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Management of Brain Metastases

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Book cover Lung Cancer

Part of the book series: Current Cancer Research ((CUCR))

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Abstract

Brain metastases account for the majority of malignant brain tumors and as newer cancer treatments improve patient survival, the reported incidence of brain metastases is increasing. Lung cancer is the most frequent origin of metastases to the brain, and this diagnosis is associated with significant morbidity as well as decreased quality of life and a worse prognosis. The treatment for brain metastases in NSCLC has historically been local therapy, either surgery or radiation, as many chemotherapies have limited efficacy in the brain. These strategies are highly effective but can be a source of morbidity themselves. Newer systemic therapies, including targeted small molecule drugs and immunotherapy, have shown promise in treating NSCLC associated CNS disease either alone or in combination with local therapies. Increasing evidence for this strategy is accumulating as more clinical trials allow the inclusion of patients with untreated asymptomatic brain metastases. This chapter summarizes the current use of systemic therapy in the treatment of brain metastases in NSCLC.

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References

  1. Svokos KA, Salhia B, Toms SA (2014) Molecular biology of brain metastasis. Int J Mol Sci 15(6):9519–9530

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Peters S et al (2016) The impact of brain metastasis on quality of life, resource utilization and survival in patients with non-small-cell lung cancer. Cancer Treat Rev 45:139–162

    Article  PubMed  Google Scholar 

  3. Laurie Gaspar, C.S.M, Rotman M, Asbell S, Phillips T, Wasserman T, McKenna WG, Byhardt R (1997) Recursive Partition Analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys 37:745–751

    Article  Google Scholar 

  4. Cagney DN et al (2017) Incidence and prognosis of patients with brain metastases at diagnosis of systemic malignancy: a population-based study. Neuro-Oncology 19(11):1511–1521

    Article  PubMed  PubMed Central  Google Scholar 

  5. Kromer C et al (2017) Estimating the annual frequency of synchronous brain metastasis in the United States 2010-2013: a population-based study. J Neuro-Oncol 134(1):55–64

    Article  Google Scholar 

  6. Barnholtz-Sloan JS et al (2004) Incidence proportions of brain metastases in patients diagnosed (1973 to 2001) in the Metropolitan Detroit Cancer Surveillance System. J Clin Oncol 22(14):2865–2872

    Article  PubMed  Google Scholar 

  7. Brown PD, MSA, Kahn OH, Asher AL, Wefel JS, Gondi V (2018) Whole brain radiotherapy for brain metastases: evolution or revolution. J Clin Oncol 36:483

    Article  CAS  PubMed  Google Scholar 

  8. <Weinberg2001_Article_SurgicalManagementOfBrainMetas.pdf>

    Google Scholar 

  9. Grant FC (1926) Concerning Intrcranial malignant metastases: their frequency and the value of surgery in their treatment. Ann Surg 84:635–646

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Narayan Sundaresan JHG (1985) Surgical treatment of brain metastases. Cancer 55:1382–1388

    Article  Google Scholar 

  11. Markesbery WR, Brooks WH, Gupta GD, Young AB (1978) Treatment for patients with cerebral metastases. JAMA Neurol 35:754–756

    CAS  Google Scholar 

  12. Mandell L et al (1986) The treatment of single brain metastasis from non-oat cell lung carcinoma. Surgery and radiation versus radiation therapy alone. Cancer 58(3):641–649

    Article  CAS  PubMed  Google Scholar 

  13. White KT, Fleming TR, Laws ER Jr (1981) Single metastasis to the brain. Surgical treatment in 122 consecutive patients. Mayo Clin Proc 56(7):424–428

    CAS  PubMed  Google Scholar 

  14. Bindal RK et al (1993) Surgical treatment of multiple brain metastases. J Neurosurg 79(2):210–216

    Article  CAS  PubMed  Google Scholar 

  15. Mintz AH et al (1996) A randomized trial to assess the efficacy of surgery in addition to radiotherapy in patients with a single cerebral metastasis. Cancer 78(7):1470–1476

    Article  CAS  PubMed  Google Scholar 

  16. Brown PD et al (2016) Effect of radiosurgery alone vs radiosurgery with whole brain radiation therapy on cognitive function in patients with 1 to 3 brain metastases: a randomized clinical trial. JAMA 316(4):401–409

