostic significance of cerebrospinal fluid EGFR mutation analysis for leptomeningeal metastasis in non-small-cell lung cancer patients harboring an active EGFR mutation following gefinitib therapy failure..Respir Investig2016;54:14-9

[68] Zheng MM,Jiang BY,Tang WF.Clinical utility of cerebrospinal fluid cell-free DNA as liquid biopsy for leptomeningeal metastases in ALK-rearranged NSCLC..J Thorac Oncol2019;14:924-32

[69] Ying S,Ding Y,Tang X.Unique genomic profiles obtained from cerebrospinal fluid cell-free DNA of non small cell lung cancer patients with leptomeningeal metastases..Cancer Biol Ther2019;20:562-70 PMCID:PMC6422486

[70] Hata A,Yoshioka H,Tanaka K.Rebiopsy of non-small cell lung cancer patients with acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitor: comparison between T790M mutation-positive and mutation-negativee populations..Cancer2013;119:4325-32

[71] Zhao J,Xu Y,Zhong W.EGFR mutation status of paired cerebrospinal fluid and plasma samples in EGFR mutant non-small cell lung cancer with leptomeningeal metastases..Cancer Chemother Pharmacol2016;78:1305-10

[72] Huang R,Zhou X,Liao L.Epidermal growth factor receptor mutation detection in cerebrospinal fluid of lung adenocarcinoma patients with leptomeningeal metastasis..Cancer Biother Radiopharm2019;34:128-33

[73] Li YS,Yang JJ,Zhang Z.Unique genetic profiles from cerebrospinal fluid cell-free DNA in leptomeningeal metastases of EGFR-mutant non-small-cell lung: a new medium of liquid biopsy..Ann Oncol2018;29:945-52

[74] Ma C,Tang D,Li J.Tyrosine kinase inhibitors could be effective against non-small-cell lung cancer brain metastases harboring uncommon EGFR mutations..Front Oncol2020;10:224 PMCID:PMC7066117

[75] Ma C,Xing W,Si T.Detection of circulating tumor DNA from non-small cell lung cancer brain metastasis in cerebrospinal fluid samples..Thorac Cancer2020;11:588-93 PMCID:PMC7049513

[76] Nevel KS,Lin X,Ogilvie SQ.A retrospective, quantitative assessment of disease burden in patients with leptomeningeal metastases from non-small-cell lung cancer..Neuro Oncol2020;22:675-83 PMCID:PMC7229251

[77] Oechsle K,Kruell A,de Wit M.Prognostic factors and treatment options in patients with leptomeningeal metastases of different primary tumors: a retrospective analysis..J Cancer Res Clin Oncol2010;136:1729-35

[78] Wolf A,Silverman JS,Lee J K.Stereotactic radiosurgery for focal leptomeningeal disease in patients with brain metastases..J Neurooncol2017;134:139-43

[79] Gani C,Eckert F,Pantazis G.Outcome after whole brain radiotherapy alone in intracranial leptomeningeal carcinomatosis from solid tumors..Strahlenther Onkol2012;188:148-53

[80] Ozdemir Y,Topkan E.Whole brain radiotherapy in management of non-small-cell lung carcinoma associated leptomeningeal carcinomatosis: evaluation of prognostic factors..J Neurooncol2016;129:329-35

[81] Brower JV,Rosenberg SA,Robins HI.Management of leptomeningeal metastases: prognostic factors and associated outcomes..J Clin Neurosci2016;27:130-7

[82] Hermann B,Sautter-Bihl ML.Radiotherapy of the neuroaxis for palliative treatment of leptomeningeal carcinomatosis..Strahlenther Onkol2001;177:195-9

[83] Devecka M,Wilkens JJ,Borm KJ.Craniospinal irradiation(CSI) in patients with leptomeningeal metastases: risk-benefit-profile and development of a prognostic score for decision making in the palliative setting..BMC Cancer2020;20:501 PMCID:PMC7268696

[84] Yang TJ,Yamada J,Mehallow M.Clinical trial of proton craniospinal irradiation for leptomeningeal metastases..Neuro Oncol2020;noaa152:

[85] Central Nervous System Cancers: leptomeningeal Metastases (2020). v.2.2020. Available from: http://www.nccn.org. [Last accessed on 21 Oct 2020]

