Advertisement

Management of brain metastases in non-small cell lung cancer in the era of tyrosine kinase inhibitors

Published:October 20, 2018DOI:https://doi.org/10.1016/j.ctrv.2018.10.011

      Highlights

      • EGFR- and ALK positive NSCLCs show particularly high incidence of brain metastases.
      • Brain metastasis management: extending survival with good neurocognitive function.
      • Stereotactic radiosurgery is preferred radiotherapy technique for brain metastases.
      • New generation EGFR and ALK TKIs are highly active in the CNS.
      • Potential new paradigm: from primary cranial radiotherapy to CNS-penetrating TKIs.

      Abstract

      Lung cancer represents the most common cause of brain dissemination. Oncogene-addicted (EGFR- and ALK-positive) non-small cell lung cancers (NSCLCs) are characterized by a unique metastatic neurotropism resulting in a particularly high incidence of brain metastases. The goal of optimal brain metastases management is to improve both overall survival and quality of life, with the focus on neurocognitive function preservation.
      Neurosurgery is offered to patients presenting with limited intracranial tumor burden located in surgically accessible un-eloquent regions of the brain, whereas stereotactic radiosurgery represents the preferred radiotherapy option for patients not amenable to surgery. Whole brain radiotherapy, owing to its neurocognitive sequelae, should be reserved for patients with multiple lesions.
      EGFR and ALK tyrosine kinase inhibitors (TKIs) provide significantly superior systemic response rates and progression-free survival compared to standard chemotherapy in the molecularly defined NSCLC subpopulations. An apparent intracranial activity of new generation TKIs triggered the discussion on their role in brain metastases in lieu of local therapies.
      The aim of this review is to summarize the current therapeutic landscape of brain metastases management in NSCLC, with a particular focus on EGFR-mutated and ALK-rearranged NSCLC subtypes.

      Keywords

      To read this article in full you will need to make a payment
      ESMO Member Login
      Login with your ESMO username and password.
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Purchase one-time access:

      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Wang B.X.
        • Ou W.
        • Mao X.Y.
        • Liu Z.
        • Wu H.Q.
        • Wang S.Y.
        Impacts of EGFR mutation and EGFR-TKIs on incidence of brain metastases in advanced non-squamous NSCLC.
        Clin Neurol Neurosurg. 2017; 160: 96-100
        • Preusser M.
        • Winkler F.
        • Valiente M.
        • Manegold C.
        • Moyal E.
        • Widhalm G.
        • et al.
        Recent advances in the biology and treatment of brain metastases of non-small cell lung cancer: summary of a multidisciplinary roundtable discussion.
        ESMO Open. 2018; 3: e000262
        • Oechsle K.
        • Lange-Brock V.
        • Kruell A.
        • Bokemeyer C.
        • de Wit M.
        Prognostic factors and treatment options in patients with leptomeningeal metastases of different primary tumors: a retrospective analysis.
        J Cancer Res Clin Oncol. 2010; 136: 1729-1735
        • Rangachari D.
        • Yamaguchi N.
        • VanderLaan P.A.
        • Folch E.
        • Mahadevan A.
        • Floyd S.R.
        • et al.
        Brain metastases in patients with EGFR-mutated or ALK-rearranged non-small-cell lung cancers.
        Lung Cancer. 2015; 88: 108-111
        • Jackman D.M.
        • Holmes A.J.
        • Lindeman N.
        • Wen P.Y.
        • Kesari S.
        • Borras A.M.
        • et al.
        Response and resistance in a non-small-cell lung cancer patient with an epidermal growth factor receptor mutation and leptomeningeal metastases treated with high-dose gefitinib.
        J Clin Oncol. 2006; 24: 4517-4520
        • Patchell R.A.
        • Tibbs P.A.
        • Regine W.F.
        • Dempsey R.J.
        • Mohiuddin M.
        • Kryscio R.J.
        • et al.
        Postoperative radiotherapy in the treatment of single metastases to the brain: a randomized trial.
        JAMA. 1998; 280: 1485-1489
        • Brown P.D.
        • Ballman K.V.
        • Cerhan J.H.
        • Anderson S.K.
        • Carrero X.W.
        • Whitton A.C.
        • Greenspoon J.
        • Parney I.F.
        • Laack N.N.I.
        • Ashman J.B.
        • et al.
        Postoperative stereotactic radiosurgery compared with whole brain radiotherapy for resected metastatic brain disease (NCCTG N107C/CEC. 3): a multicentre, randomised, controlled, phase 3 trial.
