Skip to main content

Integrating Osimertinib in Clinical Practice for Non-Small Cell Lung Cancer Treatment

Abstract

Treatment of non-small cell lung cancer (NSCLC) is evolving with the use of precision medicine for patients with sensitizing epidermal growth factor receptor (EGFR) mutation. First- and second-generation EGFR tyrosine kinase inhibitors (TKIs) remained the standard of care for patients with EGFR-mutated advanced NSCLC for about a decade. However, treatment resistance eventually develops for most patients who experience initial response to these agents. The most commonly acquired resistance mechanism is the T790M gatekeeper mutation. Poor drug penetration leading to central nervous system (CNS) relapse and dose-limiting toxicities are other concerns. The third-generation EGFR-TKI osimertinib, initially approved as the second-line treatment for patients with T790-mutant NSCLC, demonstrated survival benefits in TKI-naïve EGFR-mutated patients, especially in patients with CNS metastasis. The FLAURA study has shown statistically significant progression-free survival benefit and prolongation of all post-progression outcome endpoints, time to first subsequent therapy, second subsequent therapy, and second progression on subsequent treatment, along with acceptable toxicity and better quality of life outcomes. These data favor osimertinib in the first-line setting for EGFR-mutated NSCLC. This is an important milestone since sequencing the TKI therapy based on accurate prediction of T790M is clinically challenging. In countries like India, T790M testing is not routinely conducted and two-thirds of patients with NSCLC do not receive any second-line therapy. Osimertinib can be administered pragmatically as a first-line therapy. Mature overall survival data from the FLAURA study will be important and could help define the optimal personalized treatment for patients with advanced NSCLC.

Funding: AstraZeneca Pharma India Ltd.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2

References

  1. 1.

    Molina JR, Yang P, Cassivi SD, Schild SE, Adjei AA. Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorship. Mayo Clin Proc. 2008;83:584–94.

    Article  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Sahoo R, Harini VV, Babu VC, et al. Screening for EGFR mutations in lung cancer, a report from India. Lung Cancer. 2011;73:316–9.

    Article  PubMed  Google Scholar 

  3. 3.

    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;350:2129–39.

    Article  CAS  Google Scholar 

  4. 4.

    Stewart EL, Tan SZ, Liu G, Tsao MS. Known and putative mechanisms of resistance to EGFR targeted therapies in NSCLC patients with EGFR mutations—a review. Transl Lung Cancer Res. 2015;4:67–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5.

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

    Article  CAS  PubMed  Google Scholar 

  6. 6.

    Santarpia M, Liguori A, Karachaliou N, et al. Osimertinib in the treatment of non-small-cell lung cancer: design, development and place in therapy. Lung Cancer (Auckl). 2017;8:109–25.

    CAS  Google Scholar 

  7. 7.

    Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med. 2005;353:123–32.

    Article  CAS  Google Scholar 

  8. 8.

    Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361:947–57.

    Article  CAS  Google Scholar 

  9. 9.

    Douillard JY, Ostoros G, Cobo M, et al. First-line gefitinib in Caucasian EGFR mutation-positive NSCLC patients: a phase-IV, open-label, single-arm study. Br J Cancer. 2014;110:55–62.

    Article  CAS  PubMed  Google Scholar 

  10. 10.

    Paz-Ares L, Tan EH, O’Byrne K, et al. Afatinib versus gefitinib in patients with EGFR mutation-positive advanced non-small-cell lung cancer: overall survival data from the phase IIb LUX-Lung 7 trial. Ann Oncol. 2017;28:270–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Nakamura A, Inoue A, Morita S, et al. Phase III study comparing gefitinib monotherapy (G) to combination therapy with gefitinib, carboplatin, and pemetrexed (GCP) for untreated patients (pts) with advanced non-small cell lung cancer (NSCLC) with EGFR mutations (NEJ009). J Clin Oncol. 2018;36:9005.

    Article  Google Scholar 

  12. 12.

    Furuya N, Fukuhara T, Saito H, et al. Phase III study comparing bevacizumab plus erlotinib to erlotinib in patients with untreated NSCLC harboring activating EGFR mutations: NEJ026. J Clin Oncol. 2018;36:9006.