    Article  PubMed  PubMed Central  Google Scholar 

  17. Jen-Hung Chao, RP, Nickson JJ (1954) Roentgen-ray therapy of cerebral metastases. Cancer 7:682–689

    Article  PubMed  Google Scholar 

  18. Borgelt BGR, Kramer S, Brady LW, Chang CH, Davis LW, Perez CA, Hendrickson FR (1980) The palliation of brain metastases: final results of the first two studies by the Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 6:1

    Article  CAS  PubMed  Google Scholar 

  19. Sneed PK, Larson DA, Wara WM (1996) Radiotherapy for cerebral metastases. Neurosurg Clin N Am 7(3):505–516

    Article  CAS  PubMed  Google Scholar 

  20. Katz HR (1981) The relative effectiveness of radiation therapy, corticosteroids, and surgery in the management of melanoma metastatic to the central nervous system. Int J Radiat Oncol Biol Phys 7(7):897–906

    Article  CAS  PubMed  Google Scholar 

  21. Hussain A et al (2007) Stereotactic radiosurgery for brainstem metastases: survival, tumor control, and patient outcomes. Int J Radiat Oncol Biol Phys 67(2):521–524

    Article  PubMed  Google Scholar 

  22. Tallet AV et al (2012) Neurocognitive function impairment after whole brain radiotherapy for brain metastases: actual assessment. Radiat Oncol 7:77

    Article  PubMed  PubMed Central  Google Scholar 

  23. Schimmel WCM et al (2018) Cognitive effects of stereotactic radiosurgery in adult patients with brain metastases: a systematic review. Adv Radiat Oncol 3(4):568–581

    Article  PubMed  PubMed Central  Google Scholar 

  24. Minniti G et al (2011) Stereotactic radiosurgery for brain metastases: analysis of outcome and risk of brain radionecrosis. Radiat Oncol 6:48

    Article  PubMed  PubMed Central  Google Scholar 

  25. Chin LS, Ma L, DiBiase S (2001) Radiation necrosis following gamma knife surgery: a case-controlled comparison of treatment parameters and long-term clinical follow up. J Neurosurg 94(6):899–904

    Article  CAS  PubMed  Google Scholar 

  26. Network, N.C.C. Small cell lung cancer (version 1.2021. 2020 November 15, 2020]; Available from: https://www.nccn.org/professionals/physician_gls/pdf/sclc_blocks.pdf

  27. Ribatti D et al (2006) Development of the blood-brain barrier: a historical point of view. Anat Rec B New Anat 289(1):3–8

    Article  PubMed  Google Scholar 

  28. Saunders NR et al (2014) The rights and wrongs of blood-brain barrier permeability studies: a walk through 100 years of history. Front Neurosci 8:404

    Article  PubMed  PubMed Central  Google Scholar 

  29. Fricker G et al (2014) The Blood Brain Barrier (BBB). Springer, Berlin, Heidelberg

    Book  Google Scholar 

  30. Stamatovic SM, Keep RF, Andjelkovic AV (2008) Brain endothelial cell-cell junctions: how to “open” the blood brain barrier. Curr Neuropharmacol 6(3):179–192

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Galea I, Bechmann I, Perry VH (2007) What is immune privilege (not)? Trends Immunol 28(1):12–18

    Article  CAS  PubMed  Google Scholar 

  32. Louveau A et al (2015) Structural and functional features of central nervous system lymphatic vessels. Nature 523(7560):337–341

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Cserr HF, Harling-Berg CJ, Knopf PM (1992) Drainage of brain extracellular fluid into blood and deep cervical lymph and its immunological significance. Brain Pathol 2(4):269–276

    Article  CAS  PubMed  Google Scholar 

  34. Kida S, Pantazis A, Weller RO (1993) CSF drains directly from the subarachnoid space into nasal lymphatics in the rat. Anatomy, histology and immunological significance. Neuropathol Appl Neurobiol 19(6):480–488

    Article  CAS  PubMed  Google Scholar 

  35. Wekerle H, Sun DM (2010) Fragile privileges: autoimmunity in brain and eye. Acta Pharmacol Sin 31(9):1141–1148

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Berghoff AS et al (2016) Tumor infiltrating lymphocytes and PD-L1 expression in brain metastases of small cell lung cancer (SCLC). J Neuro-Oncol 130(1):19–29