        Lancet Oncol. 2017; 18: 1049-1060
        • Patchell R.A.
        • Tibbs P.A.
        • Walsh J.W.
        • Dempsey R.J.
        • Maruyama Y.
        • Kryscio R.J.
        • et al.
        A randomized trial of surgery in the treatment of single metastases to the brain.
        N Engl J Med. 1990; 322: 494-500
        • Noordijk E.M.
        • Vecht C.J.
        • Haaxma-Reiche H.
        • Padberg G.W.
        • Voormolen J.H.
        • Hoekstra F.H.
        • et al.
        The choice of treatment of single brain metastasis should be based on extracranial tumor activity and age.
        Int J Radiat Oncol Biol Phys. 1994; 29: 711-717
        • Mahajan A.
        • Ahmed S.
        • McAleer M.F.
        • Weinberg J.S.
        • Li J.
        • Brown P.
        • et al.
        Post-operative stereotactic radiosurgery versus observation for completely resected brain metastases: a single-centre, randomised, controlled, phase 3 trial.
        Lancet Oncol. 2017; 18: 1040-1048
        • Chao J.H.
        • Phillips R.
        • Nickson J.J.
        Roentgen-ray therapy of cerebral metastases.
        Cancer. 1954; 7: 682-689
        • Borgelt B.
        • Gelber R.
        • Kramer S.
        • Brady L.W.
        • Chang C.H.
        • Davis L.W.
        • 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
        • Mulvenna P.
        • Nankivell M.
        • Barton R.
        • Faivre-Finn C.
        • Wilson P.
        • McColl E.
        • et al.
        Dexamethasone and supportive care with or without whole brain radiotherapy in treating patients with non-small cell lung cancer with brain metastases unsuitable for resection or stereotactic radiotherapy (QUARTZ): results from a phase 3, non-inferiority, randomised trial.
        Lancet. 2016; 388: 2004-2014
        • Habets E.J.
        • Dirven L.
        • Wiggenraad R.G.
        • Verbeek-de Kanter A.
        • Lycklama A.N.G.J.
        • Zwinkels H.
        • et al.
        Neurocognitive functioning and health-related quality of life in patients treated with stereotactic radiotherapy for brain metastases: a prospective study.
        Neuro Oncol. 2016; 18: 435-444
        • Andrews D.W.
        • Scott C.B.
        • Sperduto P.W.
        • Flanders A.E.
        • Gaspar L.E.
        • Schell M.C.
        • et al.
        Whole brain radiation therapy with and without stereotactic radiosurgery boost for patients with one to three brain metastases: Phase III results of the RTOG 9508 randomized trial.
        Lancet. 2004; 363: 1665-1672
        • Yamamoto M.
        • Serizawa T.
        • Shuto T.
        • Akabane A.
        • Higuchi Y.
        • Kawagishi J.
        • et al.
        Stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901): a multi-institutional prospective observational study.
        Lancet Oncol. 2014; 15: 387-395
        • Yamamoto M.
        • Serizawa T.
        • Higuchi Y.
        • Sato Y.
        • Kawagishi J.
        • Yamanaka K.
        • et al.
        A multi-institutional prospective observational study of stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901 study update): irradiation-related complications and long-term maintenance of mini-mental state examination scores.
        Int J Radiat Oncol Biol Phys. 2017; 99: 31-40
        • Won Y.K.
        • Lee J.Y.
        • Kang Y.N.
        • Jang J.S.
        • Kang J.H.
        • Jung S.L.
        • et al.
        Stereotactic radiosurgery for brain metastasis in non-small cell lung cancer.
        Radiat Oncol J. 2015; 33: 207-216
        • Jeong W.J.
        • Park J.H.
        • Lee E.J.
        • Kim J.H.
        • Kim C.J.
        • Cho Y.H.
        Efficacy and safety of fractionated stereotactic radiosurgery for large brain metastases.
        J Korean Neurosurg Soc. 2015; 58: 217-224
        • Brown P.D.
        • Pugh S.
        • Laack N.N.
        • Wefel J.S.
        • Khuntia D.
        • Meyers C.
        • et al.
        Memantine for the prevention of cognitive dysfunction in patients receiving whole-brain radiotherapy: a randomized, double-blind, placebo-controlled trial.
        Neuro Oncol. 2013; 15: 1429-1437
        • Gondi V.
        • Tolakanahalli R.
        • Mehta M.P.
        • Tewatia D.
        • Rowley H.
        • Kuo J.S.
