Skip to main content
SpringerLink
Log in

Systemic Therapy of Brain Metastases: Lung Cancer

  • Chapter
  • First Online:
Central Nervous System Metastases

Abstract

Lung cancer is the most common primary tumor that metastasizes to the brain, accounting for around 50% of all diagnosed brain metastases. Lung cancer is broken down into small cell lung cancer and non-small cell lung cancer (NSCLC), and while treatment strategies vary between them, both have the propensity to metastasize to the brain. Between 10% and 30% of patients with NSCLC will develop brain metastases at some point during their disease course, portending a poor prognosis for these patients. Traditionally, brain metastases were managed with local treatments such as surgery and radiation (either whole-brain radiation therapy or stereotactic radiosurgery), but systemic chemotherapy was thought to have little intracranial efficacy. However, advances in targeted therapies, which inhibit specific driver mutations, and immune checkpoint inhibitors are altering this dogma. As a result of targeted therapies, the prognosis for patients with EGFR and ALK mutations has drastically improved, while immune checkpoint inhibitors are providing a durable response in a subset of patients. Translational research and innovative clinical trials will continue to produce new therapeutic options, hopefully improving the outcomes for patients with lung cancer brain metastases.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 249.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  1. Noone AM, Howlader N, Krapcho M, Miller D, Brest A, Yu M, Ruhl J, Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA, editors. SEER cancer statistics review, 1975–2015. Bethesda: National Cancer Institute; 2018.

    Google Scholar 

  2. Kohler BA, Ward E, McCarthy BJ, 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(9):714–36. https://doi.org/10.1093/jnci/djr077.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Herbst RS, Heymach JV, Lippman SM. Lung cancer. N Engl J Med. 2008;359(13):1367–80. https://doi.org/10.1056/NEJMra0802714.

    Article  CAS  PubMed  Google Scholar 

  4. Castrucci WA, Knisely JPS. An update on the treatment of CNS metastases in small cell lung cancer. Cancer J Sudbury Massachusetts. 2008;14(3):138–46. https://doi.org/10.1097/PPO.0b013e318172d6e1.

    Article  Google Scholar 

  5. Sørensen JB, Hansen HH, Hansen M, Dombernowsky P. Brain metastases in adenocarcinoma of the lung: frequency, risk groups, and prognosis. J Clin Oncol Off J Am Soc Clin Oncol. 1988;6(9):1474–80. https://doi.org/10.1200/JCO.1988.6.9.1474.

    Article  Google Scholar 

  6. Sperduto PW, Yang TJ, Beal K, 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.

    Article  PubMed  Google Scholar 

  7. Kris MG, Johnson BE, Berry LD, et al. Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. JAMA. 2014;311(19):1998–2006. https://doi.org/10.1001/jama.2014.3741.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Alamgeer M, Ganju V, Watkins DN. Novel therapeutic targets in non-small cell lung cancer. Curr Opin Pharmacol. 2013;13(3):394–401. https://doi.org/10.1016/j.coph.2013.03.010.

    Article  CAS  PubMed  Google Scholar 

  9. Savas P, Hughes B, Solomon B. Targeted therapy in lung cancer: IPASS and beyond, keeping abreast of the explosion of targeted therapies for lung cancer. J Thorac Dis. 2013;5(Suppl 5):S579–92. https://doi.org/10.3978/j.issn.2072-1439.2013.08.52.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Dong J, Li B, Lin D, Zhou Q, Huang D. Advances in targeted therapy and immunotherapy for non-small cell lung cancer based on accurate molecular typing. Front Pharmacol. 2019;10:230. https://doi.org/10.3389/fphar.2019.00230.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. 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(1):54–9. https://doi.org/10.2478/v10019-012-0007-1.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Fischer B, Marinov M, Arcaro A. Targeting receptor tyrosine kinase signalling in small cell lung cancer (SCLC): what have we learned so far? Cancer Treat Rev. 2007;33(4):391–406. https://doi.org/10.1016/j.ctrv.2007.01.006.