[86] Montes de Oca Delgado M,Santos Zambrano J,López Martínez M S.The comparative treatment of intraventricular chemotherapy by ommaya reservoir vs. lumbar puncture in patients with leptomeningeal carcinomatosis..Front Oncol2018;8:509 PMCID:PMC6256195

[87] Zairi F,Bertrand N,Taillibert S.Complications related to the use of an intraventricular access device for the treatment of leptomeningeal metastases from solid tumor: a single centre experience in 112 patients,.J Neurooncol2015;124:317-23

[88] Grossman SA,Ruckdeschel JC,Moynihan T.Randomized prospective comparison of intraventricular methotrexate and thiotepa in patients with previously untreated neoplastic meningitis. Eastern Cooperative Oncology Group..J Clin Oncol1993;11:561-9

[89] Hitchins RN,Woods RL.A prospective randomized trial of single-agent versus combination chemotherapy in meningeal carcinomatosis..J Clin Oncol1987;5:1655-62

[90] Glantz MJ,Chamberlain MC,Recht L.A randomized controlled trial comparing intrathecal sustained-release cytarabine (DepoCyt) to intrathecal methotrexate in patients with neoplastic meningitis from solid tumors..Clin Cancer Res1999;5:3394-402

[91] Boogerd W,van der Sande JJ.Meningeal carcinomatosis in breast cancer. Prognostic factors and influence of treatment..Cancer1991;67:1685-95

[92] Lin Y,Huang M,Yin Z.Use of ommaya reservoirs to deliver pemetrexed in leptomeningeal metastasis from non-small cell lung cancer: a case report and review of the literature..Zhongguo Fei Ai Za Zhi2019;22:546-50 PMCID:PMC6717864

[93] Wu YL,Lu Y.Intrathecal chemotherapy as a treatment for leptomeningeal metastasis of non-small cell lung cancer: a pooled analysis..Oncol Lett2016;12:1301-14 PMCID:PMC4950629

[94] Park JH,Lee JO,Kim JH.Clinical outcomes of leptomeningeal metastasis in patients with non-small cell lung cancer in the modern chemotherapy era..Lung Cancer2012;76:387-92

[95] Ariyasu R,Koyama J,Sonoda T.Efficacy of bevacizumab and erlotinib combination for leptomeningeal carcinomatosis after failure of erlotinib..Anticancer Drugs2017;28:565-7

[96] Li Y S,Yang JJ,Zhou Q.Leptomeningeal metastases in patients with NSCLC with EGFR mutations..J Thorac Oncol2016;11:1962-9

[97] Kuiper JL,van der Wekken AJ,Bahce I.Treatment and survival of patients with EGFR-mutated non-small-cell cancer and leptomeningeal metastasis: a retrospective cohort analysis..Lung Cancer2015;89:255-61

[98] Lee E,Kim DW,Lee SH.Erlotinib versus gefitinib for control of leptomeningeal carcinomatosis in non-small-cell lung cancer..J Thorac Oncol2013;8:1069-74

[99] Yang H,Zhang Y,Deng Q.Erlotinib in combination with pemetrexed/cisplatin for leptomeningeal metastases and cerebrospinal fluid drug concentrations in lung adenocarcinoma patients after gefitinib failure..Target Oncol2015;10:135-40

[100] Kawamura T,Takeshita J,Hayashi M.High-dose erlotinib for refractory leptomeningeal metastases after failure of standard-dose EGFR-TKIs..Cancer Chemother Pharmacol2015;75:1261-6

[101] Jackman DM,Jacobs L,Morse LK.A phase I trial of high dose gefitinib for patients with leptomeningeal metastases from non-small cell lung cancer..Oncotarget2015;6:4527-36 PMCID:PMC4414209

[102] Liao BC,Lin CC,Chang CH.Epidermal growth factor receptor tyrosine kinase inhibitors for non-small-cell lung cancer patients with leptomeningeal carcinomatosis..J Thorac Oncol2015;10:1754-61

[103] Mok TS,Ahn MJ,Kim HR.Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer..N Engl J Med2017;376:629-40 PMCID:PMC6762027

[104] Yang JCH,Kim DW,Cho BC.Osimertinib in patients with epidermal growth factor receptor mutation-positive non-small-cell lung cancer and leptomeningeal metastases: the bloom study..J Clin Oncol2020;38:538-47 PMCID:PMC7030895

