Top

Published in:

01-11-2018 | Neuro-oncology (R Soffietti, Section Editor)

Novel Systemic Treatments for Brain Metastases From Lung Cancer

Authors: Bicky Thapa, MD, Adam Lauko, BS (Medical Student), Kunal Desai, MD, Vyshak Alva Venur, MD, Manmeet S. Ahluwalia, MD, FACP

Published in: Current Treatment Options in Neurology | Issue 11/2018

Abstract

Purpose of review

Brain metastases are frequent complication of lung cancer and are associated with poor prognosis. Patients with brain metastases secondary to lung cancer have traditionally been managed with surgery and radiation with limited role for systemic chemotherapy. In the past decade, however, this paradigm has shifted largely due to the advent of targeted therapies and immunotherapies, both of which have demonstrated efficacy in the treatment of brain metastases and extracranial disease.

Recent findings

While patients with brain metastases secondary to lung cancer have historically been excluded from trials, recent data suggest efficacy of novel targeted therapies and immunotherapies in these patients. In fact, there are multiple ongoing trials to further evaluate these therapies in this patient profile.

Summary

Targeted therapies and immunotherapies have the potential to improve outcomes in patients with brain metastases secondary to lung cancer.

American Cancer Society, Cancer facts & figures 2017.

Schouten LJ, Rutten J, Huveneers HA, Twijnstra A. Incidence of brain metastases in a cohort of patients with carcinoma of the breast, colon, kidney, and lung and melanoma. Cancer. 2002;94(10):2698–705.CrossRefPubMed

Barnholtz-Sloan JS, Sloan AE, Davis FG, Vigneau FD, Lai P, Sawaya RE. Incidence proportions of brain metastases in patients diagnosed (1973 to 2001) in the metropolitan Detroit cancer surveillance system. J Clin Oncol. 2004;22(14):2865–72. https://doi.org/10.1200/jco.2004.12.149.CrossRefPubMed

Davey P: Brain metastases: treatment options to improve outcomes. CNS Drugs 16;2002;325–338.CrossRefPubMed

Kromer, Courtney, Jordan Xu, Quinn T. Ostrom, Haley Gittleman, Carol Kruchko, Raymond Sawaya, and Jill S. Barnholtz-Sloan. Estimating the annual frequency of synchronous brain metastasis in the United States 2010–2013: a population-based study. J Neuro-Oncol 134(1);2017:55–64. https://doi.org/10.1007/s11060-017-2516-7.CrossRefPubMed

Howlader N, Noone AM, Krapcho M, et al., editors. SEER Cancer Statistics Review, 1975–2008. Bethesda (MD): National Cancer Institute; 2010. Available at: http://seer.cancer.gov/csr/1975_2008/, based on November 2010 SEER data submission, posted to the SEER web site, 2011.

Kohler B, Ward E, McCarthy B, et al. Annual report to the nation on the status of cancer, 1975–2007, featuring tumors of the brain and other nervous system. J Natl Cancer Inst. 2011;103:1–23.CrossRef

Herbst RS, Heymach JV, Lippman SM. Lung cancer. N Engl J Med. 2008;359(13):1367–80.CrossRefPubMed

Sørense J, Hansen H, Hansen M, Dombernowsky P. Brain metastases in adenocarcinoma of the lung: frequency, risk groups, and prognosis. J Clin Oncol. 1988;6:1474–80.CrossRef

10.

Castrucci W, Knisely J. An update on the treatment of CNS metastases in small cell lung cancer. Cancer J. 2008;14:138–46.CrossRefPubMed

11.

Venur VA, Ahluwalia MS. Prognostic scores for brain metastasis patients: use in clinical practice and trial design. Chin Clin Oncol. 2015;4(2):18. https://doi.org/10.3978/j.issn.2304-3865.2015.06.01.CrossRefPubMed

12.

SperdutoPW, Chao ST, Sneed PK, LuoX, Suh J, Roberge D, et al. Diagnosis-specific prognostic factors, indexes, and treatment outcomes for patients with newly diagnosed brain metastases: a multi-institutional analysis of 4,259 patients. Int J Radiat Oncol Biol Phys. 2010;77(3):655–61. https://doi.org/10.1016/j.ijrobp.2009.08.025.CrossRef

13.

Sperduto PW, 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(6):827–31. https://doi.org/10.1001/jamaoncol.2016.3834.CrossRefPubMed

14.

