Skip to main content
SpringerLink
Log in

Osimertinib for EGFR-Mutant Non-Small-Cell Lung Cancer Central Nervous System Metastases: Current Evidence and Future Perspectives on Therapeutic Strategies

  • Review Article
  • Published:
Targeted Oncology Aims and scope Submit manuscript

A Correction to this article was published on 08 February 2023

This article has been updated

Abstract

Central nervous system (CNS) metastases are common in non-small-cell lung cancer (NSCLC) and associated with poor prognosis and high disease burden. Effective options are needed to treat CNS metastases, and delay or prevent their formation. For epidermal growth factor receptor mutation-positive (EGFRm) advanced NSCLC and brain metastases, upfront EGFR-tyrosine kinase inhibitors (TKIs) are recommended by the joint European Association of Neuro-Oncology–European Society for Medical Oncology and experts. While early-generation EGFR-TKIs have limited CNS efficacy, the third-generation, irreversible, EGFR-TKI osimertinib has potent efficacy in NSCLC CNS metastases. This review discusses the CNS data of osimertinib in the context of therapeutic strategies and future prospects based on expert review of published literature and relevant clinical, real-world, and ongoing studies in this setting. Osimertinib penetrates the blood–brain barrier and achieves greater exposure in the brain compared with other EGFR-TKIs. Osimertinib has demonstrated CNS efficacy, including in leptomeningeal metastases, in EGFRm advanced disease. In EGFRm stage IB–IIIA NSCLC, adjuvant osimertinib reduced CNS disease recurrence versus placebo. The burden and poor prognosis of CNS metastases necessitate more therapeutic options for their management and reduced risk of recurrence in patients with EGFRm NSCLC. Clinical studies are ongoing in advanced disease to investigate osimertinib combinations with chemotherapy/radiation therapy and optimal treatment post-CNS progression with osimertinib. Further prospective research evaluating treatments using CNS-specific endpoints and evaluating CNS resistance is needed to improve outcomes for patients with CNS metastases.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Change history

References

  1. Mizuno T, Konno H, Nagata T, et al. Osteogenic and brain metastases after non-small cell lung cancer resection. Int J Clin Oncol. 2021;26(10):1840–6.

    Article  CAS  PubMed  Google Scholar 

  2. Kenmotsu H, Yamamoto N, Yamanaka T, et al. Randomized phase III study of pemetrexed plus cisplatin versus vinorelbine plus cisplatin for completely resected stage II to IIIA nonsquamous non-small-cell lung cancer. J Clin Oncol. 2020;38(19):2187–96.

    Article  CAS  PubMed  Google Scholar 

  3. Cagney DN, Martin AM, Catalano PJ, et al. Incidence and prognosis of patients with brain metastases at diagnosis of systemic malignancy: a population-based study. Neuro Oncol. 2017;19(11):1511–21.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Tamura T, Kurishima K, Nakazawa K, et al. Specific organ metastases and survival in metastatic non-small-cell lung cancer. Mol Clin Oncol. 2015;3(1):217–21.

    Article  PubMed  Google Scholar 

  5. Waqar SN, Samson PP, Robinson CG, et al. Non-small-cell lung cancer with brain metastasis at presentation. Clin Lung Cancer. 2018;19(4):e373–9.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Han G, Bi J, Tan W, et al. A retrospective analysis in patients with EGFR-mutant lung adenocarcinoma: is EGFR mutation associated with a higher incidence of brain metastasis? Oncotarget. 2016;7(35):56998–7010.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Suda K, Mitsudomi T, Shintani Y, et al. Clinical impacts of EGFR mutation status: analysis of 5780 surgically resected lung cancer cases. Ann Thorac Surg. 2021;111(1):269–76.

    Article  PubMed  Google Scholar 

  8. Heon S, Yeap BY, Britt GJ, et al. Development of central nervous system metastases in patients with advanced non-small cell lung cancer and somatic EGFR mutations treated with gefitinib or erlotinib. Clin Cancer Res. 2010;16(23):5873–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Rangachari D, Yamaguchi N, VanderLaan PA, et al. Brain metastases in patients with EGFR-mutated or ALK-rearranged non-small-cell lung cancers. Lung Cancer. 2015;88(1):108–11.