[105] Saboundji K,Perol M,Janicot H.Efficacy of osimertinib in EGFR mutated non-small-cell lung cancer with leptomeningeal metastases pretreated with EGFR tyrosine kinase inhibitors..Target Oncol2018;13:501-7

[106] Ahn MJ,Cheng Y,Goldberg SB.Osimertinib for patients with leptomeningeal metastases associated with EGFR T790M-positive advanced NSCLC: the AURA leptomeningeal metastases analysis..J Thorac Oncol2020;15:637-48

[107] Park S,Seong M,Cho BC.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 Oncol2020;S0923-7534(20)39927-0:

[108] Okuno T,Yoshida T.Efficacy of osimertinib in a patient with leptomeningeal metastasis and EGFR uncommon S768I mutation..Lung Cancer2020;143:95-6

[109] Ahn MJ,Kim TM,Ratnayake J.Phase I study of AZD3759, a CNS penetrable EGFR inhibitor, for the treatment of non-small-cell lung cancer (NSCLC) with brain metastasis (BM) and leptomeningeal metastasis (LM)..J Clin Oncol2016;9003:

[110] Cho BC,Lee J,Kim SW.Phase I study (BLOOM) of AZD3759, a BBB penetrable EGFR inhibitor, in EGFRm NSCLC patients with leptomeningeal metastasis (LM) who progressed after other anticancer therapy..J Clin Oncol2017;2069:(abstr)

[111] Macias A,Santiesteban E,Nicacio L.505 POSTER preliminary results of a phase II clinical trial of the anti EGFR monoclonal antibody Nimotuzumab in combination with whole brain radiation therapy in patients diagnosed with advanced non-small cell lung cancer tumors unresectable brain metastases..Eur J Cancer Suppl2008;6:160-1

[112] Xu H,Lu Y,Cheng P.Dual targeting of the epidermal growth factor receptor using combination of nimotuzumab and erlotinib in advanced non-small-cell lung cancer with leptomeningeal metastases: a report of three cases..Onco Targets Ther2020;13:647-56 PMCID:PMC6982442

[113] Costa DB,Ou SH,Riely GJ.Clinical experience with crizotinib in patients with advanced ALK-rearranged non-small-cell lung cancer and brain metastases.J Clin Oncol2015;33:1881-8 PMCID:PMC4451171

[114] Ahn HK,Lee SJ,Sun SM.ALK inhibitor crizotinib combined with intrathecal methotrexate treatment for non-small cell lung cancer with leptomeningeal carcinomatosis..Lung Cancer2012;76:253-4

[115] Crinò L,De Marinis F,Wakelee H.Multicenter phase II study of whole-body and intracranial activity with ceritinib in patients with ALK-rearranged non-small-cell lung cancer previously treated with chemotherapy and crizotinib: results from ASCEND-2..J Clin Oncol2016;34:2866-73

[116] Shaw AT,Crinò L,Kiura K.Ceritinib versus chemotherapy in patients with ALK-rearranged non-small-cell lung cancer previously given chemotherapy and crizotinib (ASCEND-5): a randomised, controlled, open-label, phase 3 trial..Lancet Oncol2017;18:874-86

[117] Arrondeau J,Besse B.LDK378 compassionate use for treating carcinomatous meningitis in an ALK translocated non-small-cell lung cancer..J Thorac Oncol2014;9:e62-3

[118] Dudnik E,Zach L,Flex D.Durable brain response with pulse-dose crizotinib and ceritinib in ALK-positive non-small cell lung cancer compared with brain radiotherapy..J Clin Neurosci2016;26:46-9

[119] Chow LQ, Barlesi F, Bertino EM, Branle F, Shi M, et al. Results of the ASCEND-7 phase II study evaluating ALK inhibitor ceritinib in patients with ALK+ non-small cell lung cancer metastatic to the brain. ESMO Congress 2019. Abstract 1478O. Available from: https://www.annalsofoncology.org/article/S0923-7534(19)59686-7/fulltext. [Last accessed on 22 Oct 2020]

[120] Hida T,Kondo M,Azuma K.Alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer (J-ALEX): an open-label, randomised phase 3 trial..Lancet2017;390:29-39

[121] Peters S,Shaw AT,Ahn JS.Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer..N Engl J Med2017;377:829-38

[122] Gainor JF,Willoughby K,Kennedy E.Alectinib salvages CNS relapses in ALK-positive lung cancer patients previously treated with crizotinib and ceritinib..J Thorac Oncol2015;10:232-6 PMCID:PMC4304931