Balasubramanian SK, Alva Venur V, Chao ST, et al. Impact of EGFR and ALK mutation on the outcomes of non-small cell lung cancer (NSCLC) patients with brain metastases. J Clin Oncol. 2016;34(15_suppl):2005. https://doi.org/10.1200/JCO.2016.34.15_suppl.2005.CrossRef

15.

Nonaka H, Akima M, Hatori T, et al. The microvascular of the cerebral white matter: arteries of the subcortical white matter. J Neuropathol Exp Neurol. 2003;62:154–61.CrossRefPubMed

16.

Porter AT, David M. Palliative care for bone, spinal cord, brain and liver metastases. In: Gunderson LL, Tepper JE, editors. Clinical radiation oncology. Philadelphia: Elsevier; 2007. p. 437–55.

17.

Narayana A, Liebel SA. Primary and metastatic brain tumors. In: Liebel SA, Phillips TL, editors. Textbook of radiation oncology. Philadelphia: Elsevier; 2004. p. 463–95.

18.

Hwang TL, Close TP, Grego JM, et al. Predilection of brain metastasis in gray and white matter junction and vascular border zones. Cancer. 1996;77:1551–5.CrossRefPubMed

19.

Valastyan S, Weinberg RA. Tumor metastasis: molecular insights and evolving paradigms. Cell. 2011;147(2):275–92.CrossRefPubMedPubMedCentral

20.

Ebben D, Johnathan, You M. Brain metastasis in lung cancer: building a molecular and systems-level understanding to improve outcomes. Int J Biochem Cell Biol. 2016;78:P14. https://doi.org/10.1016/j.biocel.2016.07.025.CrossRef

21.

Fidler IJ. The biology of brain metastasis challenges for therapy. Cancer J. 2015;21(4):284–93.CrossRefPubMed

22.

Ciminera AK, Jandial R, Termini J. Metabolic advantages and vulnerabilities in brain metastases. Clin Exp Metastasis. 2017;34(6–7):401–10. https://doi.org/10.1007/s10585-017-9864-8.CrossRefPubMedPubMedCentral

23.

Boroughs LK, De Berardinis RJ. Metabolic pathways promoting cancer cell survival and growth. Nat Cell Biol. 2015;17:351–9.CrossRefPubMedPubMedCentral

24.

Johansson BB. The physiology of the blood-brain barrier. Adv Exp Med Biol. 1990;274:25–39.CrossRefPubMed

25.

Gregoire N. The blood-brain barrier. J Neuroradiol. 1989;16:238–50.PubMed

26.

Felgenhauer K. The blood-brain barrier redefined. J Neurol. 1986;233:193–4.CrossRefPubMed

27.

Shapiro WR, Shapiro JR. Principles of brain tumor chemotherapy. Semin Oncol. 1986;13:56–69.PubMed

28.

Iannotti F, Fleschi C, Alfano B, et al. Simplified, noninvasive PET measurement of blood brain barrier permeability. J Comput Assist Tomogr. 1987;11:390–7.CrossRefPubMed

29.

Frong D, Israel O, Kohn S, et al. The blood-tissue barrier of human brain tumors: correlation of scintigraphic and ultrastructural findings (concise communication). J Nucl Med. 1984;25:461–5.

30.

Lin Q, Balasubramanian K, Fan D, et al. Reactive astrocytes protect melanoma cells from chemotherapy by sequestering intracellular calcium through gap junction channels. Neoplasia. 2010;12:748–54.CrossRefPubMedPubMedCentral

31.

Lekic M, Kovac V, Triller N, Knez L, Sadikov A, Cufer T. Outcome of small cell lung cancer (SCLC) patients with brain metastases in a routine clinical setting. Radiol Oncol. 2012;46:54–9.CrossRefPubMedPubMedCentral

32.

Sabari JK, Paik PK. Relevance of genetic alterations in squamous and small cell lung cancer. Ann Transl Med. 2017;5(18):373. https://doi.org/10.21037/atm.2017.06.72.CrossRefPubMedPubMedCentral

33.

Li T, Kung HJ, Mack PC, Gandara DR. Genotyping and genomic profiling of non-small-cell lung cancer: applications for current and future therapies. J Clin Oncol. 2013;31(8):1039–49. https://doi.org/10.1200/jco.2012.45.3753.CrossRefPubMedPubMedCentral

34.

Kris MG, Johnson BE, Berry LD, Kwiatkowski DJ, Iafrate AJ, Wistuba II, et al. Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. JAMA. (2014);311:1998–2006.CrossRefPubMedPubMedCentral

35.