    Article  PubMed  Google Scholar 

  10. Stanic K, Zwitter M, Hitij NT, et al. Brain metastases in lung adenocarcinoma: impact of EGFR mutation status on incidence and survival. Radiol Oncol. 2014;48(2):173–83.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Liao BC, Lee JH, Lin CC, et al. Epidermal growth factor receptor tyrosine kinase inhibitors for non-small-cell lung cancer patients with leptomeningeal carcinomatosis. J Thorac Oncol. 2015;10(12):1754–61.

    Article  CAS  PubMed  Google Scholar 

  12. Kuiper JS, Zuidersma M, Oude Voshaar RC, et al. Social relationships and risk of dementia: a systematic review and meta-analysis of longitudinal cohort studies. Ageing Res Rev. 2015;22:39–57.

    Article  PubMed  Google Scholar 

  13. Li YS, Jiang BY, Yang JJ, et al. Leptomeningeal metastases in patients with NSCLC with EGFR mutations. J Thorac Oncol. 2016;11(11):1962–9.

    Article  PubMed  Google Scholar 

  14. Peters S, Bexelius C, Munk V, et al. The impact of brain metastasis on quality of life, resource utilization and survival in patients with non-small-cell lung cancer. Cancer Treat Rev. 2016;45:139–62.

    Article  PubMed  Google Scholar 

  15. Schoenmaekers J, Paats MS, Dingemans AC, et al. Central nervous system metastases and oligoprogression during treatment with tyrosine kinase inhibitors in oncogene-addicted non-small cell lung cancer: how to treat and when? Transl Lung Cancer Res. 2020;9(6):2599–617.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Ali A, Goffin JR, Arnold A, et al. Survival of patients with non-small-cell lung cancer after a diagnosis of brain metastases. Curr Oncol. 2013;20(4):e300–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. 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(7):dju151.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Naresh G, Malik PS, Khurana S, et al. Assessment of brain metastasis at diagnosis in non-small-cell lung cancer: a prospective observational study from North India. JCO Glob Oncol. 2021;7:593–601.

    Article  PubMed  Google Scholar 

  19. Umemura S, Tsubouchi K, Yoshioka H, et al. Clinical outcome in patients with leptomeningeal metastasis from non-small cell lung cancer: Okayama Lung Cancer Study Group. Lung Cancer. 2012;77(1):134–9.

    Article  PubMed  Google Scholar 

  20. Riess JW, Nagpal S, Iv M, et al. Prolonged survival of patients with non-small-cell lung cancer with leptomeningeal carcinomatosis in the modern treatment era. Clin Lung Cancer. 2014;15(3):202–6.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Li W, Zhao T, Xu H, et al. The role of EGFR mutation as a prognostic factor in survival after diagnosis of brain metastasis in non-small cell lung cancer: a systematic review and meta-analysis. BMC Cancer. 2019;19:145.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Roughley A, Damonte E, Taylor-Stokes G, et al. Impact of brain metastases on quality of life and estimated life expectancy in patients with advanced non-small cell lung cancer. Value Health. 2014;17(7):A650.

    Article  CAS  PubMed  Google Scholar 

  23. Girard N, Cozzone D, de Leotoing L, et al. Extra cost of brain metastases (BM) in patients with non-squamous non-small cell lung cancer (NSCLC): a French national hospital database analysis. ESMO Open. 2018;3(6): e000414.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Nadler E, Espirito JL, Pavilack M, et al. Real-world disease burden and outcomes of brain metastases in EGFR mutation-positive non-small-cell lung cancer. Future Oncol. 2020;16(22):1575–84.

    Article  CAS  PubMed  Google Scholar 

  25. Baik CS, Chamberlain MC, Chow LQ. Targeted therapy for brain metastases in EGFR-mutated and ALK-rearranged non-small-cell lung cancer. J Thorac Oncol. 2015;10(9):1268–78.