    Article  CAS  Google Scholar 

  37. Kamath SD, Kumthekar PU (2018) Immune checkpoint inhibitors for the treatment of Central Nervous System (CNS) metastatic disease. Front Oncol 8:414

    Article  PubMed  PubMed Central  Google Scholar 

  38. Goldberg SB et al (2016) 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 17(7):976–983

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Goldberg SB et al (2020) Pembrolizumab for management of patients with NSCLC and brain metastases: long-term results and biomarker analysis from a non-randomised, open-label, phase 2 trial. Lancet Oncol 21(5):655–663

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Vittorio Franciosi GCM, Michiara M, Di Constanzo F, Fosser V, Tonato M, Carlini P, Boni C, Di Sarra S (1999) Front-line chemotheraphy with Cisplatin and Etoposide for patients with brain metastases from breast carcinoma, nonsmall cell lung carcinoma, or malignant melanoma. Cancer 85:1599–1605

    Article  Google Scholar 

  41. Bailon O et al (2012) Upfront association of carboplatin plus pemetrexed in patients with brain metastases of lung adenocarcinoma. Neuro-Oncology 14(4):491–495

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Cortes J et al (2003) Front-line paclitaxel/cisplatin-based chemotherapy in brain metastases from non-small-cell lung cancer. Oncology 64(1):28–35

    Article  CAS  PubMed  Google Scholar 

  43. Fujita A et al (2000) Combination chemotherapy of cisplatin, ifosfamide, and irinotecan with rhG-CSF support in patients with brain metastases from non-small cell lung cancer. Oncology 59(4):291–295

    Article  CAS  PubMed  Google Scholar 

  44. Quadvlieg V et al (2004) Frontline gemcitabine and cisplatin based chemotherapy in patients with NSCLC inoperable brain metastases. J Clin Oncol 22(14_suppl):7117

    Article  Google Scholar 

  45. Bearz A et al (2010) Activity of Pemetrexed on brain metastases from non-small cell lung cancer. Lung Cancer 68(2):264–268

    Article  PubMed  Google Scholar 

  46. Ardizzoni A et al (1997) Topotecan, a new active drug in the second-line treatment of small-cell lung cancer: a phase II study in patients with refractory and sensitive disease. The European Organization for research and treatment of cancer early clinical studies group and new drug development office, and the lung cancer cooperative group. J Clin Oncol 15(5):2090–2096

    Article  CAS  PubMed  Google Scholar 

  47. Korfel A, O.C, von Pawel J, Keppler U, Deppermann M, Kaubitsch S, Thiel E (2002) Response to topotecan of symptomatic brain metastases of small-cell lung cancer also after whole-brain irradiation. A multicentre phase II study. Eur J Cancer 38:1724–1729

    Article  CAS  PubMed  Google Scholar 

  48. Qin H et al (2014) Whole brain radiotherapy plus concurrent chemotherapy in non-small cell lung cancer patients with brain metastases: a meta-analysis. PLoS One 9(10):e111475

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Sandler A et al (2006) Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 355(24):2542–2550

    Article  CAS  PubMed  Google Scholar 

  50. Besse B et al (2015) Bevacizumab in patients with nonsquamous non-small cell lung cancer and asymptomatic, untreated Brain metastases (BRAIN): a nonrandomized, phase II study. Clin Cancer Res 21(8):1896–1903

    Article  CAS  PubMed  Google Scholar 

  51. Barlesi F et al (2016) Routine molecular profiling of patients with advanced non-small-cell lung cancer: results of a 1-year nationwide programme of the French Cooperative Thoracic Intergroup (IFCT). Lancet 387(10026):1415–1426

    Article  CAS  PubMed  Google Scholar 

  52. Kris MG et al (2014) Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. JAMA 311(19):1998–2006

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Shi Y et al (2014) A prospective, molecular epidemiology study of EGFR mutations in Asian patients with advanced non-small-cell lung cancer of adenocarcinoma histology (PIONEER). J Thorac Oncol 9(2):154–162

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Iuchi T et al (2015) Frequency of brain metastases in non-small-cell lung cancer, and their association with epidermal growth factor receptor mutations. Int J Clin Oncol 20(4):674–679