Shonka N, Venur VA, Ahluwalia MS. Targeted treatment of brain metastases. Curr Neurol Neurosci Rep. 2017;17(4) https://doi.org/10.1007/s11910-017-0741-2.

36.

Welsh JW, Komaki R, Amini A, 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.CrossRefPubMedPubMedCentral

37.

Iuchi T, Shingyoji M, Sakaida T, Hatano K, Nagano O, Itakura M, et al. Phase II trial of gefitinib alone without radiaton therapy for Japanese patients with brain metastases from EGFR-mutant lung adenocarcinoma. Lung cancer (Amsterdam, Netherlands). 2013;82(2):282–7. https://doi.org/10.1016/j.lungcan.2013.08.016.CrossRef

38.

Wu YL, Zhou C, Cheng Y, 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(4):993–9. https://doi.org/10.1093/annonc/mds529.CrossRefPubMed

39.

Lee SM, Lewanski CR, Counsell N, et al. Randomized trial of erlotinib plus whole-brain radiotherapy for NSCLC patients with multiple brain metastases. J Natl Cancer Inst. 2014;106:dju151.PubMedPubMedCentral

40.

•• Yang JJ, Zhou C, Huang 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(9):707–16. https://doi.org/10.1016/S2213-2600(17)30262-X. In this phase III, multicenter clinical trial in China, icotinib showed longer intracranial PFS as compared to WBRT plus chemotherapy in patients with EGFR-mutant NSCLC.CrossRefPubMed

41.

•• Mok TS, Wu YL, Ahn MJ, Garassino MC, Kim HR, Ramalingam SS, et al. Osimertinib or platinum pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med. 2016; https://doi.org/10.1056/NEJMoa1612674. In this phase III clinical trial, osimertinib demonstrated better efficacy as compared to standard chemotherapy in patients with EGFR-mutant brain metastases in non-small cell lung cancer.CrossRefPubMed

42.

•• Solomon BJ, Cappuzzo F, Felip E, 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(24):2858–65. In this phase III PROFILE 1014 study, crizotinib showed better intracranial activity in patients with ALK-positive NSCLC brain metastases as compared to standard chemotherapy.CrossRefPubMed

43.

•• Crino L, Ahn MJ, De Marinis F, Groen HJ, Wakelee H, Hida T, et al. 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 Oncol. 2016;34(24):2866–73. https://doi.org/10.1200/JCO.2015.65.5936. This phase II study included patients ALK-positive NSCLC, previously treated with chemotherapy and crizotinib. Ceritinib demonstrated durable intracranial response in patients with brain metastases.CrossRefPubMed

44.

•• Peters S, Camidge DR, Shaw AT, et al. Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer. N Engl J Med. 2017;377(9):829–38. https://doi.org/10.1056/NEJMoa1704795. In this phase III clinical trial, alectinib demonstrated longer PFS as compared to crizotinib in patients with ALK positive NSCLC brain metastases.CrossRefPubMed

45.

•• Goldberg SB, Gettinger SN, Mahajan A, et al. Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial. Lancet Oncol. 2016;17(7):976–83. https://doi.org/10.1016/S1470-2045(16)30053-5. The only prospective trial in patients with lung cancer brain metastases assessing efficacy of immunotherapy. Pembrolizumab demonstrated intracranial activity in patients with lung cancer brain metastases.CrossRefPubMedPubMedCentral

46.

Sharma SV, Bell DW, Settleman J, Haber DA. Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer. 2007;7(3):169–81.CrossRefPubMed

47.

Gupta R, Dastane AM, Forozan F, Riley-Portuguez A, Chung F, Lopategui J, et al. Evaluation of EGFR abnormalities in patients with pulmonary adenocarcinoma: the need to test neoplasms with more than one method. Mod Pathol. 2009;22:128–33.CrossRefPubMed

48.

Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, 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(21):2129–39. https://doi.org/10.1056/NEJMoa040938.CrossRefPubMed

49.

Pao W, Miller VA. Epidermal growth factor receptor mutations, small-molecule kinase inhibitors, and non-small-cell lung cancer: current knowledge and future directions. J Clin Oncol. 2005;23(11):2556–68. https://doi.org/10.1200/jco.2005.07.799.CrossRefPubMed

50.

Pao W, Miller V, Zakowski M, et al. EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A. 2004;101(36):13306–11.CrossRefPubMedPubMedCentral

51.