        • et al.
        Hippocampal-sparing whole-brain radiotherapy: a “how-to” technique using helical tomotherapy and linear accelerator-based intensity-modulated radiotherapy.
        Int J Radiat Oncol Biol Phys. 2010; 78: 1244-1252
        • Mehta M.P.
        • Shapiro W.R.
        • Phan S.C.
        • Gervais R.
        • Carrie C.
        • Chabot P.
        • et al.
        Motexafin gadolinium combined with prompt whole brain radiotherapy prolongs time to neurologic progression in non-small-cell lung cancer patients with brain metastases: results of a phase III trial.
        Int J Radiat Oncol Biol Phys. 2009; 73: 1069-1076
        • DeAngelis L.M.
        • Currie V.E.
        • Kim J.H.
        • Krol G.
        • O'Hehir M.A.
        • Farag F.M.
        • et al.
        The combined use of radiation therapy and lonidamine in the treatment of brain metastases.
        J Neurooncol. 1989; 7: 241-247
        • Komarnicky L.T.
        • Phillips T.L.
        • Martz K.
        • Asbell S.
        • Isaacson S.
        • Urtasun R.
        A randomized phase III protocol for the evaluation of misonidazole combined with radiation in the treatment of patients with brain metastases (RTOG-7916).
        Int J Radiat Oncol Biol Phys. 1991; 20: 53-58
        • Postmus P.E.
        • Haaxma-Reiche H.
        • Smit E.F.
        • Groen H.J.
        • Karnicka H.
        • Lewinski T.
        • et al.
        Treatment of brain metastases of small-cell lung cancer: comparing teniposide and teniposide with whole-brain radiotherapy–a phase III study of the European Organization for the Research and Treatment of Cancer Lung Cancer Cooperative Group.
        J Clin Oncol. 2000; 18: 3400-3408
        • Antonadou D.
        • Paraskevaidis M.
        • Sarris G.
        • Coliarakis N.
        • Economou I.
        • Karageorgis P.
        • et al.
        Phase II randomized trial of temozolomide and concurrent radiotherapy in patients with brain metastases.
        J Clin Oncol. 2002; 20: 3644-3650
        • Zhao Q.
        • Qin Q.
        • Sun J.
        • Han D.
        • Wang Z.
        • Teng J.
        • et al.
        Brain radiotherapy plus concurrent temozolomide versus radiotherapy alone for patients with brain metastases: a meta-analysis.
        PLoS ONE. 2016; 11: e0150419
        • Edelman M.J.
        • Belani C.P.
        • Socinski M.A.
        • Ansari R.H.
        • Obasaju C.K.
        • Chen R.
        • et al.
        Outcomes associated with brain metastases in a three-arm phase III trial of gemcitabine-containing regimens versus paclitaxel plus carboplatin for advanced non-small cell lung cancer.
        J Thorac Oncol. 2010; 5: 110-116
        • Gerstner E.R.
        • Fine R.L.
        Increased permeability of the blood-brain barrier to chemotherapy in metastatic brain tumors: establishing a treatment paradigm.
        J Clin Oncol. 2007; 25: 2306-2312
        • Bokstein F.
        • Lossos A.
        • Siegal T.
        Leptomeningeal metastases from solid tumors: a comparison of two prospective series treated with and without intra-cerebrospinal fluid chemotherapy.
        Cancer. 1998; 82: 1756-1763
        • Greenhalgh J.
        • Dwan K.
        • Boland A.
        • Bates V.
        • Vecchio F.
        • Dundar Y.
        • Jain P.
        • Green J.A.
        First-line treatment of advanced epidermal growth factor receptor (EGFR) mutation positive non-squamous non-small cell lung cancer.
        Cochrane Database Syst Rev. 2016; 5: Cd010383
        • Zhang Q.
        • Qin N.
        • Wang J.
        • Lv J.
        • Yang X.
        • Li X.
        • et al.
        Crizotinib versus platinum-based double-agent chemotherapy as the first line treatment in advanced anaplastic lymphoma kinase-positive lung adenocarcinoma.
        Thorac Cancer. 2016; 7: 3-8
        • Eichler A.F.
        • Kahle K.T.
        • Wang D.L.
        • Joshi V.A.
        • Willers H.
        • Engelman J.A.
        • et al.
        EGFR mutation status and survival after diagnosis of brain metastasis in non-small cell lung cancer.
        Neuro Oncol. 2010; 12: 1193-1199
        • Lee H.L.
        • Chung T.S.
        • Ting L.L.