    Article  CAS  PubMed  Google Scholar 

  26. Ye LY, Sun LX, Zhong XH, et al. The structure of blood–tumor barrier and distribution of chemotherapeutic drugs in non-small cell lung cancer brain metastases. Cancer Cell Int. 2021;21(1):556.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Mulvenna P, Nankivell M, Barton R, et al. Dexamethasone and supportive care with or without whole brain radiotherapy in treating patients with non-small cell lung cancer with brain metastases unsuitable for resection or stereotactic radiotherapy (QUARTZ): results from a phase 3, non-inferiority, randomised trial. Lancet. 2016;388(10055):2004–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Le Rhun E, Guckenberger M, Smits M, et al. EANO-ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up of patients with brain metastasis from solid tumours. Ann Oncol. 2021;32(11):1332–47.

    Article  PubMed  Google Scholar 

  29. Vogelbaum MA, Brown PD, Messersmith H, et al. Treatment for brain metastases: ASCO-SNO-ASTRO guideline. J Clin Oncol. 2022;40(5):492–516.

    Article  CAS  PubMed  Google Scholar 

  30. Colclough N, Chen K, Johnström P, et al., Preclinical Comparison of the Blood–brain barrier Permeability of Osimertinib with Other EGFR TKIs, with permission from AACR. Reprinted from Clinical Cancer Research, 2021;27(1):189–201

    Article  CAS  PubMed  Google Scholar 

  31. Lee YJ, Choi HJ, Kim SK, et al. Frequent central nervous system failure after clinical benefit with epidermal growth factor receptor tyrosine kinase inhibitors in Korean patients with nonsmall-cell lung cancer. Cancer. 2010;116(5):1336–43.

    Article  PubMed  Google Scholar 

  32. Park SJ, Kim HT, Lee DH, et al. Efficacy of epidermal growth factor receptor tyrosine kinase inhibitors for brain metastasis in non-small cell lung cancer patients harboring either exon 19 or 21 mutation. Lung Cancer. 2012;77(3):556–60.

    Article  CAS  PubMed  Google Scholar 

  33. He J, Su C, Liang W, et al. Icotinib versus chemotherapy as adjuvant treatment for stage II-IIIA EGFR-mutant non-small-cell lung cancer (EVIDENCE): a randomised, open-label, phase 3 trial. Lancet Respir Med. 2021;9(9):1021–9.

    Article  CAS  PubMed  Google Scholar 

  34. Tada H, Mitsudomi T, Misumi T, et al. Randomized phase III study of gefitinib versus cisplatin plus vinorelbine for patients with resected stage II-IIIA non-small-cell lung cancer with EGFR mutation (IMPACT). J Clin Oncol. 2022;40(3):231–41.

    Article  CAS  PubMed  Google Scholar 

  35. Kelly K, Altorki NK, Eberhardt WE, et al. Adjuvant erlotinib versus placebo in patients with stage IB-IIIA non-small-cell lung cancer (RADIANT): a randomized, double-blind, phase III trial. J Clin Oncol. 2015;33(34):4007–14.

    Article  CAS  PubMed  Google Scholar 

  36. Xu S-T, Xi J-J, Zhong W-Z, et al. The unique spatial-temporal treatment failure patterns of adjuvant gefitinib therapy: a post hoc analysis of the ADJUVANT trial (CTONG 1104). J Thorac Oncol. 2019;14(3):503–12.

    Article  CAS  PubMed  Google Scholar 

  37. Cross DA, 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Mok TS, Wu YL, Ahn MJ, et al. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med. 2017;376(7):629–40.

    Article  CAS  PubMed  Google Scholar 

  39. Ramalingam SS, Vansteenkiste J, Planchard D, et al. Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC. N Engl J Med. 2020;382(1):41–50.

    Article  CAS  PubMed  Google Scholar 

  40. Reungwetwattana T, Nakagawa K, Cho BC, et al. CNS Response to Osimertinib Versus Standard Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Patients With Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. Journal of Clinical Oncology, an American Society of Clinical Oncology journal. 2018;36 (33):JCO2018783118. https://doi.org/10.1200/JCO.2018.78.3118.