    Article  Google Scholar 

  13. 13.

    Morgillo F, Della Corte CM, Fasano M, Ciardiello F. Mechanisms of resistance to EGFR-targeted drugs: lung cancer. ESMO Open. 2016;1:e000060.

    Article  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Mok TS, Cheng Y, Zhou X, et al. Improvement in overall survival in a randomized study that compared dacomitinib with gefitinib in patients with advanced non-small-cell lung cancer and EGFR-activating mutations. J Clin Oncol. 2018;36:2244–50.

    Article  CAS  Google Scholar 

  15. 15.

    Patil VM, Noronha V, Joshi A, et al. Phase III study of gefitinib or pemetrexed with carboplatin in EGFR-mutated advanced lung adenocarcinoma. ESMO Open. 2017;2:e000168.

    Article  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Parikh P, Chang AY, Nag S, et al. Clinical experience with gefitinib in Indian patients. J Thorac Oncol. 2008;3:380–5.

    Article  PubMed  Google Scholar 

  17. 17.

    Noronha V, Prabhash K, Thavamani A, et al. EGFR mutations in Indian lung cancer patients: clinical correlation and outcome to EGFR targeted therapy. PLoS One. 2013;8:e61561.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Louis RA, Rajendranath R, Ganesan P, Sagar TG, Krishnamurthy A. First report of upfront treatment with gefitinib in comparison with chemotherapy in advanced non-small cell lung cancer patients from south India: analysis of 120 patients. Indian J Med Paediatr Oncol. 2012;33:146–54.

    Article  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Cortot AB, Jänne PA. Molecular mechanisms of resistance in epidermal growth factor receptor-mutant lung adenocarcinomas. Eur Respir Rev. 2014;23:356–66.

    Article  PubMed  Google Scholar 

  20. 20.

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

    Article  PubMed  Google Scholar 

  21. 21.

    Chamberlain M, Kormanik P. Carcinoma meningitis secondary to non-small cell lung cancer: combined modality therapy. Arch Neurol. 1998;5:506–12.

    Article  Google Scholar 

  22. 22.

    Liao B, Lee J, Lin C, et al. Epidermal growth factor receptor tyrosine kinase inhibitors for non-small-cell lung cancer patients with leptomeningeal carcinomatosis. J Thorac Oncol. 2015;10:1754–61.

    Article  CAS  PubMed  Google Scholar 

  23. 23.

    Omuro A, Kris M, Miller V, et al. High incidence of disease recurrence in the brain and leptomeninges in patients with nonsmall cell lung carcinoma after response to gefitinib. Cancer. 2005;103:2344–8.

    Article  CAS  PubMed  Google Scholar 

  24. 24.

    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;116:1336–43.

    Article  PubMed  Google Scholar 

  25. 25.

    Jamal-Hanjani M, Spicer J. Epidermal growth factor receptor tyrosine kinase inhibitors in the treatment of epidermal growth factor receptor-mutant non-small cell lung cancer metastatic to the brain. Clin Cancer Res. 2012;18:938–44.

    Article  CAS  PubMed  Google Scholar 

  26. 26.

    Hoffknecht P, Tufman A, Wehler T, et al. Efficacy of the irreversible ErbB family blocker afatinib in epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)-pretreated non-small-cell lung cancer patients with brain metastases or leptomeningeal disease. J Thorac Oncol. 2015;10:156–63.

    Article  CAS  PubMed  Google Scholar 

  27. 27.

    Noronha V, Joshi A, Gokarn A, et al. The importance of brain metastasis in EGFR mutation positive NSCLC patients. Chemother Res Pract. 2014;2014:856156.

    PubMed  PubMed Central  Google Scholar 

  28. 28.

    Biswas B, Ghadyalpatil N, Krishna MV, Deshmukh J. A review on adverse event profiles of epidermal growth factor receptor-tyrosine kinase inhibitors in nonsmall cell lung cancer patients. Indian J Cancer. 2017;54:S55–64.