    Article  CAS  PubMed  Google Scholar 

  55. Shin DY et al (2014) EGFR mutation and brain metastasis in pulmonary adenocarcinomas. J Thorac Oncol 9(2):195–199

    Article  CAS  PubMed  Google Scholar 

  56. Omuro AM et al (2005) High incidence of disease recurrence in the brain and leptomeninges in patients with nonsmall cell lung carcinoma after response to gefitinib. Cancer 103(11):2344–2348

    Article  CAS  PubMed  Google Scholar 

  57. Deng Y et al (2014) The concentration of erlotinib in the cerebrospinal fluid of patients with brain metastasis from non-small-cell lung cancer. Mol Clin Oncol 2(1):116–120

    Article  CAS  PubMed  Google Scholar 

  58. Masuda T et al (2011) Erlotinib efficacy and cerebrospinal fluid concentration in patients with lung adenocarcinoma developing leptomeningeal metastases during gefitinib therapy. Cancer Chemother Pharmacol 67(6):1465–1469

    Article  CAS  PubMed  Google Scholar 

  59. Porta R et al (2011) Brain metastases from lung cancer responding to erlotinib: the importance of EGFR mutation. Eur Respir J 37(3):624–631

    Article  CAS  PubMed  Google Scholar 

  60. Wu YL et al (2013) 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 24(4):993–999

    Article  PubMed  Google Scholar 

  61. Park SJ et al (2012) 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 77(3):556–560

    Article  CAS  PubMed  Google Scholar 

  62. Zhao J et al (2013) Cerebrospinal fluid concentrations of gefitinib in patients with lung adenocarcinoma. Clin Lung Cancer 14(2):188–193

    Article  CAS  PubMed  Google Scholar 

  63. Zhang Q et al (2016) Effects of epidermal growth factor receptor-tyrosine kinase inhibitors alone on EGFR-mutant non-small cell lung cancer with brain metastasis. Thorac Cancer 7(6):648–654

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Ma S et al (2009) Treatment of brain metastasis from non-small cell lung cancer with whole brain radiotherapy and Gefitinib in a Chinese population. Lung Cancer 65(2):198–203

    Article  PubMed  Google Scholar 

  65. Iuchi T et al (2013) Phase II trial of gefitinib alone without radiation therapy for Japanese patients with brain metastases from EGFR-mutant lung adenocarcinoma. Lung Cancer 82(2):282–287

    Article  CAS  PubMed  Google Scholar 

  66. Ceresoli GL et al (2004) Gefitinib in patients with brain metastases from non-small-cell lung cancer: a prospective trial. Ann Oncol 15(7):1042–1047

    Article  CAS  PubMed  Google Scholar 

  67. Wu C et al (2007) Gefitinib in the treatment of advanced non-small cell lung cancer with brain metastasis. Zhonghua Zhong Liu Za Zhi 29(12):943–945

    CAS  PubMed  Google Scholar 

  68. Hata A et al (2015) Spatiotemporal T790M heterogeneity in individual patients with EGFR-mutant non-small-cell lung cancer after acquired resistance to EGFR-TKI. J Thorac Oncol 10(11):1553–1559

    Article  CAS  PubMed  Google Scholar 

  69. Grommes C et al (2011) "Pulsatile" high-dose weekly erlotinib for CNS metastases from EGFR mutant non-small cell lung cancer. Neuro-Oncology 13(12):1364–1369

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Yu HA et al (2017) 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 28(2):278–284

    Article  CAS  PubMed  Google Scholar 

  71. Arbour KC et al (2018) Twice weekly pulse and daily continuous-dose erlotinib as initial treatment for patients with epidermal growth factor receptor-mutant lung cancers and brain metastases. Cancer 124(1):105–109

    Article  CAS  PubMed  Google Scholar 

  72. Sequist LV et al (2013) Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol 31(27):3327–3334

    Article  CAS  PubMed  Google Scholar 

  73. Wu Y-L et al (2014) 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 15(2):213–222

    Article  CAS  PubMed  Google Scholar 

  74. Schuler M et al (2016) 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 11(3):380–390

    Article  PubMed  Google Scholar 

  75. Hoffknecht P et al (2015) 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 10(1):156–163

    Article  CAS  PubMed  Google Scholar 

  76. Gerber NK et al (2014) Erlotinib versus radiation therapy for brain metastases in patients with EGFR-mutant lung adenocarcinoma. Int J Radiat Oncol Biol Phys 89(2):322–329