    Article  PubMed  Google Scholar 

  41. Tsuboi M, Wu Y-L, He J, et al. Osimertinib adjuvant therapy in patients (pts) with resected EGFR-mutated (EGFRm) NSCLC (ADAURA): central nervous system (CNS) disease recurrence. Ann Oncol. 2020;31(suppl 6):S1378.

    Article  Google Scholar 

  42. Wu YL, Ahn MJ, Garassino MC, et al. CNS Efficacy of Osimertinib in Patients With T790M-Positive Advanced Non-Small-Cell Lung Cancer: Data From a Randomized Phase III Trial (AURA3). Journal of Clinical Oncology, an American Society of Clinical Oncology journal. 2018;36(26):2702‒2709. https://doi.org/10.1200/JCO.2018.77.9363

    Article  CAS  PubMed  Google Scholar 

  43. Kadry H, Noorani B, Cucullo L. A blood–brain barrier overview on structure, function, impairment, and biomarkers of integrity. Fluids Barriers CNS. 2020;17(1):69.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Gerstner ER, Fine RL. Increased permeability of the blood–brain barrier to chemotherapy in metastatic brain tumors: establishing a treatment paradigm. J Clin Oncol. 2007;25(16):2306–12.

    Article  PubMed  Google Scholar 

  45. Ballard P, Yates JW, Yang Z, et al. Preclinical comparison of osimertinib with other EGFR-TKIs in EGFR-mutant NSCLC brain metastases models, and early evidence of clinical brain metastases activity. Clin Cancer Res. 2016;22(20):5130–40.

    Article  CAS  PubMed  Google Scholar 

  46. Varrone A, Varnas K, Jucaite A, et al. A PET study in healthy subjects of brain exposure of (11)C-labelled osimertinib—a drug intended for treatment of brain metastases in non-small cell lung cancer. J Cereb Blood Flow Metab. 2020;40(4):799–807.

    Article  CAS  PubMed  Google Scholar 

  47. Ekman S, Cselényi Z, Varrone A, et al. P76.72 A PET and MRI study exploring osimertinib brain exposure and efficacy in EGFRm NSCLC CNS metastases. J Thorac Oncol. 2021;16(3):S620.

    Article  Google Scholar 

  48. Goss G, Tsai CM, Shepherd FA, et al. CNS response to osimertinib in patients with T790M-positive advanced NSCLC: pooled data from two phase II trials. Ann Oncol. 2018;29(3):687–93.

    Article  CAS  PubMed  Google Scholar 

  49. Eide IJZ, Helland Å, Ekman S, et al. Osimertinib in T790M-positive and -negative patients with EGFR-mutated advanced non-small cell lung cancer (the TREM-study). Lung Cancer. 2020;143:27–35.

    Article  PubMed  Google Scholar 

  50. Eide IJZ, Grut H, Helland Å, et al. Intracranial effect of osimertinib in relapsed EGFR-mutated T790M-positive and -negative non-small cell lung cancer patients: results from a phase II study. Acta Oncol. 2021;60:1565–71.

    Article  CAS  PubMed  Google Scholar 

  51. Peled N, Kian W, Inbar E, et al. Osimertinib in advanced EGFR-mutant Lung Adenocarcinoma with asymptomatic brain metastases: an open-label, three-arm, phase II pilot study. Neurooncol Adv. 2021;4(1):vdab188.

    PubMed  PubMed Central  Google Scholar 

  52. Goldstein IM, Roisman LC, Keren-Rosenberg S, et al. Dose escalation of osimertinib for intracranial progression in EGFR mutated non-small-cell lung cancer with brain metastases. Neurooncol Adv. 2020;2(1):vdaa125.

    PubMed  PubMed Central  Google Scholar 

  53. Park S, Lee MH, Seong M, et al. A phase II, multicenter, two cohort study of 160 mg osimertinib in EGFR T790M-positive non-small-cell lung cancer patients with brain metastases or leptomeningeal disease who progressed on prior EGFR TKI therapy. Ann Oncol. 2020;31(10):1397–404.