        • Tsai J.T.
        • Chen S.W.
        • Chiou J.F.
        • et al.
        EGFR mutations are associated with favorable intracranial response and progression-free survival following brain irradiation in non-small cell lung cancer patients with brain metastases.
        Radiat Oncol. 2012; 7: 181
        • Park S.J.
        • Kim H.T.
        • Lee D.H.
        • Kim K.P.
        • Kim S.W.
        • Suh C.
        • et al.
        Efficacy of epidermal growth factor receptor tyrosine kinase inhibitors for brain metastasis in non-small cell lung cancer patients harboring either exon 19 or 21 mutation.
        Lung Cancer. 2012; 77: 556-560
        • Heon S.
        • Yeap B.Y.
        • Lindeman N.I.
        • Joshi V.A.
        • Butaney M.
        • Britt G.J.
        • 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
        • Porta R.
        • Sanchez-Torres J.M.
        • Paz-Ares L.
        • Massuti B.
        • Reguart N.
        • Mayo C.
        • et al.
        Brain metastases from lung cancer responding to erlotinib: the importance of EGFR mutation.
        Eur Respir J. 2011; 37: 624-631
        • Togashi Y.
        • Masago K.
        • Fukudo M.
        • Terada T.
        • Fujita S.
        • Irisa K.
        • et al.
        Cerebrospinal fluid concentration of erlotinib and its active metabolite OSI-420 in patients with central nervous system metastases of non-small cell lung cancer.
        J Thorac Oncol. 2010; 5: 950-955
        • Togashi Y.
        • Masago K.
        • Masuda S.
        • Mizuno T.
        • Fukudo M.
        • Ikemi Y.
        • et al.
        Cerebrospinal fluid concentration of gefitinib and erlotinib in patients with non-small cell lung cancer.
        Cancer Chemother Pharmacol. 2012; 70: 399-405
        • Deng Y.
        • Feng W.
        • Wu J.
        • Chen Z.
        • Tang Y.
        • Zhang H.
        • et al.
        The concentration of erlotinib in the cerebrospinal fluid of patients with brain metastasis from non-small-cell lung cancer.
        Mol Clin Oncol. 2014; 2: 116-120
        • Wu Y.L.
        • Zhou C.
        • Cheng Y.
        • Lu S.
        • Chen G.Y.
        • Huang C.
        • et al.
        Erlotinib as second-line treatment in patients with advanced non-small-cell lung cancer and asymptomatic brain metastases: a phase II study (CTONG-0803).
        Ann Oncol. 2013; 24: 993-999
        • Ceresoli G.L.
        • Cappuzzo F.
        • Gregorc V.
        • Bartolini S.
        • Crino L.
        • Villa E.
        Gefitinib in patients with brain metastases from non-small-cell lung cancer: a prospective trial.
        Ann Oncol. 2004; 15: 1042-1047
        • Kashima J.
        • Okuma Y.
        • Miwa M.
        • Hosomi Y.
        Survival of patients with brain metastases from non-small cell lung cancer harboring EGFR mutations treated with epidermal growth factor receptor tyrosine kinase inhibitors.
        Med Oncol. 2016; 33: 129
        • Fan Y.
        • Xu X.
        • Xie C.
        EGFR-TKI therapy for patients with brain metastases from non-small-cell lung cancer: a pooled analysis of published data.
        Onco Targets Ther. 2014; 7: 2075-2084
        • Milton D.T.
        • Azzoli C.G.
        • Heelan R.T.
        • Venkatraman E.
        • Gomez J.E.
        • Kris M.G.
        • et al.
        A phase I/II study of weekly high-dose erlotinib in previously treated patients with nonsmall cell lung cancer.
        Cancer. 2006; 107: 1034-1041
        • Grommes C.
        • Oxnard G.R.
        • Kris M.G.
        • Miller V.A.
        • Pao W.
        • Holodny A.I.
        • et al.
        “Pulsatile” high-dose weekly erlotinib for CNS metastases from EGFR mutant non-small cell lung cancer.
        Neuro Oncol. 2011; 13: 1364-1369
        • Kawamura T.
        • Hata A.
        • Takeshita J.
        • Fujita S.
        • Hayashi M.
        • Tomii K.
        • et al.
        High-dose erlotinib for refractory leptomeningeal metastases after failure of standard-dose EGFR-TKIs.
        Cancer Chemother Pharmacol. 2015; 75: 1261-1266
        • Jackman D.M.
        • Cioffredi L.A.
        • Jacobs L.