    Article  CAS  PubMed  Google Scholar 

  29. 29.

    Yang JC, Ahn MJ, Kim DW, et al. Osimertinib in pretreated T790M-positive advanced non-small-cell lung cancer: AURA study phase II extension component. J Clin Oncol. 2017;35:1288–96.

    Article  CAS  PubMed  Google Scholar 

  30. 30.

    Singh M, Jadhav HR. Targeting non-small cell lung cancer with small-molecule EGFR tyrosine kinase inhibitors. Drug Discov Today. 2018;23:745–53.

    Article  CAS  PubMed  Google Scholar 

  31. 31.

    Zhang H. Osimertinib making a breakthrough in lung cancer targeted therapy. Onco Targets Ther. 2016;6:5489–93.

    Article  Google Scholar 

  32. 32.

    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;4:1046–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Yang J, Ramalingam SS, Janne PA, Cantarini M, Mitsudomi T. Osimertinib (AZD9291) in pre-treated pts with T790M-positive advanced NSCLC: updated Phase 1 (P1) and pooled Phase 2 (P2) results. J Thorac Oncol. 2016;11:S152–3.

    Article  Google Scholar 

  34. 34.

    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;376:629–40.

    Article  CAS  PubMed  Google Scholar 

  35. 35.

    Janne PA, Yang JC, Kim DW, et al. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med. 2015;372:1689–99.

    Article  PubMed  Google Scholar 

  36. 36.

    Yang JC, Ahn MJ, Kim DW, et al. Osimertinib in pretreated T790M-positive advanced non-small-cell lung cancer: AURA study phase II extension component. J Clin Oncol. 2017;35:1288–96.

    Article  CAS  PubMed  Google Scholar 

  37. 37.

    Goss G, Tsai CM, Shepherd FA, et al. Osimertinib for pretreated EGFR Thr790Met-positive advanced non-small-cell lung cancer (AURA2): a multicentre, open-label, single-arm, phase 2 study. Lancet Oncol. 2016;17:1643–52.

    Article  CAS  Google Scholar 

  38. 38.

    Mok T, Ju Ahn M, Youn Han J, Kang JH, Katakami N, Kim HR. CNS response to osimertinib in patients (pts) with T790M-positive advanced NSCLC: Data from a randomized phase III trial (AURA3). Accessed from: http://ascopubs.org/doi/abs/10.1200/JCO.2017.35.15_suppl.9005#affiliationsContainer. 2018. Accessed 20 Sep 2018.

  39. 39.

    Ramalingam SS, Yang JC, Lee CK, et al. Osimertinib as first-line treatment of EGFR mutation-positive advanced non-small-cell lung cancer. J Clin Oncol. 2018;36:841–9.

    Article  CAS  PubMed  Google Scholar 

  40. 40.

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

  41. 41.

    Yang JC, Cho BC, Kim DW, et al. Osimertinib for patients (pts) with leptomeningeal metastases (LM) from EGFR-mutant non-small cell lung cancer (NSCLC): updated results from the BLOOM study. http://ascopubs.org/doi/abs/10.1200/JCO.2017.35.15_suppl.2020. 2018. Accessed 20 Sep 2018.

  42. 42.

    Lee CK, Novello S, Rydén A, Mann H, Mok T. Patient-reported symptoms and impact of treatment with osimertinib versus chemotherapy in advanced non-small-cell lung cancer: the AURA3 trial. J Clin Oncol. 2018;36:1853–60.

    Article  CAS  PubMed  Google Scholar 

  43. 43.

    Zanwar S, Noronha V, Joshi A, et al. Repeat biopsy in epidermal growth factor receptor mutation-positive nonsmall cell lung cancer: feasibility, limitations, and clinical utility in Indian patients. Indian J Cancer. 2017;54:280–4.

    Article  CAS  PubMed  Google Scholar 

  44. 44.

    Popat S. Osimertinib as first-line treatment in EGFR-mutated non-small-cell lung cancer. N Engl J Med. 2018;378:192–3.

    Article  PubMed  Google Scholar 

  45. 45.