    Article  CAS  PubMed  Google Scholar 

  54. Soria JC, Ohe Y, Vansteenkiste J, et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med. 2018;378(2):113–25.

    Article  CAS  PubMed  Google Scholar 

  55. Cheng Y, He Y, Li W, et al. Osimertinib versus comparator EGFR TKI as first-line treatment for EGFR-mutated advanced NSCLC: FLAURA China, A randomized study. Target Oncol. 2021;16(2):165–76.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Lin NU, Lee EQ, Aoyama H, et al. Response assessment criteria for brain metastases: proposal from the RANO group. Lancet Oncol. 2015;16(6):e270–8.

    Article  PubMed  Google Scholar 

  57. Lu S, Dong X, Jian H, et al. AENEAS: A randomized phase III trial of aumolertinib versus gefitinib as first-line therapy for locally advanced or metastatic non-small-cell lung cancer with EGFR exon 19 deletion or L858R mutations. J Clin Oncol. 2022;40(27):3162–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Lu S, Dong X, Jian H, et al. Aumolertinib activity in patients with CNS metastases and EGFR-mutated NSCLC treated in the randomized double-blind phase III trial (AENEAS). J Clin Oncol. 2022;40(16 suppl):9096.

    Article  Google Scholar 

  59. Shi Y, Chen G, Wang X, et al. Furmonertinib (AST2818) versus gefitinib as first-line therapy for Chinese patients with locally advanced or metastatic EGFR mutation-positive non-small-cell lung cancer (FURLONG): a multicentre, double-blind, randomised phase 3 study. Lancet Respir Med. 2022;10(11):1019–28.

    Article  CAS  PubMed  Google Scholar 

  60. Shi Y, Chen G, Wang X, et al. Central nervous system efficacy of furmonertinib (AST2818) versus gefitinib as first-line treatment for EGFR-mutated NSCLC: results from the FURLONG study. J Thorac Oncol. 2022;17(11):1297–305. https://doi.org/10.1016/j.jtho.2022.07.1143.

    Article  PubMed  Google Scholar 

  61. Mu Y, Xing P, Hao X, et al. Real-world data of osimertinib in patients with pretreated non-small cell lung cancer: a retrospective study. Cancer Manag Res. 2019;11:9243–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Yu X, Fan Y. P1.01-100 Effect of osimertinib in non-small cell lung cancer patients with brain metastases after progression following front-line EGFR-TKI therapy. J Thorac Oncol. 2019;14(10):S400.

    Article  Google Scholar 

  63. Yu F, Ni J, Zeng W, et al. Clinical value of upfront cranial radiation therapy in osimertinib-treated epidermal growth factor receptor-mutant non-small cell lung cancer with brain metastases. Int J Radiat Oncol Biol Phys. 2021;111(3):804–15.

    Article  PubMed  Google Scholar 

  64. Xing P, Mu Y, Hao X, et al. Data from real world to evaluate the efficacy of osimertinib in non-small cell lung cancer patients with central nervous system metastasis. Clin Transl Oncol. 2019;21(10):1424–31.

    Article  CAS  PubMed  Google Scholar 

  65. Metro G, Provencio M, Kim DW, et al. Osimertinib in epidermal growth factor receptor (EGFR) T790M advanced non-small cell lung cancer (NSCLC): analysis of patients with central nervous system (CNS) metastases in a real-world study (ASTRIS). Ann Oncol. 2019;30: v624.

    Article  Google Scholar 

  66. Xie L, Nagpal S, Wakelee HA, et al. Osimertinib for EGFR-mutant lung cancer with brain metastases: results from a single-center retrospective study. Oncologist. 2019;24(6):836–43.

    Article  CAS  PubMed  Google Scholar 

  67. Yang JCH, Kim SW, Kim DW, et al. Osimertinib in patients with epidermal growth factor receptor mutation-positive non-small-cell lung cancer and leptomeningeal metastases: the BLOOM study. J Clin Oncol. 2020;38(6):538–47.

    Article  CAS  PubMed  Google Scholar 

  68. Ahn MJ, Chiu CH, Cheng Y, et al. Osimertinib for patients with leptomeningeal metastases associated with EGFR T790M-positive advanced NSCLC: the AURA leptomeningeal metastases analysis. J Thorac Oncol. 2020;15(4):637–48.