    Article  CAS  PubMed  Google Scholar 

  13. Herbst RS, Morgensztern D, Boshoff C. The biology and management of non-small cell lung cancer. Nature. 2018;553(7689):446–54. https://doi.org/10.1038/nature25183.

    Article  CAS  PubMed  Google Scholar 

  14. Giaccone G, Herbst RS, Manegold C, et al. Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase III trial – INTACT 1. J Clin Oncol Off J Am Soc Clin Oncol. 2004;22(5):777–84. https://doi.org/10.1200/JCO.2004.08.001.

    Article  CAS  Google Scholar 

  15. Herbst RS, Giaccone G, Schiller JH, et al. Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial – INTACT 2. J Clin Oncol Off J Am Soc Clin Oncol. 2004;22(5):785–94. https://doi.org/10.1200/JCO.2004.07.215.

    Article  CAS  Google Scholar 

  16. Herbst RS, Prager D, Hermann R, et al. TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2005;23(25):5892–9. https://doi.org/10.1200/JCO.2005.02.840.

    Article  CAS  Google Scholar 

  17. Gatzemeier U, Pluzanska A, Szczesna A, et al. Phase III study of erlotinib in combination with cisplatin and gemcitabine in advanced non-small-cell lung cancer: the Tarceva Lung Cancer Investigation Trial. J Clin Oncol Off J Am Soc Clin Oncol. 2007;25(12):1545–52. https://doi.org/10.1200/JCO.2005.05.1474.

    Article  CAS  Google Scholar 

  18. Paez JG, Jänne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004;304(5676):1497–500. https://doi.org/10.1126/science.1099314.

    Article  CAS  PubMed  Google Scholar 

  19. 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(21):2129–39. https://doi.org/10.1056/NEJMoa040938.

    Article  CAS  PubMed  Google Scholar 

  20. 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. https://doi.org/10.1073/pnas.0405220101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Rosell R, Moran T, Queralt C, et al. Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med. 2009;361(10):958–67. https://doi.org/10.1056/NEJMoa0904554.

    Article  CAS  PubMed  Google Scholar 

  22. Mok TS, Wu Y-L, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361(10):947–57. https://doi.org/10.1056/NEJMoa0810699.

    Article  CAS  PubMed  Google Scholar 

  23. Eichler AF, Kahle KT, Wang DL, et al. EGFR mutation status and survival after diagnosis of brain metastasis in nonsmall cell lung cancer. Neuro-Oncology. 2010;12(11):1193–9. https://doi.org/10.1093/neuonc/noq076.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Gow C-H, Chien C-R, Chang Y-L, et al. Radiotherapy in lung adenocarcinoma with brain metastases: effects of activating epidermal growth factor receptor mutations on clinical response. Clin Cancer Res Off J Am Assoc Cancer Res. 2008;14(1):162–8. https://doi.org/10.1158/1078-0432.CCR-07-1468.

    Article  CAS  Google Scholar 

  25. Hotta K, Kiura K, Ueoka H, 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):255–61. https://doi.org/10.1016/j.lungcan.2004.04.036.

    Article  Google Scholar 

  26. Kim J-E, Lee DH, Choi Y, et al. Epidermal growth factor receptor tyrosine kinase inhibitors as a first-line therapy for never-smokers with adenocarcinoma of the lung having asymptomatic synchronous brain metastasis. Lung Cancer Amsterdam Netherlands. 2009;65(3):351–4. https://doi.org/10.1016/j.lungcan.2008.12.011.

    Article  Google Scholar 

  27. Porta R, Sánchez-Torres JM, Paz-Ares L, 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.

    Article  CAS  PubMed  Google Scholar 

  28. 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(1):116–20. https://doi.org/10.3892/mco.2013.190.

    Article  CAS  PubMed  Google Scholar 

  29. Zhao J, Chen M, Zhong W, et al. Cerebrospinal fluid concentrations of gefitinib in patients with lung adenocarcinoma. Clin Lung Cancer. 2013;14(2):188–93. https://doi.org/10.1016/j.cllc.2012.06.004.