    Leighl N, Karaseva N, Nakagawa K, et al. Patient-reported outcomes from FLAURA: osimertinib versus standard of care (SoC) epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) in patients with EGFR-mutated advanced non-small cell lung cancer (NSCLC). J Thorac Oncol. 2018;13:S81–2.

    Article  Google Scholar 

  46. 46.

    Cho BC, Chewaskulyong B, Lee KH, et al. Osimertinib vs standard of care (SoC) EGFR-TKI as first-line treatment in patients with EGFR-TKI sensitising mutation (EGFRm) positive advanced non-small cell lung cancer (NSCLC): FLAURA Asian subset. Ann Oncol. 2017;28(mdx729):008.

    Google Scholar 

  47. 47.

    Wang F, Mishina S, Takai S, et al. Systemic treatment patterns with advanced or recurrent non-small cell lung cancer in Japan: a retrospective hospital administrative database study. Clin Ther. 2017;39:1146–60.

    Article  PubMed  Google Scholar 

  48. 48.

    Enewold L, Thomas A. Real-world patterns of EGFR testing and treatment with erlotinib for non-small cell lung cancer in the United States. PLoS One. 2016;11:e0156728.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Wu YL, Sequist LV, Tan EH, et al. Afatinib as first-line treatment of older patients with EGFR mutation-positive non-small-cell lung cancer: subgroup analyses of the LUX-Lung 3, LUX-Lung 6, and LUX-Lung 7 trials. Clin Lung Cancer. 2018;19:e465–79.

    Article  CAS  PubMed  Google Scholar 

  50. 50.

    Asahina H, Yamazaki K, Kinoshita I, et al. A phase II trial of gefitinib as first-line therapy for advanced non-small cell lung cancer with epidermal growth factor receptor mutations. Br J Cancer. 2006;95:998–1004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012;13:239–46.

  52. 52.

    Marinis FD, Cho C, Kim DW, et al. ASTRIS: a real world treatment study of osimertinib in patients (pts) with EGFR T790M positive non-small cell lung cancer (NSCLC). J Clin Oncol. 2017;35:9036.

    Article  Google Scholar 

  53. 53.

    Hochmair M, Holzer S, Filipits M, et al. EGFR T790M resistance mutation in NSCLC: real-life data of Austrian patients treated with osimertinib. J Thorac Oncol. 2017;12:S1254.

    Article  Google Scholar 

  54. 54.

    Devjak R, Hitij NT, Rajer M, Cufer T. CNS response to osimertinib in patients with EGFR mutated lung adenocarcinoma: real world data. J Thorac Oncol. 2018;13:S92–3.

    Article  Google Scholar 

  55. 55.

    Noronha V, Pinninti R, Patil VM, Joshi A, Prabhash K. Lung cancer in the Indian subcontinent. South Asian J Cancer. 2016;5:95–103.

    Article  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Batra U, Lokeshwar N, Gupta S, Shirsath P. Role of epidermal growth factor receptor-tyrosine kinase inhibitors in the management of central nervous system metastases in epidermal growth factor receptor mutation-positive nonsmall cell lung cancer patients. Indian J Cancer. 2017;54:S37–44.

    Article  CAS  PubMed  Google Scholar 

  57. 57.

    Tang ZH, Lu JJ. Osimertinib resistance in non-small cell lung cancer: mechanisms and therapeutic strategies. Cancer Lett. 2018;420:242–6.

    Article  CAS  PubMed  Google Scholar 

  58. 58.

    Piotrowska Z, Thress KS, Mooradian M, et al. MET amplification (amp) as a resistance mechanism to osimertinib. J Clin Oncol. 2017;35:9020.

    Article  Google Scholar 

  59. 59.

    Kim TM, Song A, Kim DW, et al. Mechanisms of acquired resistance to AZD9291: a mutation-selective, irreversible EGFR inhibitor. J Thorac Oncol. 2015;10:1736–44.

    Article  CAS  PubMed  Google Scholar 

  60. 60.

    Li L, Wang H, Li C, Wang Z, Zhang P, Yan X. Transformation to small-cell carcinoma as an acquired resistance mechanism to AZD9291: a case report. Oncotarget. 2017;8:18609–14.