        • Sharmeen F.
        • Morse L.K.
        • Lucca J.
        • et al.
        A phase I trial of high dose gefitinib for patients with leptomeningeal metastases from non-small cell lung cancer.
        Oncotarget. 2015; 6: 4527-4536
        • Hoffknecht P.
        • Tufman A.
        • Wehler T.
        • Pelzer T.
        • Wiewrodt R.
        • Schutz M.
        • et al.
        Efficacy of the irreversible ErbB family blocker afatinib in epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)-pretreated non-small-cell lung cancer patients with brain metastases or leptomeningeal disease.
        J Thorac Oncol. 2015; 10: 156-163
        • Yang J.C.
        • Wu Y.L.
        • Schuler M.
        • Sebastian M.
        • Popat S.
        • Yamamoto N.
        • et al.
        Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials.
        Lancet Oncol. 2015; 16: 141-151
        • Gerber N.K.
        • Yamada Y.
        • Rimner A.
        • Shi W.
        • Riely G.J.
        • Beal K.
        • et al.
        Erlotinib versus radiation therapy for brain metastases in patients with EGFR-mutant lung adenocarcinoma.
        Int J Radiat Oncol Biol Phys. 2014; 89: 322-329
        • Magnuson W.J.
        • Lester-Coll N.H.
        • Wu A.J.
        • Yang T.J.
        • Lockney N.A.
        • Gerber N.K.
        • et al.
        Management of brain metastases in tyrosine kinase inhibitor-naive epidermal growth factor receptor-mutant non-small-cell lung cancer: a retrospective multi-institutional analysis.
        J Clin Oncol. 2017; 35: 1070-1077
        • Soon Y.Y.
        • Leong C.N.
        • Koh W.Y.
        • Tham I.W.
        EGFR tyrosine kinase inhibitors versus cranial radiation therapy for EGFR mutant non-small cell lung cancer with brain metastases: a systematic review and meta-analysis.
        Radiother Oncol. 2015; 114: 167-172
        • Yang J.J.
        • Zhou C.
        • Huang Y.
        • Feng J.
        • Lu S.
        • Song Y.
        • et al.
        Icotinib versus whole-brain irradiation in patients with EGFR-mutant non-small-cell lung cancer and multiple brain metastases (BRAIN): a multicentre, phase 3, open-label, parallel, randomised controlled trial.
        Lancet Respir Med. 2017; 5: 707-716
        • Chinnaiyan P.
        • Huang S.
        • Vallabhaneni G.
        • Armstrong E.
        • Varambally S.
        • Tomlins S.A.
        • et al.
        Mechanisms of enhanced radiation response following epidermal growth factor receptor signaling inhibition by erlotinib (Tarceva).
        Cancer Res. 2005; 65: 3328-3335
        • Baumann M.
        • Krause M.
        • Dikomey E.
        • Dittmann K.
        • Dorr W.
        • Kasten-Pisula U.
        • et al.
        EGFR-targeted anti-cancer drugs in radiotherapy: preclinical evaluation of mechanisms.
        Radiother Oncol. 2007; 83: 238-248
        • Zeng Y.D.
        • Liao H.
        • Qin T.
        • Zhang L.
        • Wei W.D.
        • Liang J.Z.
        • et al.
        Blood-brain barrier permeability of gefitinib in patients with brain metastases from non-small-cell lung cancer before and during whole brain radiation therapy.
        Oncotarget. 2015; 6: 8366-8376
        • Schuler M.
        • Wu Y.L.
        • Hirsh V.
        • O'Byrne K.
        • Yamamoto N.
        • Mok T.
        • et al.
        First-line Afatinib versus chemotherapy in patients with non-small cell lung cancer and common epidermal growth factor receptor gene mutations and brain metastases.
        J Thorac Oncol. 2016; 11: 380-390
        • Lind J.S.
        • Lagerwaard F.J.
        • Smit E.F.
        • Senan S.
        Phase I study of concurrent whole brain radiotherapy and erlotinib for multiple brain metastases from non-small-cell lung cancer.
        Int J Radiat Oncol Biol Phys. 2009; 74: 1391-1396
        • Lee S.M.
        • Lewanski C.R.
        • Counsell N.
        • Ottensmeier C.
        • Bates A.
        • Patel N.
        • et al.
        Faivre-Finn C: randomized trial of erlotinib plus whole-brain radiotherapy for NSCLC patients with multiple brain metastases.
        J Natl Cancer Inst. 2014; 106
        • Welsh J.W.
        • Komaki R.