    Article  CAS  PubMed  Google Scholar 

  30. Clarke JL, Pao W, Wu N, Miller VA, 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 Neuro-Oncol. 2010;99(2):283–6. https://doi.org/10.1007/s11060-010-0128-6.

    Article  Google Scholar 

  31. Grommes C, Oxnard GR, Kris MG, 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Yu HA, Sima C, Feldman D, et al. Phase 1 study of twice weekly pulse dose and daily low-dose erlotinib as initial treatment for patients with EGFR-mutant lung cancers. Ann Oncol. 2017;28(2):278–84. https://doi.org/10.1093/annonc/mdw556.

    Article  CAS  PubMed  Google Scholar 

  33. Wu Y-L, 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.

    Article  PubMed  Google Scholar 

  34. 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 Off J Am Soc Clin Oncol. 2013;31(7):895–902. https://doi.org/10.1200/JCO.2011.40.1174.

    Article  CAS  Google Scholar 

  35. Iuchi T, Shingyoji M, Sakaida T, et al. Phase II trial of gefitinib alone without radiation 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.

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  37. Yang J-J, 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.

    Article  CAS  PubMed  Google Scholar 

  38. 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(8):786–92. https://doi.org/10.1056/NEJMoa044238.

    Article  CAS  PubMed  Google Scholar 

  39. Sequist LV, Waltman BA, Dias-Santagata D, et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med. 2011;3(75):75ra26. https://doi.org/10.1126/scitranslmed.3002003.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Camidge DR, Pao W, Sequist LV. Acquired resistance to TKIs in solid tumours: learning from lung cancer. Nat Rev Clin Oncol. 2014;11(8):473–81. https://doi.org/10.1038/nrclinonc.2014.104.

    Article  CAS  PubMed  Google Scholar 

  41. 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(25):2380–8. https://doi.org/10.1056/NEJMoa0909530.

    Article  CAS  PubMed  Google Scholar 

  42. Sequist LV, Yang JC-H, Yamamoto N, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol Off J Am Soc Clin Oncol. 2013;31(27):3327–34. https://doi.org/10.1200/JCO.2012.44.2806.

    Article  CAS  Google Scholar 

  43. Wu Y-L, Zhou C, Hu C-P, 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.

    Article  CAS  PubMed  Google Scholar 

  44. Jänne PA, Yang JC-H, Kim D-W, et al. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med. 2015;372(18):1689–99. https://doi.org/10.1056/NEJMoa1411817.

    Article  PubMed  Google Scholar 

  45. 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;378(2):113–25. https://doi.org/10.1056/NEJMoa1713137.

    Article  PubMed  Google Scholar 

  46. Mok TS, Wu Y-L, Ahn M-J, et al. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med. 2017;376(7):629–40. https://doi.org/10.1056/NEJMoa1612674.

    Article  CAS  PubMed  Google Scholar 

  47. Morris SW, Kirstein MN, Valentine MB, et al. Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin’s lymphoma. Science. 1995;267(5196):316–7.

    Article  CAS  PubMed  Google Scholar 

  48. Lin JJ, Riely GJ, Shaw AT. Targeting ALK: precision medicine takes on drug resistance. Cancer Discov. 2017;7(2):137–55. https://doi.org/10.1158/2159-8290.CD-16-1123.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Soda M, Choi YL, Enomoto M, et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature. 2007;448(7153):561–6. https://doi.org/10.1038/nature05945.

    Article  CAS  PubMed  Google Scholar 

  50. Takeuchi K, Choi YL, Soda M, et al. Multiplex reverse transcription-PCR screening for EML4-ALK fusion transcripts. Clin Cancer Res Off J Am Assoc Cancer Res. 2008;14(20):6618–24. https://doi.org/10.1158/1078-0432.CCR-08-1018.

    Article  CAS  Google Scholar 

  51. Shaw AT, Yeap BY, Mino-Kenudson M, et al. Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. J Clin Oncol Off J Am Soc Clin Oncol. 2009;27(26):4247–53. https://doi.org/10.1200/JCO.2009.22.6993.