Eichler AF, Kahle KT, Wang DL, et al. EGFR mutation status and survival after diagnosis of brain metastasis in nonsmall cell lung cancer. Neuro Oncol. 2010;12:1193–9.CrossRefPubMedPubMedCentral

52.

Ladanyi M, Pao W. Lung adenocarcinoma: guiding EGFR-targeted therapy and beyond. Mod Pathol. 2008;21(Suppl 2):S16–22. https://doi.org/10.1038/modpathol.3801018.CrossRefPubMed

53.

Sordella, et al. Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways. Science. 2004;305(5687):1163–7.CrossRefPubMed

54.

Pao W, Miller V, Zakowski M, Doherty J, Politi K, Sarkaria I, et al. EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci USA. 2004;101:13306–11.CrossRef

55.

Rosell R, Moran T, Queralt C, Porta R, Cardenal F, Camps C, et al. Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med. 2009;361:958–67.CrossRefPubMed

56.

•• Soria J-C, Ohe Y, Vansteenkiste J, et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med. 2017;NEJMoa1713137. https://doi.org/10.1056/NEJMoa1713137. The phase III clinical trial included patients with previously untreated, EGFR-mutant advanced NSCLC and compared the efficacy of osimertinib with standard EGFR TKIs. Osimertinib demonstrated better efficacy as compared to standard EGFR TKIs.CrossRefPubMed

57.

Nakamichi S, Seike M, Miyanaga A, et al. RT-PCR for Detecting ALK translocations in cytology samples from lung cancer patients. Anticancer Res. 2017;37(6):3295–9. https://doi.org/10.21873/anticanres.11696.CrossRefPubMed

58.

Soda M, Choi YL, Enomoto M, Takada S, Yamashita Y, Ishikawa S, et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature. 2007;448:561–6.CrossRefPubMed

59.

Takeuchi K, Choi YL, Soda M, Inamura K, Togashi Y, Hatano S, et al. Multiplex reverse transcription-PCR screening for EML4-ALK fusion transcripts. Clin Cancer Res. 2008;14:6618–24.CrossRefPubMed

60.

Shaw AT, Yeap BY, Mino-Kenudson M, Digumarthy SR, Costa DB, Heist RS, et al. Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. J Clin Oncol. 2009;27:4247–53.CrossRefPubMedPubMedCentral

61.

Wong DW-S, Leung EL-H, So KK-T, Tam IY-S, Sihoe AD-L, Cheng L-C, et al. The EML4-ALK fusion gene is involved in various histologic types of lung cancers from nonsmokers with wild-type EGFR and KRAS. Cancer. 2009;115:1723–33.

62.

Agata Y, Kawasaki A, Nishimura H, et al. Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. Int Immunol. 1996;8(5):765–72.CrossRefPubMed

63.

Schalper KA, Venur VA, Velcheti V. Programmed death-1/programmed death-1 ligand axis as a therapeutic target in oncology: current insights. J Receptor Ligand Channel Res. 2015;8:1–7. https://doi.org/10.2147/JRLCR.S39986.CrossRef

64.

Mitsudomi T, Morita S, Yatabe Y, et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol. 2010;11:121–8.CrossRefPubMed

65.

Deng Y, Feng W, Wu J, 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;2:116e120.

66.

Wang M, Jing Z, Minjiang C. Cerebral penetration of gefitinib in patients with lung adenocarcinoma. J Clin Oncol. 2011;29(15_suppl):7608. https://doi.org/10.1200/jco.2011.29.15_suppl.7608.CrossRef

67.

Jeffrey V. Brower & H. Ian Robins (2016) Erlotinib for the treatment of brain metastases in non-small cell lung cancer, Expert Opinion on Pharmacotherapy 17(7):1013–1021,DOI: https://doi.org/10.1517/14656566.2016.1165206.CrossRefPubMed

68.

Hotta K, Kiura K, Ueoka H, Tabata M, Fujiwara K, Kozuki T,et al. Effect of gefitinib (‘Iressa’, ZD1839) on brain metastases in patients with advanced non-small-cell lung cancer. Lung cancer (Amsterdam, Netherlands). 2004;46(2):255–261. doi:https://doi.org/10.1016/j.lungcan.2004.04.036.CrossRefPubMed

69.

Kim JE, Lee DH, Choi Y, et al. Epidermal growth factor receptor tyrosine kinase inhibitors as a first-line therapy for neversmokers with adenocarcinoma of the lung having asymptomatic synchronous brain metastasis. Lung Cancer. 2009;65:351e354.