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Soon YY et al (2015) 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 114(2):167–172

    Article  CAS  PubMed  Google Scholar 

  78. Magnuson WJ et al (2017) 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 35(10):1070–1077

    Article  CAS  PubMed  Google Scholar 

  79. Soria JC et al (2018) Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med 378(2):113–125

    Article  CAS  PubMed  Google Scholar 

  80. Network, N.C.C. Lung cancer (Version 7.2019). August 15., 2019]; Available from: https://www.nccn.org/professionals/physician_gls/pdf/nscl_blocks.pdf

  81. Ballard P et al (2016) 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 22(20):5130–5140

    Article  CAS  PubMed  Google Scholar 

  82. Mok TS et al (2017) Osimertinib or platinum-Pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med 376(7):629–640

    Article  CAS  PubMed  Google Scholar 

  83. Goss G et al (2018) CNS response to osimertinib in patients with T790M-positive advanced NSCLC: pooled data from two phase II trials. Ann Oncol 29(3):687–693

    Article  CAS  PubMed  Google Scholar 

  84. Yang JC-H et al (2017) 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 35(15_suppl):2020

    Article  Google Scholar 

  85. Rodig SJ et al (2009) Unique clinicopathologic features characterize ALK-rearranged lung adenocarcinoma in the western population. Clin Cancer Res 15(16):5216–5223

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Rangachari D et al (2015) Brain metastases in patients with EGFR-mutated or ALK-rearranged non-small-cell lung cancers. Lung Cancer 88(1):108–111

    Article  PubMed  Google Scholar 

  87. Costa DB et al (2015) Clinical experience with Crizotinib in patients with advanced ALK-rearranged non-small-cell lung cancer and brain metastases. J Clin Oncol 33(17):1881–1888

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Solomon BJ et al (2016) Intracranial efficacy of Crizotinib versus chemotherapy in patients with advanced ALK-positive non-small-cell lung cancer: results from PROFILE 1014. J Clin Oncol 34(24):2858–2865

    Article  CAS  PubMed  Google Scholar 

  89. Costa DB et al (2011) CSF concentration of the anaplastic lymphoma kinase inhibitor crizotinib. J Clin Oncol 29(15):e443–e445

    Article  PubMed  Google Scholar 

  90. Kodama T et al (2014) Antitumor activity of the selective ALK inhibitor alectinib in models of intracranial metastases. Cancer Chemother Pharmacol 74(5):1023–1028

    Article  CAS  PubMed  Google Scholar 

  91. Gadgeel SM et al (2016) Pooled analysis of CNS response to Alectinib in two studies of pretreated patients with ALK-positive non-small-cell lung cancer. J Clin Oncol 34(34):4079–4085

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Novello S et al (2018) Alectinib versus chemotherapy in crizotinib-pretreated anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer: results from the phase III ALUR study. Ann Oncol 29(6):1409–1416

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Peters S et al (2017) Alectinib versus Crizotinib in untreated ALK-positive non-small-cell lung cancer. N Engl J Med 377(9):829–838

    Article  CAS  PubMed  Google Scholar 

  94. Lin JJ et al (2019) Efficacy of Alectinib in patients with ALK-positive NSCLC and symptomatic or large CNS metastases. J Thorac Oncol 14(4):683–690

    Article  CAS  PubMed  Google Scholar 

  95. Kim D-W et al (2016) 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 17(4):452–463

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Shaw AT et al (2017) 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 Oncol 18(7):874–886

    Article  CAS  PubMed  Google Scholar 

  97. Soria J-C et al (2017) First-line ceritinib versus platinum-based chemotherapy in advanced ALK -rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study. Lancet 389(10072):917–929

    Article  CAS  PubMed  Google Scholar 

  98. Kim DW et al (2017) Brigatinib in patients with Crizotinib-refractory anaplastic lymphoma kinase-positive non-small-cell lung cancer: a randomized, multicenter phase II trial. J Clin Oncol 35(22):2490–2498