    PubMed  PubMed Central  Google Scholar 

  61. 61.

    Bersanelli M, Minari R, Bordi P, et al. L718Q mutation as new mechanism of acquired resistance to AZD9291 in EGFR-mutated NSCLC. J Thorac Oncol. 2016;11:e121–3.

    Article  PubMed  Google Scholar 

  62. 62.

    Planchard D, Loriot Y, Andre F, et al. EGFR-independent mechanisms of acquired resistance to AZD9291 in EGFR T790M-positive NSCLC patients. Ann Oncol. 2015;26:2073–8.

    Article  CAS  PubMed  Google Scholar 

  63. 63.

    Ho CC, Liao WY, Lin CA, Shih JY, Yu CJ, Chih-Hsin Yang J. Acquired BRAF V600E mutation as resistant mechanism after treatment with osimertinib. J Thorac Oncol. 2017;12:567–72.

    Article  Google Scholar 

  64. 64.

    Eberlein CA, Stetson D, Markovets AA, et al. Acquired resistance to the mutant-selective EGFR inhibitor AZD9291 is associated with increased dependence on RAS signaling in preclinical models. Cancer Res. 2015;75:2489–500.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. 65.

    Ortiz-Cuaran S, Scheffler M, Plenker D, et al. Heterogeneous mechanisms of primary and acquired resistance to third-generation EGFR inhibitors. Clin Cancer Res. 2016;22:4837–47.

    Article  CAS  PubMed  Google Scholar 

  66. 66.

    Uchibori K, Inase N, Araki M, et al. Brigatinib combined with anti-EGFR antibody overcomes osimertinib resistance in EGFR-mutated non-small-cell lung cancer. Nat Commun. 2017;8:14768.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. 67.

    Uchibori K, Inase N, Nishio M, Fujita N, Katayama R. Identification of mutation accumulation as resistance mechanism emerging in first-line osimertinib treatment. J Thorac Oncol. 2018;13:915–25.

    Article  PubMed  Google Scholar 

  68. 68.

    Yu HA, Hayes SA, Young RJ, Ni A, Rodriguez C, Makhnin A. A phase 1 study of osimertinib and bevacizumab as initial treatment for patients with EGFR-mutant lung cancers. J Clin Oncol. 2017;35:9033.

  69. 69.

    Yu H, Planchard D, Yang JC, et al. P1. 04-001 osimertinib with ramucirumab or necitumumab in advanced T790M-positive EGFR-Mutant NSCLC: preliminary Ph1 study results. J Thorac Oncol. 2017;12:S1972.

Download references

Acknowledgements

Funding

The preparation of this article and funding of the journal’s article processing charges were supported by AstraZeneca Pharma India Ltd. All authors had full access to all of the data in this study and take complete responsibility for the integrity of the data and accuracy of the data analysis.

Medical Writing Assistance

The authors thank Chinmayee Joshi from Sciformix Technologies Pvt. Ltd., Mumbai for providing medical writing assistance in the development of this manuscript. The authors also thank AstraZeneca Pharma India Ltd. for funding this assistance.

Authorship

All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.

Disclosures

Senthil Rajappa, M Vamshi Krishna, and Prasad Narayanan have nothing to disclose.

Compliance with Ethics Guidelines

This article is based on previously conducted studies and does not contain any studies with human participants or animals performed by any of the authors.

Data Availability

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Senthil Rajappa.

Additional information

Enhanced Digital Features

To view enhanced digital features for this article go to https://doi.org/10.6084/m9.figshare.7751570.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Rajappa, S., Krishna, M.V. & Narayanan, P. Integrating Osimertinib in Clinical Practice for Non-Small Cell Lung Cancer Treatment. Adv Ther 36, 1279–1290 (2019). https://doi.org/10.1007/s12325-019-00917-6

Download citation

Keywords

  • Epidermal growth factor receptor tyrosine kinase inhibitors
  • First-line
  • Non-small cell lung cancer
  • Osimertinib
  • T790M