    Article  CAS  PubMed  Google Scholar 

  69. Chamberlain M, Junck L, Brandsma D, et al. Leptomeningeal metastases: a RANO proposal for response criteria. Neuro Oncol. 2017;19(4):484–92.

    PubMed  Google Scholar 

  70. Xu H, Chen H, Kong J, et al. Osimertinib for the treatment of epidermal growth factor receptor-mutated non-small cell lung cancer patients with leptomeningeal metastases and different T790M status. Ann Transl Med. 2021;9(11):937.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Zhang M, Ma W, Liu H, et al. Osimertinib improves overall survival in patients with leptomeningeal metastases associated with EGFR-mutated non-small-cell lung cancer regardless of cerebrospinal fluid T790M mutational status. Evid Based Complement Alternat Med. 2021;2021:6968194.

    PubMed  PubMed Central  Google Scholar 

  72. Saboundji K, Auliac JB, Perol M, et al. Efficacy of osimertinib in EGFR-mutated non-small cell lung cancer with leptomeningeal metastases pretreated with EGFR-tyrosine kinase inhibitors. Target Oncol. 2018;13(4):501–7.

    Article  PubMed  Google Scholar 

  73. Lee J, Choi Y, Han J, et al. Osimertinib improves overall survival in patients with EGFR-mutated NSCLC with leptomeningeal metastases regardless of T790M mutational status. J Thorac Oncol. 2020;15(11):1758–66.

    Article  CAS  PubMed  Google Scholar 

  74. Wu Y-L, Tsuboi M, He J, et al. Osimertinib in resected EGFR-mutated non-small-cell lung cancer. N Engl J Med. 2020;383(18):1711–23.

    Article  CAS  PubMed  Google Scholar 

  75. ClinicalTrials.gov. NCT04765059 (COMPEL study). https://clinicaltrials.gov/ct2/show/NCT04765059. Accessed 16 Sep 2021.

  76. AstraZeneca. AstraZeneca and Roche announce partnership to develop companion diagnostic test for AZD9291 (press release); 2014. http://www.astrazeneca.com/Media/Press-releases/Article/28072014--diagnostic-collaboration-cbrs-layout-2. Accessed 13 March 2015.

  77. Iyengar P, Kavanagh BD, Wardak Z, et al. Phase II trial of stereotactic body radiation therapy combined with erlotinib for patients with limited but progressive metastatic non-small-cell lung cancer. J Clin Oncol. 2014;32(34):3824–30.

    Article  PubMed  Google Scholar 

  78. ClinicalTrials.gov. NCT04563871 (BLOSSOM study). https://clinicaltrials.gov/ct2/show/NCT04563871. Accessed 16 Sep 2021.

  79. Leonetti A, Sharma S, Minari R, et al. Resistance mechanisms to osimertinib in EGFR-mutated non-small cell lung cancer. Br J Cancer. 2019;121(9):725–37.

    Article  PubMed  PubMed Central  Google Scholar 

  80. Pedrosa RMSM, Mustafa DAM, Aerts JGJV, et al. Potential molecular signatures predictive of lung cancer brain metastasis. Front Oncol. 2018;8:159.

    Article  PubMed  PubMed Central  Google Scholar 

  81. Shi L, Tang J, Tao H, et al. Detection of EGFR mutations in cerebrospinal fluid of EGFR-mutant lung adenocarcinoma with brain metastases. Front Oncol. 2021;11: 622142.

    Article  PubMed  PubMed Central  Google Scholar 

  82. De Mattos-Arruda L, Mayor R, Ng CKY, et al. Cerebrospinal fluid-derived circulating tumour DNA better represents the genomic alterations of brain tumours than plasma. Nat Commun. 2015;6:8839.

    Article  PubMed  PubMed Central  Google Scholar 

  83. Li YS, Jiang BY, Yang JJ, et al. Unique genetic profiles from cerebrospinal fluid cell-free DNA in leptomeningeal metastases of EGFR-mutant non-small-cell lung cancer: a new medium of liquid biopsy. Ann Oncol. 2018;29(4):945–52.