    Article  CAS  PubMed  Google Scholar 

  99. Camidge DR et al (2018) Brigatinib versus Crizotinib in ALK-positive non-small-cell lung cancer. N Engl J Med 379(21):2027–2039

    Article  CAS  PubMed  Google Scholar 

  100. Shaw AT et al (2017) 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 18(12):1590–1599

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Solomon BJ et al (2018) Lorlatinib in patients with ALK-positive non-small-cell lung cancer: results from a global phase 2 study. Lancet Oncol 19(12):1654–1667

    Article  CAS  PubMed  Google Scholar 

  102. Solomon B et al (2020) LBA2 Lorlatinib vs crizotinib in the first-line treatment of patients (pts) with advanced ALK-positive non-small cell lung cancer (NSCLC): results of the phase III CROWN study. Ann Oncol 31:S1180–S1181

    Article  Google Scholar 

  103. Goodman A Lorlatinib improves outcomes over Crizotinib in first-line setting of ALK-positive NSCLC: CROWN trial. In: The ASCO post 2020. HSP News Service, L.L.C

    Google Scholar 

  104. Selvaggi G et al (2020) ID:1882 phase III randomized study of Ensartinib vs Crizotinib in anaplastic lymphoma kinase (ALK) POSITIVE NSCLC patients: eXalt3. J Thorac Oncol 15(10):e41–e42

    Article  Google Scholar 

  105. Solomon B et al (2017) OA 05.06 phase 2 study of Lorlatinib in patients with advanced ALK+/ROS1+ non-small-cell lung cancer. J Thorac Oncol 12(11):S1756

    Article  Google Scholar 

  106. Lim SM et al (2017) Open-label, multicenter, phase II study of Ceritinib in patients with non-small-cell lung cancer harboring ROS1 rearrangement. J Clin Oncol 35(23):2613–2618

    Article  CAS  PubMed  Google Scholar 

  107. Drilon A et al (2020) Entrectinib in ROS1 fusion-positive non-small-cell lung cancer: integrated analysis of three phase 1–2 trials. Lancet Oncol 21(2):261–270

    Article  CAS  PubMed  Google Scholar 

  108. Drilon A et al (2018) Frequency of brain metastases and multikinase inhibitor outcomes in patients with RET-rearranged lung cancers. J Thorac Oncol 13(10):1595–1601

    Article  PubMed  PubMed Central  Google Scholar 

  109. Lin JJ et al (2016) Clinical activity of Alectinib in advanced RET-rearranged non-small cell lung Cancer. J Thorac Oncol 11(11):2027–2032

    Article  PubMed  Google Scholar 

  110. Velcheti V et al (2017) OA 12.07 LOXO-292, a potent, highly selective RET inhibitor, in MKI-resistant RET fusion-positive lung cancer patients with and without brain metastases. J Thorac Oncol 12(11):S1778

    Article  Google Scholar 

  111. Guo R et al (2019) Response to selective RET inhibition with LOXO-292 in a patient with RET fusion-positive lung cancer with leptomeningeal metastases. JCO Precis Oncol 3:1

    Google Scholar 

  112. Drilon A et al (2020) Efficacy of Selpercatinib in RET fusion-positive non-small-cell lung cancer. N Engl J Med 383(9):813–824

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Falchook GS et al (2012) Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial. Lancet 379(9829):1893–1901

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Davies MA et al (2017) Dabrafenib plus trametinib in patients with BRAFV600-mutant melanoma brain metastases (COMBI-MB): a multicentre, multicohort, open-label, phase 2 trial. Lancet Oncol 18(7):863–873

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Planchard D et al (2016) Dabrafenib in patients with BRAFV600E-positive advanced non-small-cell lung cancer: a single-arm, multicentre, open-label, phase 2 trial. Lancet Oncol 17(5):642–650

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Planchard D et al (2016) Dabrafenib plus trametinib in patients with previously treated BRAFV600E-mutant metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trial. Lancet Oncol 17(7):984–993

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Planchard D et al (2017) Dabrafenib plus trametinib in patients with previously untreated BRAFV600E-mutant metastatic non-small-cell lung cancer: an open-label, phase 2 trial. Lancet Oncol 18(10):1307–1316