        • Amini A.
        • Munsell M.F.
        • Unger W.
        • Allen P.K.
        • et al.
        Phase II trial of erlotinib plus concurrent whole-brain radiation therapy for patients with brain metastases from non-small-cell lung cancer.
        J Clin Oncol. 2013; 31: 895-902
        • Zeng Y.D.
        • Zhang L.
        • Liao H.
        • Liang Y.
        • Xu F.
        • Liu J.L.
        • et al.
        Gefitinib alone or with concomitant whole brain radiotherapy for patients with brain metastasis from non-small-cell lung cancer: a retrospective study.
        Asian Pac J Cancer Prev. 2012; 13: 909-914
        • Jiang T.
        • Min W.
        • Li Y.
        • Yue Z.
        • Wu C.
        • Zhou C.
        Radiotherapy plus EGFR TKIs in non-small cell lung cancer patients with brain metastases: an update meta-analysis.
        Cancer Med. 2016; 5: 1055-1065
        • Sperduto P.W.
        • Wang M.
        • Robins H.I.
        • Schell M.C.
        • Werner-Wasik M.
        • Komaki R.
        • et al.
        A phase 3 trial of whole brain radiation therapy and stereotactic radiosurgery alone versus WBRT and SRS with temozolomide or erlotinib for non-small cell lung cancer and 1 to 3 brain metastases: Radiation Therapy Oncology Group 0320.
        Int J Radiat Oncol Biol Phys. 2013; 85: 1312-1318
        • Huang Y.J.
        • Liu S.F.
        • Wang C.J.
        • Huang M.Y.
        Exacerbated radiodermatitis and bilateral subdural hemorrhage after whole brain irradiation combined with epidermal growth factor receptor tyrosine kinase inhibitors for brain metastases in lung cancer.
        Lung Cancer. 2008; 59: 407-410
        • Ballard P.
        • Yates J.W.
        • Yang Z.
        • Kim D.W.
        • Yang J.C.
        • Cantarini M.
        • 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
        • Ahn M.J.
        • Kim D.W.
        • Cho B.C.
        • Kim S.W.
        • Lee J.S.
        • Ahn J.S.
        • et al.
        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. 2017; 5: 891-902
        • Goldman J.W.
        • Soria J.-C.
        • Wakelee H.A.
        • Camidge D.R.
        • Gadgeel S.M.
        • Yu H.A.
        • Reckamp K.L.
        • Papadimitrakopoulou V.
        • Perol M.
        • Ou S.-H.I.
        • et al.
        Updated results from TIGER-X, a phase I/II open label study of rociletinib in patients (pts) with advanced, recurrent T790M-positive non-small cell lung cancer (NSCLC).
        J Clin Oncol. 2016; 34 (9045–9045)
        • Yang J.C.-H.
        • Cho B.C.
        • Kim D.-W.
        • Kim S.-W.
        • Lee J.-S.
        • Su W.-C.
        • John T.
        • Kao S.C.-H.
        • Natale R.
        • Goldman J.W.
        • et al.
        Osimertinib for patients (pts) with leptomeningeal metastases (LM) from EGFR-mutant non-small cell lung cancer (NSCLC): updated results from the BLOOM study.
        J Clin Oncol. 2017; 35 (2020–2020)
        • Goss G.
        • Tsai C.M.
        • Shepherd F.A.
        • Ahn M.J.
        • Bazhenova L.
        • Crino L.
        • et al.
        CNS response to osimertinib in patients with T790M-positive advanced NSCLC: pooled data from two Phase II trials.
        Ann Oncol. 2017;
        • Mok T.S.
        • Wu Y.L.
        • Ahn M.J.
        • Garassino M.C.
        • Kim H.R.
        • Ramalingam S.S.
        • et al.
        Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer.
        N Engl J Med. 2017; 376: 629-640
        • Reungwetwattana T.
        • Nakagawa K.
        • Cho B.C.
        • Cobo M.
        • Cho E.K.
        • Bertolini A.
        • Bohnet S.
        • Zhou C.
        • Lee K.H.
        • Nogami N.
        • et al.
        CNS response to osimertinib vs standard epidermal growth factor tyrosine kinase inhibitors in patients with untreated EGFR-mutated advanced non-small cell lung cancer.
        J Clin Oncol. 2018; (in press)https://doi.org/10.1200/JCO.2018.78.3118
        • Solomon B.J.
        • Mok T.
        • Kim D.W.
        • Wu Y.L.
        • Nakagawa K.
        • Mekhail T.
        • et al.
        First-line crizotinib versus chemotherapy in ALK-positive lung cancer.
        N Engl J Med. 2014; 371: 2167-2177
        • Costa D.B.
        • Shaw A.T.
        • Ou S.H.
        • Solomon B.J.
        • Riely G.J.
        • Ahn M.J.
        • et al.
        Clinical experience with crizotinib in patients with advanced ALK-rearranged non-small-cell lung cancer and brain metastases.
        J Clin Oncol. 2015; 33: 1881-1888
        • Hallberg B.
        • Palmer R.H.
        The role of the ALK receptor in cancer biology.
        Ann Oncol. 2016; 27: iii4-iii15
        • Solomon B.J.
        • Cappuzzo F.
        • Felip E.
        • Blackhall F.H.
        • Costa D.B.
        • Kim D.W.
        • et al.
        Intracranial efficacy of crizotinib versus chemotherapy in patients with advanced ALK-positive non-small-cell lung cancer: results from PROFILE 1014.
        J Clin Oncol. 2016; 34: 2858-2865
        • Peled N.
        • Zach L.
        • Liran O.
        • Ilouze M.
        • Bunn Jr., P.A.
        • Hirsch F.R.
        Effective crizotinib schedule for brain metastases in ALK rearrangement metastatic non-small-cell lung cancer.
        J Thorac Oncol. 2013; 8: e112-e113
        • Gandhi L.
        • Drappatz J.
        • Ramaiya N.H.
        • Otterson G.A.
        High-dose pemetrexed in combination with high-dose crizotinib for the treatment of refractory CNS metastases in ALK-rearranged non-small-cell lung cancer.
        J Thorac Oncol. 2013; 8: e3-e5
        • Dai Y.
        • Wei Q.
        • Schwager C.
        • Moustafa M.
        • Zhou C.
        • Lipson K.E.
        • et al.
        Synergistic effects of crizotinib and radiotherapy in experimental EML4-ALK fusion positive lung cancer.
        Radiother Oncol. 2015; 114: 173-181
        • Sun Y.
        • Nowak K.A.
        • Zaorsky N.G.
        • Winchester C.L.
        • Dalal K.
        • Giacalone N.J.
        • et al.
        ALK inhibitor PF02341066 (crizotinib) increases sensitivity to radiation in non-small cell lung cancer expressing EML4-ALK.
        Mol Cancer Ther. 2013; 12: 696-704
        • Ou S.H.
        • Weitz M.
        • Jalas J.R.
        • Kelly D.F.
        • Wong V.
        • Azada M.C.
        • et al.
        Alectinib induced CNS radiation necrosis in an ALK+NSCLC patient with a remote (7 years) history of brain radiation.
        Lung Cancer. 2016; 96: 15-18
        • Metro G.
        • Lunardi G.
        • Floridi P.
        • Pascali J.P.
        • Marcomigni L.
        • Chiari R.
        • et al.
        CSF concentration of Crizotinib in two ALK-positive non-small-cell lung cancer patients with CNS metastases deriving clinical benefit from treatment.
        J Thorac Oncol. 2015; 10: e26-e27
        • Mima T.
        • Toyonaga S.
        • Mori K.
        • Taniguchi T.
        • Ogawa Y.
        Early decrease of P-glycoprotein in the endothelium of the rat brain capillaries after moderate dose of irradiation.
        Neurol Res. 1999; 21: 209-215
        • Weickhardt A.J.
        • Scheier B.
        • Burke J.M.
        • Gan G.
        • Lu X.
        • Bunn Jr., P.A.
        • et al.
        Local ablative therapy of oligoprogressive disease prolongs disease control by tyrosine kinase inhibitors in oncogene-addicted non-small-cell lung cancer.
        J Thorac Oncol. 2012; 7: 1807-1814
        • Doherty M.K.
        • Korpanty G.J.
        • Tomasini P.
        • Alizadeh M.
        • Jao K.
        • Labbe C.
        • et al.
        Treatment options for patients with brain metastases from EGFR/ALK-driven lung cancer.
        Radiother Oncol. 2017; 123: 195-202
        • Johung K.L.
        • Yeh N.
        • Desai N.B.
        • Williams T.M.
        • Lautenschlaeger T.
        • Arvold N.D.
        • et al.
        Extended survival and prognostic factors for patients with ALK-rearranged non-small-cell lung cancer and brain metastasis.
        J Clin Oncol. 2016; 34: 123-129
        • Sperduto P.W.
        • Yang T.J.
        • Beal K.
        • Pan H.
        • Brown P.D.
        • Bangdiwala A.
        • et al.
        Estimating survival in patients with lung cancer and brain metastases: an update of the graded prognostic assessment for lung cancer using molecular markers (Lung-molGPA).
        JAMA Oncol. 2017; 3: 827-831
        • Kodama T.
        • Hasegawa M.
        • Takanashi K.
        • Sakurai Y.
        • Kondoh O.
        • Sakamoto H.
        Antitumor activity of the selective ALK inhibitor alectinib in models of intracranial metastases.
        Cancer Chemother Pharmacol. 2014; 74: 1023-1028
        • Gadgeel S.M.
        • Gandhi L.
        • Riely G.J.
        • Chiappori A.A.
        • West H.L.
        • Azada M.C.
        • et al.
        Safety and activity of alectinib against systemic disease and brain metastases in patients with crizotinib-resistant ALK-rearranged non-small-cell lung cancer (AF-002JG): results from the dose-finding portion of a phase 1/2 study.
        Lancet Oncol. 2014; 15: 1119-1128
        • Shaw A.T.
        • Gandhi L.
        • Gadgeel S.
        • Riely G.J.
        • Cetnar J.
        • West H.
        • et al.
        Alectinib in ALK-positive, crizotinib-resistant, non-small-cell lung cancer: a single-group, multicentre, phase 2 trial.
        Lancet Oncol. 2016; 17: 234-242
        • Ou S.H.
        • Ahn J.S.
        • De Petris L.
        • Govindan R.
        • Yang J.C.
        • Hughes B.
        • et al.
        Alectinib in crizotinib-refractory ALK-rearranged non-small-cell lung cancer: a phase II global study.
        J Clin Oncol. 2016; 34: 661-668
        • Peters S.
        • Camidge D.R.
        • Shaw A.T.
        • Gadgeel S.
        • Ahn J.S.
        • Kim D.W.
        • et al.
        Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer.
        N Engl J Med. 2017; 377: 829-838
        • Felip E.
        • Crino L.
        • Kim D.W.
        • Spigel D.R.
        • Nishio M.
        • Mok T.
        • et al.
        141PD: whole body and intracranial efficacy of ceritinib in patients (pts) with crizotinib (CRZ) pretreated, ALK-rearranged (ALK+) non-small cell lung cancer (NSCLC) and baseline brain metastases (BM): results from ASCEND-1 and ASCEND-2 trials.
        J Thorac Oncol. 2016; 11: S118-S119
        • Kim D.W.
        • Mehra R.
        • Tan D.S.
        • Felip E.
        • Chow L.Q.
        • Camidge D.R.
        • et al.
        Activity and safety of ceritinib in patients with ALK-rearranged non-small-cell lung cancer (ASCEND-1): updated results from the multicentre, open-label, phase 1 trial.
        Lancet Oncol. 2016; 17: 452-463
        • Rosell R.
        • Gettinger S.N.
        • Bazhenova L.A.
        • Langer C.J.
        • Salgia R.
        • Shaw A.T.
        • et al.
        1330: Brigatinib efficacy and safety in patients (Pts) with anaplastic lymphoma kinase (ALK)-positive (ALK+) non-small cell lung cancer (NSCLC) in a phase 1/2 trial.
        J Thorac Oncol. 2016; 11: S114
        • Kim D.W.
        • Tiseo M.
        • Ahn M.J.
        • Reckamp K.L.
        • Hansen K.H.
        • Kim S.W.
        • et al.
        Brigatinib in patients with crizotinib-refractory anaplastic lymphoma kinase-positive non-small-cell lung cancer: a randomized, multicenter phase II trial.
        J Clin Oncol. 2017; 35: 2490-2498
        • Shaw A.T.
        • Felip E.
        • Bauer T.M.
        • Besse B.
        • Navarro A.
        • Postel-Vinay S.
        • et al.
        Lorlatinib in non-small-cell lung cancer with ALK or ROS1 rearrangement: an international, multicentre, open-label, single-arm first-in-man phase 1 trial.
        Lancet Oncol. 2017; 18: 1590-1599
        • Shi W.
        • Dicker A.P.
        CNS metastases in patients with non-small-cell lung cancer and ALK gene rearrangement.
        J Clin Oncol. 2016; 34: 107-109
        • Rusthoven C.G.
        • Doebele R.C.
        Management of brain metastases in ALK-positive non-small-cell lung cancer.
        J Clin Oncol. 2016; 34: 2814-2819