    Article  CAS  PubMed  Google Scholar 

  84. Aldea M, Hendriks L, Mezquita L, et al. Circulating tumor DNA analysis for patients with oncogene-addicted NSCLC with isolated central nervous system progression. J Thorac Oncol. 2020;15(3):383–91.

    Article  CAS  PubMed  Google Scholar 

  85. Huang R, Xu X, Li D, et al. Digital PCR-based detection of EGFR mutations in paired plasma and CSF samples of lung adenocarcinoma patients with central nervous system metastases. Target Oncol. 2019;14(3):343–50.

    Article  PubMed  Google Scholar 

  86. Arulananda S, Do H, Rivalland G, et al. Standard dose osimertinib for erlotinib refractory T790M-negative EGFR-mutant non-small cell lung cancer with leptomeningeal disease. J Thorac Dis. 2019;11(5):1756–64.

    Article  PubMed  PubMed Central  Google Scholar 

  87. Hayman JA, Dekker A, Feng M, et al. Minimum data elements for radiation oncology: an American Society for Radiation Oncology consensus paper. Pract Radiat Oncol. 2019;9(6):395–401.

    Article  PubMed  Google Scholar 

  88. U.S Food and Drug Administration. Evaluating Cancer Drugs in Patients with Central Nervous System Metastases Guidance for Industry; 2021. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/evaluating-cancer-drugs-patients-central-nervous-system-metastases. Accessed 16 Sep 2021.

  89. Camidge DR, Lee EQ, Lin NU, et al. Clinical trial design for systemic agents in patients with brain metastases from solid tumours: a guideline by the Response Assessment in Neuro-Oncology Brain Metastases working group. Lancet Oncol. 2018;19(1):e20–32.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to acknowledge Sally Cotterill, PhD, CMPP, and (as contracted) Jean Scott, PhD, of Ashfield MedComms, an Inizio Company, for medical writing support that was funded by AstraZeneca, Cambridge, UK, in accordance with Good Publications Practice (GPP) guidelines (https://www.ismpp.org/gpp-2022). Shankar Siva is supported by the Cancer Council Victoria Colebatch Fellowship.

Author information

Authors and Affiliations

  1. Lung Unit, Royal Marsden Hospital, London, UK

    Sanjay Popat

  2. Division of Clinical Studies, Institute of Cancer Research, London, UK

    Sanjay Popat

  3. Department of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea

    Myung-Ju Ahn

  4. Theme Cancer, Thoracic Oncology Center, Karolinska University Hospital, Stockholm, Sweden

    Simon Ekman

  5. Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden

    Simon Ekman

  6. Medical Oncology, Princess Margaret Cancer Center, Toronto, Canada

    Natasha B. Leighl

  7. Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA

    Suresh S. Ramalingam

  8. Division of Medical Oncology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, 10400, Thailand

    Thanyanan Reungwetwattana

  9. Department of Radiation Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia

    Shankar Siva

  10. Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia

    Shankar Siva

  11. Department of Thoracic Surgery and Oncology, National Cancer Center Hospital East, Kashiwa, Japan

    Masahiro Tsuboi

  12. Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China

    Yi-Long Wu

  13. Department of Oncology, National Taiwan University Hospital Cancer Center, Taipei, Taiwan

    James Chih-Hsin Yang

Authors
  1. Sanjay Popat
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Myung-Ju Ahn
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Simon Ekman
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Natasha B. Leighl
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Suresh S. Ramalingam
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Thanyanan Reungwetwattana
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Shankar Siva
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Masahiro Tsuboi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yi-Long Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. James Chih-Hsin Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sanjay Popat.

Ethics declarations

Funding

AstraZeneca provided funding for medical writing support of this review in accordance with Good Publications Practice (GPP) guidelines (https://www.ismpp.org/gpp-2022).