    Article  CAS  PubMed  Google Scholar 

  118. Robinson SD et al (2014) BRAF V600E-mutated lung adenocarcinoma with metastases to the brain responding to treatment with vemurafenib. Lung Cancer 85(2):326–330

    Article  PubMed  Google Scholar 

  119. Yamamoto G et al (2019) Response of BRAF(V600E)-mutant lung adenocarcinoma with brain metastasis and leptomeningeal dissemination to Dabrafenib plus Trametinib treatment. J Thorac Oncol 14(5):e97–e99

    Article  PubMed  Google Scholar 

  120. Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12(4):252–264

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Drugs FDA approved for lung cancer (2019, Sept 18) [cited 2019 October 10, 2019]; Available from: https://www.cancer.gov/about-cancer/treatment/drugs/lung#1

  122. Hellmann MD et al (2019) Nivolumab plus Ipilimumab in advanced non-small-cell lung Cancer. N Engl J Med 381(21):2020–2031

    Article  CAS  PubMed  Google Scholar 

  123. Reck M et al (2020) Nivolumab (NIVO) + ipilimumab (IPI) + 2 cycles of platinum-doublet chemotherapy (chemo) vs 4 cycles chemo as first-line (1L) treatment (tx) for stage IV/recurrent non-small cell lung cancer (NSCLC): CheckMate 9LA. J Clin Oncol 38(15_suppl):9501

    Article  Google Scholar 

  124. Reardon DA et al (2016) Glioblastoma eradication following immune checkpoint blockade in an orthotopic, immunocompetent model. Cancer Immunol Res 4(2):124–135

    Article  CAS  PubMed  Google Scholar 

  125. Berghoff AS, Preusser M (2018) New developments in brain metastases. Ther Adv Neurol Disord 11:1756286418785502

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  126. Borghaei H et al (2015) Nivolumab versus docetaxel in advanced nonsquamous non–small-cell lung cancer. N Engl J Med 373(17):1627–1639

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Goldman JW et al (2016) Nivolumab (nivo) in patients (pts) with advanced (adv) NSCLC and central nervous system (CNS) metastases (mets). J Clin Oncol 34(15_suppl):9038

    Article  Google Scholar 

  128. Reck M et al (2016) Pembrolizumab versus chemotherapy for PD-L1–positive non–small-cell. Lung Cancer 375(19):1823–1833

    CAS  Google Scholar 

  129. Gandhi L et al (2018) Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med 378(22):2078–2092

    Article  CAS  PubMed  Google Scholar 

  130. Garassino MC et al (2019) Abstract CT043: outcomes among patients (pts) with metastatic nonsquamous NSCLC with liver metastases or brain metastases treated with pembrolizumab (pembro) plus pemetrexed-platinum: results from the KEYNOTE-189 study. 79(13 Supplement):CT043

    Google Scholar 

  131. Rittmeyer A et al (2017) Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet 389(10066):255–265

    Article  PubMed  Google Scholar 

  132. Gadgeel SM et al (2019) Atezolizumab in patients with advanced non-small cell lung cancer and history of asymptomatic, treated brain metastases: exploratory analyses of the phase III OAK study. Lung Cancer 128:105–112

    Article  PubMed  Google Scholar 

  133. Lukas RV et al (2017) Safety and efficacy analyses of atezolizumab in advanced non-small cell lung cancer (NSCLC) patients with or without baseline brain metastases. Ann Oncol 28:1128

    Article  Google Scholar 

  134. Crino L et al (2019) Nivolumab and brain metastases in patients with advanced non-squamous non-small cell lung cancer. Lung Cancer 129:35–40

    Article  PubMed  Google Scholar 

  135. Cortinovis D et al (2019) Italian cohort of the Nivolumab EAP in squamous NSCLC: efficacy and safety in patients with CNS metastases. Anticancer Res 39(8):4265–4271

    Article  CAS  PubMed  Google Scholar 

  136. Molinier O et al (2017) 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 12(11):S1793

    Article  Google Scholar 

  137. Hendriks LEL et al (2019) Outcome of patients with non-small cell lung Cancer and brain metastases treated with checkpoint inhibitors. J Thorac Oncol 14:1244