[123] Ou SH,Azada MC.Alectinib induces a durable (>15 months) complete response in an ALK-positive non-small cell lung cancer patient who progressed on crizotinib with diffuse leptomeningeal carcinomatosis..Oncologist2015;20:224-6 PMCID:PMC4319629

[124] Gainor JF,Logan J,Oh KS.Alectinib dose escalation reinduces central nervous system responses in patients with anaplastic lymphoma kinase-positive non-small cell lung cancer relapsing on standard dose alectinib..J Thorac Oncol2016;11:256-60 PMCID:PMC4743545

[125] Gettinger SN,Langer CJ,Gold KA.Activity and safety of brigatinib in ALK-rearranged non-small-cell lung cancer and other malignancies: a single-arm, open-label, phase 1/2 trial..Lancet Oncol2016;17:1683-96

[126] Gaye E,Bore P,Lucia F.Intra-cranial efficacy of brigatinib in an ALK-positive non-small cell lung cancer patient presenting leptomeningeal carcinomatosis..Lung Cancer2019;133:1-3

[127] Califano R,Gridelli C,Camidge DR.Brigatinib (BRG) vs crizotinib (CRZ) in the phase III ALTA-1L trial..Ann Oncol2019;30:ii41

[128] Pellerino A,Rudà R.Complete response of spinal metastases from non-small cell lung cancer with ALK inhibitors..Neurology2019;93:217-9

[129] Brahmer J,Baas P,Eberhardt WEE.Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer..N Engl J Med2015;373:123-35 PMCID:PMC4681400

[130] Borghaei H,Horn L,Steins M.Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer..N Engl J Med2015;373:1627-39 PMCID:PMC5705936

[131] Herbst RS,Kim DW,Pérez-Gracia JL.Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial..Lancet2016;387:1540-50

[132] Barlesi F,Ciardiello F,Gadgeel S.Primary analysis from OAK, a randomized phase III study comparing atezolizumab with docetaxel in advanced NSCLC..ESMO2016;LBA44-PR:

[133] Hulsbergen AFC,Nagtegaal SHJ,Kavouridis V.Programmed death receptor ligand one expression may independently predict survival in patients with non-small cell lung carcinoma brain metastases receiving immunotherapy..Int J Radiat Oncol Biol Phys2020;S0360-3016(20)31036-1:

[134] Gion MRJ,Soria J,Besse B.Symptomatic leptomeningeal metastasis improvement with nivolumab in advanced non-small celll lung cancer patient..Lung Cancer2017;108:72-4

[135] Dudnik E,Nechushtan H,Zer A.Intracranial response to nivolumab in NSCLC patients with untreated or progressing CNS metastases..Lung Cancer2016;98:114-7

[136] Hendriks LEL,Mourlanette J,Mezquita L.Survival of patients with non-small cell lung cancer having leptomeningeal metastases treated with immune checkpoint inhibitors..Eur J Cancer2019;116:182-9

[137] Brastianos PK,Cohen JV,Lin NU.Publisher correction: single-arm, open-label phase 2 trial of pembrolizumab in patients with leptomeningeal carcinomatosis..Nat Med2020;

[138] Salvador E,Förster C.Glucocorticoids and endothelial cell barrier function..Cell Tissue Res2014;355:597-605 PMCID:PMC3972429

[139] Bebawy JF.Perioperative steroids for peritumoral intracranial edema: a review of mechanisms, efficacy, and side effects..J Neurosurg Anesthesiol2012;24:173-7

[140] Suzuki T,Koyama H,Uchida I.Inhibitory effect of glucocorticoids on human-cloned 5-hydroxytryptamine3A receptor expressed in xenopus oocytes..Anesthesiology2004;101:660-5

[141] Ho CM,Wang JJ,Chai CY.Dexamethasone has a central antiemetic mechanism in decerebrated cats..Anesth Analg2004;99:734-9

[142] Roth P,Weller M.Corticosteroid use in neuro-oncology: an update..Neurooncol Pract2015;2:6-12 PMCID:PMC4369706

[143] Yin K,Zheng MM,Li WF.A molecular graded prognostic assessment (molGPA) model specific for estimating survival in lung cancer patients with leptomeningeal metastases..Lung Cancer2019;131:134-8