Conflict of interest

S. Popat declares membership of the board of directors for the Mesothelioma Applied Research Foundation; consulting fees from Amgen, AstraZeneca, Bayer, BeiGene, Blueprint, Bristol-Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, GSK, Guardant Health, Incyte, Janssen, Merck KGaA, Roche, Takeda, Pfizer, Seattle Genetics, Turning Point Therapeutics, and Xcovery. M-J. Ahn declares participating in advisory councils or committees for Alpha Pharmaceutical, AstraZeneca, Bristol-Myers Squibb, MSD, Ono Pharmaceutical, Roche, and Takeda; receiving honoraria from AstraZeneca, Bristol-Myers Squibb, MSD, Ono Pharmaceutical, and Roche. S. Ekman declares an unrestricted grant from Boehringer Ingelheim for an investigator-initiated study; non-remunerated expert meetings sponsored by AbbVie, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, and Takeda; sponsoring of study to his institution by BMS. N.B. Leighl declares honoraria from Bristol-Myers Squibb and MSD; consulting fees from EMD Serono; and grants or funds from AstraZeneca and Bristol-Myers Squibb. S.S. Ramalingham declares participating in advisory councils or committees for Amgen, AstraZeneca, Bristol-Myers Squibb, Genentech, GSK, Merck, Tesaro, and Takeda; consulting fees from Amgen, AstraZeneca, Bristol-Myers Squibb, Genentech, Merck, Tesaro, and Takeda; and grants or funds, to his institution, from Amgen, Advaxis, AstraZeneca, Bristol-Myers Squibb, Genmab, Merck, Tesaro, and Takeda. T. Reungwetwattana declares honoraria from Amgen, AstraZeneca, Bristol-Myers Squibb, MSD, Novartis, Pfizer, Roche, Takeda, Yuhan, and Zuellig; advisory councils or committees for Amgen, AstraZeneca, Bristol-Myers Squibb, MSD, Pfizer, Roche, and Takeda; and grants or funds, to her institution, from AstraZeneca, Novartis, Pfizer, and Roche. S. Siva declares participating in an advisory council or committee for AstraZeneca; and honoraria from AstraZeneca. M. Tsuboi declares receiving lecture fees from Johnson & Johnson Japan, Teijin Pharma, Taiho Pharma, and Medtronic Japan; grant support, paid to his institution, lecture fees, and advisory board fees from AstraZeneca and Merck Sharp & Dohme; grant support, paid to his institution, and lecture fees from Eli Lilly Japan, Bristol-Myers Squibb, and Ono Pharmaceutical; lecture fees and advisory board fees from Chugai Pharmaceutical; grant support, paid to his institution, from Boehringer Ingelheim Japan; and grant support, paid to his institution, and advisory board fees from Novartis. Y-L. Wu declares honoraria from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly & Co., MSD, Pfizer Inc., Roche AG, and Sanofi; and grants or funds from AstraZeneca, Bristol-Myers Squibb, Pfizer Inc., and Roche AG. J.C-H. Yang declares advisory councils or committees for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, GlaxoSmithKline, Johnson & Johnson, Merck KGaA, MSD, Novartis, Ono Pharmaceuticals, Pfizer, Puma Technology, Roche/Genentech, Takeda Oncology, and Yuhan Pharmaceuticals; and grants or funds from AstraZeneca and Bayer.

Ethics approval

Not applicable.

Code availability

Not applicable.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Availability of data and materials

Data underlying the findings described in this manuscript may be obtained in accordance with AstraZeneca’s data sharing policy described at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Author contributions

Substantial contributions to the conception or design of the work: S. Popat, S. Ekman, N.B. Leighl, S.S. Ramalingham, T. Reungwetwattana, M. Tsuboi, Y-L. Wu, J.C-H. Yang. Substantial contributions to the acquisition, analysis, or interpretation of data for the work: S. Popat, M-J. Ahn, S. Ekman, S.S. Ramalingham, S. Siva, J.C-H. Yang. Drafting the work or revising it critically for important intellectual content: all authors. Final approval of the version to be published: all authors. Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved: all authors.

Additional information

The original article has been updated: Due to textual changes.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 268 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Popat, S., Ahn, MJ., Ekman, S. et al. Osimertinib for EGFR-Mutant Non-Small-Cell Lung Cancer Central Nervous System Metastases: Current Evidence and Future Perspectives on Therapeutic Strategies. Targ Oncol 18, 9–24 (2023). https://doi.org/10.1007/s11523-022-00941-7

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11523-022-00941-7

Search

Navigation