    Article  CAS  Google Scholar 

  52. Wong DW-S, Leung EL-H, So KK-T, 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(8):1723–33. https://doi.org/10.1002/cncr.24181.

    Article  CAS  PubMed  Google Scholar 

  53. Cui JJ, Tran-Dubé M, Shen H, et al. Structure based drug design of crizotinib (PF-02341066), a potent and selective dual inhibitor of mesenchymal-epithelial transition factor (c-MET) kinase and anaplastic lymphoma kinase (ALK). J Med Chem. 2011;54(18):6342–63. https://doi.org/10.1021/jm2007613.

    Article  CAS  PubMed  Google Scholar 

  54. Solomon BJ, Mok T, Kim D-W, et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med. 2014;371(23):2167–77. https://doi.org/10.1056/NEJMoa1408440.

    Article  CAS  PubMed  Google Scholar 

  55. 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 Off J Am Soc Clin Oncol. 2016;34(24):2858–65. https://doi.org/10.1200/JCO.2015.63.5888.

    Article  CAS  Google Scholar 

  56. Shaw AT, Kim D-W, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med. 2013;368(25):2385–94. https://doi.org/10.1056/NEJMoa1214886.

    Article  CAS  PubMed  Google Scholar 

  57. Shaw AT, Kim D-W, Mehra R, et al. Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J Med. 2014;370(13):1189–97. https://doi.org/10.1056/NEJMoa1311107.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Shaw AT, Gandhi L, Gadgeel S, et al. Alectinib in ALK-positive, crizotinib-resistant, non-small-cell lung cancer: a single-group, multicentre, phase 2 trial. Lancet Oncol. 2016;17(2):234–42. https://doi.org/10.1016/S1470-2045(15)00488-X.

    Article  CAS  PubMed  Google Scholar 

  59. Kim D-W, Tiseo M, Ahn M-J, 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 Off J Am Soc Clin Oncol. 2017;35(22):2490–8. https://doi.org/10.1200/JCO.2016.71.5904.

    Article  CAS  Google Scholar 

  60. Shaw A, Mehra R, Tan DSW, et al. BM-32CERITINIB (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-Oncology. 2014;16(Suppl 5):v39. https://doi.org/10.1093/neuonc/nou240.32.

    Article  PubMed Central  Google Scholar 

  61. 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(10):1119–28. https://doi.org/10.1016/S1470-2045(14)70362-6.

    Article  CAS  PubMed  Google Scholar 

  62. 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 London England. 2017;390(10089):29–39. https://doi.org/10.1016/S0140-6736(17)30565-2.

    Article  CAS  Google Scholar 

  63. 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.

    Article  CAS  PubMed  Google Scholar 

  64. Solomon BJ, Besse B, Bauer TM, et al. Lorlatinib in patients with ALK-positive non-small-cell lung cancer: results from a global phase 2 study. Lancet Oncol. 2018;19(12):1654–67. https://doi.org/10.1016/S1470-2045(18)30649-1.

    Article  CAS  PubMed  Google Scholar 

  65. Guin S, Ru Y, Wynes MW, et al. Contributions of KRAS and RAL in non-small-cell lung cancer growth and progression. J Thorac Oncol Off Publ Int Assoc Study Lung Cancer. 2013;8(12):1492–501. https://doi.org/10.1097/JTO.0000000000000007.

    Article  CAS  Google Scholar 

  66. Chan BA, Hughes BGM. Targeted therapy for non-small cell lung cancer: current standards and the promise of the future. Transl Lung Cancer Res. 2015;4(1):36–54. https://doi.org/10.3978/j.issn.2218-6751.2014.05.01.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Wood K, Hensing T, Malik R, Salgia R. Prognostic and predictive value in KRAS in non-small-cell lung cancer: a review. JAMA Oncol. 2016;2(6):805–12. https://doi.org/10.1001/jamaoncol.2016.0405.

    Article  PubMed  Google Scholar 

  68. Riely GJ, Johnson ML, Medina C, et al. A phase II trial of Salirasib in patients with lung adenocarcinomas with KRAS mutations. J Thorac Oncol Off Publ Int Assoc Study Lung Cancer. 2011;6(8):1435–7. https://doi.org/10.1097/JTO.0b013e318223c099.