    Article  CAS  PubMed  Google Scholar 

  138. Demaria S, Formenti SC (2012) Role of T lymphocytes in tumor response to radiotherapy. Front Oncol 2:95

    Article  PubMed  PubMed Central  Google Scholar 

  139. Sharabi AB et al (2015) Radiation and checkpoint blockade immunotherapy: radiosensitisation and potential mechanisms of synergy. Lancet Oncol 16(13):e498–e509

    Article  PubMed  Google Scholar 

  140. Demaria S, Golden EB, Formenti SC (2015) Role of local radiation therapy in cancer immunotherapy. JAMA Oncol 1(9):1325

    Article  Google Scholar 

  141. Gupta A et al (2012) Radiotherapy promotes tumor-specific effector CD8+ T cells via dendritic cell activation. J Immunol 189(2):558–566

    Article  CAS  PubMed  Google Scholar 

  142. Herter-Sprie GS et al (2016) Synergy of radiotherapy and PD-1 blockade in Kras-mutant lung cancer. JCI Insight 1(9):e87415

    Article  PubMed  PubMed Central  Google Scholar 

  143. Shaverdian N et al (2017) Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in the treatment of non-small-cell lung cancer: a secondary analysis of the KEYNOTE-001 phase 1 trial. Lancet Oncol 18(7):895–903

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Ahmed KA et al (2017) Outcomes targeting the PD-1/PD-L1 axis in conjunction with stereotactic radiation for patients with non-small cell lung cancer brain metastases. J Neuro-Oncol 133(2):331–338

    Article  CAS  Google Scholar 

  145. Williams NL et al (2017) Phase 1 study of Ipilimumab combined with whole brain radiation therapy or radiosurgery for melanoma patients with brain metastases. Int J Radiat Oncol Biol Phys 99(1):22–30

    Article  CAS  PubMed  Google Scholar 

  146. Anderson ES et al (2017) Melanoma brain metastases treated with stereotactic radiosurgery and concurrent pembrolizumab display marked regression; efficacy and safety of combined treatment. J Immunother Cancer 5(1):76

    Article  PubMed  PubMed Central  Google Scholar 

  147. Lehrer EJ et al (2018) Stereotactic radiosurgery and immune checkpoint inhibitors in the management of brain metastases. Int J Mol Sci 19(10):3054

    Article  Google Scholar 

  148. Lehrer EJ et al (2019) Treatment of brain metastases with stereotactic radiosurgery and immune checkpoint inhibitors: an international meta-analysis of individual patient data. Radiother Oncol 130:104–112

    Article  PubMed  Google Scholar 

  149. Schoenfeld JD et al (2015) Ipilmumab and cranial radiation in metastatic melanoma patients: a case series and review. J Immunother Cancer 3:50

    Article  PubMed  PubMed Central  Google Scholar 

  150. Chen L et al (2018) 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 Biol Phys 100(4):916–925

    Article  PubMed  Google Scholar 

  151. Colaco RJ et al (2016) Does immunotherapy increase the rate of radiation necrosis after radiosurgical treatment of brain metastases? J Neurosurg 125(1):17–23

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Medicine (Medical Oncology), Yale School of Medicine/Yale Cancer Center, Smilow Cancer Hospital Care Center at Saint Francis, Hartford, CT, USA

    Emily F. Collier

  2. Department of Medicine (Medical Oncology), Yale School of Medicine/Yale Cancer Center, New Haven, CT, USA

    Sarah B. Goldberg

  3. Department of Neurosurgery, Yale School of Medicine/Yale Cancer Center, New Haven, CT, USA

    Veronica Chiang

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  1. Emily F. Collier
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  2. Veronica Chiang
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  3. Sarah B. Goldberg
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Correspondence to Sarah B. Goldberg .

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Editors and Affiliations

  1. Yale Comprehensive Cancer Center, Yale University, New Haevn, CT, USA

    Anne C. Chiang

  2. Yale Comprehensive Cancer Center, Yale University, New Haevn, CT, USA

    Roy S. Herbst

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Collier, E.F., Chiang, V., Goldberg, S.B. (2021). Management of Brain Metastases. In: Chiang, A.C., Herbst, R.S. (eds) Lung Cancer. Current Cancer Research. Humana, Cham. https://doi.org/10.1007/978-3-030-74028-3_6

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