70.

Porta R, Sanchez-Torres JM, 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(3):624–31. https://doi.org/10.1183/09031936.00195609.CrossRefPubMed

71.

Grommes C, Oxnard GR, Kris MG, Miller VA, Pao W, Holodny AI, et al. “Pulsatile” high-dose weekly erlotinib for CNS metastases from EGFR mutant non-small cell lung cancer. Neuro-Oncology. 2011;13(12):1364–9. https://doi.org/10.1093/neuonc/nor121.CrossRefPubMedPubMedCentral

72.

Fan Y, Huang Z, Fang L, Miao L, Gong L, Yu H, et al. A phase II study of icotinib and whole-brain radiotherapy in Chinese patients with brain metastases from nonsmall cell lung cancer. Cancer Chemother Pharmacol. 2015;76(3):517–23. https://doi.org/10.1007/s00280-015-2760-5.CrossRefPubMed

73.

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;362:2380–8.CrossRefPubMed

74.

Janne PA, Wang X, Socinski MA, et al. Randomized phase II trial of erlotinib alone or with carboplatin and paclitaxel in patients who were never or light former smokers with advanced lung adenocarcinoma: CALGB 30406 trial. J Clin Oncol.

75.

Pao W, Miller VA, Politi KA, et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med. 2005;2:e73.CrossRefPubMedPubMedCentral

76.

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;352:786–92.CrossRefPubMed

77.

Sequist LV, Yang JC, Yamamoto N, O'Byrne K, Hirsh V, Mok T, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013;31(27):3327–34. https://doi.org/10.1200/jco.2012.44.2806.CrossRefPubMed

78.

Wu Y-L, Zhou C, Hu C-P, Feng J, Lu S, Huang Y, 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(2):213–22. https://doi.org/10.1016/S1470-2045(13)70604-1.CrossRefPubMed

79.

•• Schuler M, Wu Y-L, Hirsh V, 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(3):380–90. https://doi.org/10.1016/j.jtho.2015.11.014. The subgroup analyses for both LUX-Lung 3 and LUX-lung 6 revealed improved PFS with afatinib versus chemotherapy in patients with EGFR-mutant NSCLC and asymptomatic brain metastases.CrossRefPubMed

80.

Ballard P, Yates JW, Yang Z, Kim DW, Yang JC, Cantarini M, et al. Preclinical comparison of osimertinib with other EGFRTKIs in EGFR-mutant NSCLC brain metastases models, and early evidence of clinical brain metastases activity. Clin Cancer Res. 2016; https://doi.org/10.1158/1078-0432.ccr-16-0399.CrossRefPubMed

81.

Cross DAE, Ashton SE, Ghiorghiu S, et al. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov. 2014;4(9):1046–61. https://doi.org/10.1158/2159-8290.CD-14-0337.CrossRefPubMedPubMedCentral

82.

Jänne PA, Yang JC-H, Kim D-W, et al. AZD9291 in EGFR inhibitor-resistant no-small-cell lung cancer. N Engl J Med. 2015;372(18):1689–99. https://doi.org/10.1056/NEJMoa1411817.CrossRefPubMed

83.

•• Vansteenkiste J, Reungwetwattana T, Nakagawa K, et al. LBA5CNS response to osimertinib vs standard of care (SoC) EGFR-TKI as first-line therapy in patients (pts) with EGFR-TKI sensitising mutation (EGFRm)-positive advanced non-small cell lung cancer (NSCLC): data from the FLAURA study. Ann Oncol. 2017;28(suppl_10):mdx729.007. https://doi.org/10.1093/annonc/mdx729.007. The phase III FLAURA study included patients with previously untreated EGFR-mutant NSCLC and compared osimertinib with standard EGFR TKIs (gefitinib or erlotinib). A subgroup analysis showed better CNS PFS with osimertinib as compared to standard EGFR TKIs.

84.

Ahluwalia MS, Becker K, Levy BP. Epidermal growth factor receptor tyrosine kinase inhibitors for central nervous system metastases from non-small cell lung cancer. Oncology. 2018; https://doi.org/10.1634/theoncologist.2017-0572.CrossRefPubMedPubMedCentral

85.

Bohn JP, Pall G, Stockhammer G, et al. Targeted therapies for the treatment of brain metastases in solid tumors. Target Oncol. 2016.

86.

Rangachari D, Yamaguchi N, VanderLaan PA, Folch E, Mahadevan A, Floyd SR, et al. Brain metastases in patients with EGFR-mutated or ALK-rearranged non-small-cell lung cancers. Lung Cancer. 2015;88(1):108–11. https://doi.org/10.1016/j.lungcan.2015.01.020.CrossRefPubMed

87.

The National Comprehensive Cancer Network (NCCN): Clinical practice guidelines in oncology: non-small cell lung cancer. v4.2016.

88.

Costa DB, Shaw AT, Ou SHI, et al. Clinical experience with crizotinib in patients with advanced ALK-rearranged non-small-cell lung cancer and brain metastases. J Clin Oncol. 2015;33:1881–8.CrossRefPubMedPubMedCentral

89.

Wong A. The emerging role of targeted therapy and immunotherapy in the management of brain metastases in non-small cell lung cancer. Front Oncol. 2017;7:33. https://doi.org/10.3389/fonc.2017.00033.CrossRefPubMedPubMedCentral

90.

Venur VA, Ahluwalia MS. Targeted therapy in brain metastases: ready for primetime? American Society of Clinical Oncology educational book. American Society of Clinical Oncology Meeting. 2016;35:e123–30. https://doi.org/10.14694/edbk_100006.CrossRef

91.

Shaw A, Mehra R, Tan DSW, et al. BM-32 Ceritinib (LDK378) for treatment of patients with ALK-rearranged (ALK+) non-small cell lung cancer (NSCLC) and brain metastases (BM) in the ASCEND-1 trial. Neuro Oncol. 2014;16:v39.CrossRefPubMedCentral

92.

Gadgeel SM, Gandhi L, Riely GJ, 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;15:1119–28.CrossRefPubMed

93.

Hida T, Nokihara H, Kondo M, et al. Alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer (J-ALEX): an open-label, randomised phase 3 trial. Lancet. 2017;390(10089):29–39. https://doi.org/10.1016/S0140-6736(17)30565-2.CrossRefPubMed

94.

Camidge DR, Bazhenova L, Salgia R, et al. Safety and efficacy of brigatinib (AP26113) in advanced malignancies, including ALK1 non-small cell lung cancer (NSCLC). J Clin Oncol. 33;2015(suppl; abstr 8062).

95.

Solomon B, Bauer T, Felip E, Besse B, James L, Clancy J. 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). Abstract 9009 Presented at ASCO Annual Meeting Proceedings in Chicago (2016).CrossRef

96.

Dudnik E, et al. Intracranial response to nivolumab in NSCLC patients with untreated or progressing CNS metastases. Lung Cancer (Amsterdam, Netherlands). 2016;98:114–7. https://doi.org/10.1016/j.lungcan.2016.05.031.CrossRef

97.

Watanabe H, Kubo T, Ninomiya T, et al. The effect of nivolumab treatment for central nervous system metastases in nonsmall cell lung cancer. J Clin Oncol. 2017;35(15).CrossRef

98.

Gauvain C, Vauléon E, Chouaid C, et al. Intracerebral efficacy and tolerance of nivolumab in non-small-cell lung cancer patients with brain metastases. Lung Cancer. 2018;116. https://doi.org/10.1016/j.lungcan.2017.12.008 CrossRefPubMed

99.

Thapa B, Ahluwalia M, et al. CMET-01. Efficacy and outcome of anti-PD1 therapy in patients with lung cancer brain metastasis. Neuro-Oncol. 2017;19(suppl_6):vi39. https://doi.org/10.1093/neuonc/nox168.151.CrossRefPubMedCentral

Title: Novel Systemic Treatments for Brain Metastases From Lung Cancer
Authors: Bicky Thapa, MD
Adam Lauko, BS (Medical Student)
Kunal Desai, MD
Vyshak Alva Venur, MD
Manmeet S. Ahluwalia, MD, FACP
Publication date: 01-11-2018
Publisher: Springer US
Published in: Current Treatment Options in Neurology / Issue 11/2018
Print ISSN: 1092-8480
Electronic ISSN: 1534-3138
DOI: https://doi.org/10.1007/s11940-018-0533-2

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Novel Systemic Treatments for Brain Metastases From Lung Cancer

Abstract

Purpose of review

Recent findings

Summary

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Purpose of review

Recent findings

Summary

Please log in to get access to this content

Other articles of this Issue 11/2018

Sleep, Circadian Rhythms, and Epilepsy

Stem Cell Therapy in Cerebrovascular Disease

Sleep Abnormalities in Wilson’s Disease

Managing Antiepileptic Medication in Dialysis Patients