    Article  Google Scholar 

  69. Jänne PA, van den Heuvel MM, Barlesi F, et al. Selumetinib plus docetaxel compared with docetaxel alone and progression-free survival in patients with KRAS-mutant advanced non-small cell lung cancer: the SELECT-1 randomized clinical trial. JAMA. 2017;317(18):1844–53. https://doi.org/10.1001/jama.2017.3438.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Kim JH, Kim HS, Kim BJ. Prognostic value of KRAS mutation in advanced non-small-cell lung cancer treated with immune checkpoint inhibitors: a meta-analysis and review. Oncotarget. 2017;8(29):48248–52. https://doi.org/10.18632/oncotarget.17594.

    Article  PubMed  PubMed Central  Google Scholar 

  71. Reck M, Rodríguez-Abreu D, Robinson AG, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016;375(19):1823–33. https://doi.org/10.1056/NEJMoa1606774.

    Article  CAS  PubMed  Google Scholar 

  72. Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous non–small-cell lung cancer. N Engl J Med. 2015;373(17):1627–39. https://doi.org/10.1056/NEJMoa1507643.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Horn L, Mansfield AS, Szczęsna A, et al. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med. 2018;379(23):2220–9. https://doi.org/10.1056/NEJMoa1809064.

    Article  CAS  PubMed  Google Scholar 

  74. Takamori S, Toyokawa G, Okamoto I, et al. Clinical significance of PD-L1 expression in brain metastases from non-small cell lung cancer. Anticancer Res. 2018;38(1):553–7. https://doi.org/10.21873/anticanres.12258.

    Article  CAS  PubMed  Google Scholar 

  75. Berghoff AS, Ricken G, Wilhelm D, et al. Tumor infiltrating lymphocytes and PD-L1 expression in brain metastases of small cell lung cancer (SCLC). J Neuro-Oncol. 2016;130(1):19–29. https://doi.org/10.1007/s11060-016-2216-8.

    Article  CAS  Google Scholar 

  76. Mansfield AS, Aubry MC, Moser JC, et al. Temporal and spatial discordance of programmed cell death-ligand 1 expression and lymphocyte tumor infiltration between paired primary lesions and brain metastases in lung cancer. Ann Oncol Off J Eur Soc Med Oncol. 2016;27(10):1953–8. https://doi.org/10.1093/annonc/mdw289.

    Article  CAS  Google Scholar 

  77. Berghoff AS, Fuchs E, Ricken G, et al. Density of tumor-infiltrating lymphocytes correlates with extent of brain edema and overall survival time in patients with brain metastases. Oncoimmunology. 2016;5(1):e1057388. https://doi.org/10.1080/2162402X.2015.1057388.

    Article  CAS  PubMed  Google Scholar 

  78. Berghoff AS, Lassmann H, Preusser M, Höftberger R. Characterization of the inflammatory response to solid cancer metastases in the human brain. Clin Exp Metastasis. 2013;30(1):69–81. https://doi.org/10.1007/s10585-012-9510-4.

    Article  CAS  PubMed  Google Scholar 

  79. Cloughesy TF, Mochizuki AY, Orpilla JR, et al. Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma. Nat Med. 2019;25(3):477–86. https://doi.org/10.1038/s41591-018-0337-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Schalper KA, Rodriguez-Ruiz ME, Diez-Valle R, et al. Neoadjuvant nivolumab modifies the tumor immune microenvironment in resectable glioblastoma. Nat Med. 2019;25(3):470–6. https://doi.org/10.1038/s41591-018-0339-5.

    Article  CAS  PubMed  Google Scholar 

  81. Margolin K, Ernstoff MS, Hamid O, et al. Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol. 2012;13(5):459–65. https://doi.org/10.1016/S1470-2045(12)70090-6.

    Article  CAS  PubMed  Google Scholar 

  82. Crinò L, Bidoli P, Ulivi P, et al. P1.01-053 Italian Nivolumab Expanded Access Programme (EAP): data from patients with advanced non-squamous NSCLC and brain metastases. J Thorac Oncol. 2017;12(11):S1915. https://doi.org/10.1016/j.jtho.2017.09.707.

    Article  Google Scholar 

  83. Molinier O, Audigier-Valette C, Cadranel J, et al. OA 17.05 IFCT-1502 CLINIVO: real-life experience with nivolumab in 600 patients (Pts) with advanced non-small cell lung cancer (NSCLC). J Thorac Oncol. 2017;12(11):S1793. https://doi.org/10.1016/j.jtho.2017.09.430.

    Article  Google Scholar 

  84. Gandhi L, Rodríguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus chemotherapy in metastatic non–small-cell lung cancer. N Engl J Med. 2018;378(22):2078–92. https://doi.org/10.1056/NEJMoa1801005.

    Article  CAS  PubMed  Google Scholar 

  85. El Rassy E, Botticella A, Kattan J, Le Péchoux C, Besse B, Hendriks L. Non-small cell lung cancer brain metastases and the immune system: from brain metastases development to treatment. Cancer Treat Rev. 2018;68:69–79. https://doi.org/10.1016/j.ctrv.2018.05.015.

    Article  CAS  PubMed  Google Scholar 

  86. Goldberg SB, Gettinger SN, Mahajan A, et al. Durability of brain metastasis response and overall survival in patients with non-small cell lung cancer (NSCLC) treated with pembrolizumab. J Clin Oncol. 2018;36(15_suppl):2009. https://doi.org/10.1200/JCO.2018.36.15_suppl.2009.

    Article  Google Scholar 

  87. Singh C, Qian JM, Yu JB, Chiang VL. Local tumor response and survival outcomes after combined stereotactic radiosurgery and immunotherapy in non-small cell lung cancer with brain metastases. J Neurosurg. 2019;132(2):512–7. https://doi.org/10.3171/2018.10.JNS181371.

    Article  PubMed  Google Scholar 

  88. Chen L, Douglass J, Kleinberg L, et al. Concurrent immune checkpoint inhibitors and stereotactic radiosurgery for brain metastases in non-small cell lung cancer, melanoma, and renal cell carcinoma. Int J Radiat Oncol. 2018;100(4):916–25. https://doi.org/10.1016/j.ijrobp.2017.11.041.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, OH, USA

    Adam Lauko & Manmeet S. Ahluwalia

  2. Department of Medical Oncology, University of Washington Seattle Cancer Care Alliance, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    Vyshak Alva Venur

Authors
  1. Adam Lauko
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vyshak Alva Venur
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Manmeet S. Ahluwalia
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Manmeet S. Ahluwalia .

Editor information

Editors and Affiliations

  1. Department of Neurological Surgery, NewYork-Presbyterian Hospital/Weill Cornell Medicine, Director - Brain Metastases Program, New York, NY, USA

    Rohan Ramakrishna

  2. Department of Neurology, NewYork-Presbyterian Hospital/Weill Cornell Medicine, New York, NY, USA

    Rajiv S. Magge

  3. Department of Neurological Surgery, NewYork-Presbyterian Hospital/Weill Cornell Medicine, New York, NY, USA

    Ali A. Baaj

  4. Department of Radiation Oncology, NewYork-Presbyterian Hospital/Weill Cornell Medicine, New York, NY, USA

    Jonathan P.S. Knisely

Rights and permissions

Reprints and permissions

Copyright information

© 2020 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Lauko, A., Venur, V.A., Ahluwalia, M.S. (2020). Systemic Therapy of Brain Metastases: Lung Cancer. In: Ramakrishna, R., Magge, R., Baaj, A., Knisely, J. (eds) Central Nervous System Metastases. Springer, Cham. https://doi.org/10.1007/978-3-030-42958-4_14

Download citation

  • DOI: https://doi.org/10.1007/978-3-030-42958-4_14

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-030-42957-7

  • Online ISBN: 978-3-030-42958-4

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation