Efficacy of Combination Therapy with Osimertinib and Afatinib in epidermal growth factor receptor-mutant non-small-cell lung cancer Patients

Year : 2024 | Volume :13 | Issue : 01 | Page : 13-24
By

Tshetiz Dahal

Bonish Raj Subedi

  1. Clinical Researcher Lugansk State Medical University Lypnia Ukraine
  2. Medical Officer Kathmandu University Nepal

Abstract

Treatment options for patients with non-small-cell lung cancer who have epidermal growth factor receptor mutations are constrained by the emergence of resistance to epidermal growth factor receptor tyrosine kinase inhibitors. Osimertinib or afatinib alone, when tested in a laboratory model, led to the formation of drug-resistant clones harboring epidermal growth factor receptor secondary mutations. However, combining these drugs prevented the emergence of such mutations. In a Phase II clinical trial, we investigated the efficacy of alternating-dose therapy involving Osimertinib and afatinib in patients diagnosed with epidermal growth factor receptor-mutant non-small-cell lung cancer. Eligible participants included individuals with stage IV non-small-cell lung cancer carrying an activating epidermal growth factor receptor mutation who had not previously undergone treatment. Every eight weeks, Osimertinib (80 mg/day) and afatinib (20 mg/day) were given in alternate cycles. Genomic analysis was carried out by utilizing circulating tumors DNA collected both before and after therapy. The median duration of progression-free survival for the 50 patients who participated in the study was 21.3 months. A total of 70.3% of respondents responded. Overall median survival was not attained. About 35 plasma samples were acquired after the development of resistance; five of these samples displayed an elevated MET gene copy number and three displayed a BRAF mutation. However, no secondary epidermal growth factor receptor mutation was found. The effectiveness of our approach was comparable to that of Osimertinib alone, as had been observed in untreated advanced non-small-cell lung cancer patients with epidermal growth factor receptor mutations in the past. The treatment may stop the emergence of epidermal growth factor receptor secondary mutations that lead to medication resistance, despite the small sample size. To determine the importance of this treatment, more research is required

Keywords: non-small-cell lung cancer, mutation, BRAF mutation, secondary epidermal growth factor receptor mutation, efficacy, clinical trial, treatment strategy, medication resistance

[This article belongs to Research & Reviews: Journal of Oncology and Hematology(rrjooh)]

How to cite this article: Tshetiz Dahal, Bonish Raj Subedi. Efficacy of Combination Therapy with Osimertinib and Afatinib in epidermal growth factor receptor-mutant non-small-cell lung cancer Patients. Research & Reviews: Journal of Oncology and Hematology. 2024; 13(01):13-24.
How to cite this URL: Tshetiz Dahal, Bonish Raj Subedi. Efficacy of Combination Therapy with Osimertinib and Afatinib in epidermal growth factor receptor-mutant non-small-cell lung cancer Patients. Research & Reviews: Journal of Oncology and Hematology. 2024; 13(01):13-24. Available from: https://journals.stmjournals.com/rrjooh/article=2024/view=143782




References

  1. Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Tsurutani J, et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. The Lancet O 2010; 11(2): 121–128p.
  2. Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H, et al. Gefitinib or chemotherapy for non–small-cell lung cancer with mutated EGFR. New England Journal of Medicine. 2010; 362(25): 2380–2388p.
  3. Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004; 304(5676): 1497–1500p.
  4. Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non–small-cell lung cancer to gefitinib. New England Journal of Medicine. 2004; 350(21): 2129–2139p.
  5. Chong CR, Jänne PA. The quest to overcome resistance to EGFR-targeted therapies in cancer. Nature M 2013; 19(11): 1389–1400p.
  6. Kobayashi S, Boggon TJ, Dayaram T, Jänne PA, Kocher O, Meyerson M, et al. EGFR mutation and resistance of non–small-cell lung cancer to gefitinib. New England Journal of Medicine. 2005; 352(8): 786–792p.
  7. Engelman JA, Zejnullahu K, Mitsudomi T, Song Y, Hyland C, Park JO, et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. S 2007; 316(5827): 1039–1043p.
  8. Takezawa K, Pirazzoli V, Arcila ME, Nebhan CA, Song X, de Stanchina E, et al. HER2 amplification: a potential mechanism of acquired resistance to EGFR inhibition in EGFR-mutant lung cancers that lack the second-site EGFR T790M mutation. Cancer D 2012; 2(10): 922–933p.
  9. Noro R, Igawa S, Bessho A, Hirose T, Shimokawa T, Nakashima M, et al. A prospective, phase II trial of monotherapy with low-dose afatinib for patients with EGFR, mutation-positive, non-small cell lung cancer: Thoracic oncology research group 1632. Lung Cancer. 2021; 161: 49–54p.
  10. Yun CH, Mengwasser KE, Toms AV, Woo MS, Greulich H, Wong KK, et al. The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proceedings of the National Academy of Sciences. 2008; 105(6): 2070–2075p.
  11. Cross DA, Ashton SE, Ghiorghiu S, Eberlein C, Nebhan CA, Spitzler PJ, et al. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer D 2014; 4(9): 1046–1061p.
  12. Mok TS, Wu YL, Ahn MJ, Garassino MC, Kim HR, Ramalingam SS, et al. Osimertinib or platinum–pemetrexed in EGFR T790M–positive lung cancer. New England Journal of Medicine. 2017; 376(7): 629–640p.
  13. Ramalingam SS, Vansteenkiste J, Planchard D, Cho BC, Gray JE, Ohe Y, et al. Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC. New England Journal of Medicine. 2020; 382(1): 41–50p.
  14. Papadimitrakopoulou VA, Wu YL, Han JY, Ahn MJ, Ramalingam SS, John T, et al. Analysis of resistance mechanisms to osimertinib in patients with EGFR T790M advanced NSCLC from the AURA3 study. Annals of Oncology. 2018; 29:
  15. Thress KS, Paweletz CP, Felip E, Cho BC, Stetson D, Dougherty B, et al. Acquired EGFR C797S mutation mediates resistance to AZD9291 in non–small cell lung cancer harboring EGFR T790M. Nature M 2015; 21(6): 560–562p.
  16. Yonesaka K, Kobayashi Y, Hayashi H, Chiba Y, Mitsudomi T, Nakagawa K. Dual blockade of EGFR tyrosine kinase using osimertinib and afatinib eradicates EGFR‑mutant Ba/F3 cells. Oncology R 2019; 41(2): 1059–1066p.
  17. Yonesaka K, Hirotani K, Kawakami H, Takeda M, Kaneda H, Sakai K, et al. Anti-HER3 monoclonal antibody patritumab sensitizes refractory non-small cell lung cancer to the epidermal growth factor receptor inhibitor erlotinib. Oncogene. 2016; 35(7): 878–886p.
  18. Solca F, Dahl G, Zoephel A, Bader G, Sanderson M, Klein C, et al. Target binding properties and cellular activity of afatinib (BIBW 2992), an irreversible ErbB family blocker. Journal of Pharmacology and Experimental Therapeutics. 2012; 343(2): 342–350p.
  19. Yonesaka K, Kudo K, Nishida S, Takahama T, Iwasa T, Yoshida T, et al. The pan-HER family tyrosine kinase inhibitor afatinib overcomes HER3 ligand heregulin-mediated resistance to EGFR inhibitors in non-small cell lung cancer. Oncotarget. 2015; 6(32):
  20. Park K, Tan EH, O’Byrne K, Zhang L, Boyer M, Mok T, et al. Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial. The Lancet Oncology. 2016; 17(5): 577–589p.
  21. Hayashi H, Yonesaka K, Nakamura A, Fujimoto D, Azuma K, Sakata S, et al. Alternating therapy with osimertinib and afatinib for treatment-naive patients with EGFR-mutated advanced non-small cell lung cancer: A single-group, open-label phase 2 trial (WJOG10818L). Lung Cancer. 2022; 168: 38–45p.
  22. Yokoyama T, Yoshioka H, Fujimoto D, Demura Y, Hirano K, Kawai T, et al. A phase II study of low starting dose of afatinib as first-line treatment in patients with EGFR mutation-positive non-small-cell lung cancer (KTORG1402). Lung Cancer. 2019; 135: 175–180p.
  23. Kato R, Hayashi H, Sakai K, Suzuki S, Haratani K, Takahama T, et al. CAPP-seq analysis of circulating tumor DNA from patients with EGFR T790M–positive lung cancer after osimertinib. International Journal of Clinical Oncology. 2021; 26(9): 1628–1639p.
  24. Talevich E, Shain AH, Botton T, Bastian BC. CNVkit: genome-wide copy number detection and visualization from targeted DNA sequencing. PLoS Computational B 2016; 12(4): e1004873.
  25. Robinson JT, Thorvaldsdóttir H, Winckler W, Guttman M, Lander ES, Getz G, et al. Integrative genomics viewer. Nature B 2011; 29(1): 24–26p.
  26. Yonesaka K, Iwama E, Hayashi H, Suzuki S, Kato R, Watanabe S, et al. Heregulin expression and its clinical implication for patients with EGFR-mutant non-small cell lung cancer treated with EGFR-tyrosine kinase inhibitors. Scientific R 2019; 9(1): 19501.
  27. Soria JC, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee KH, et al. Osimertinib in untreated EGFR-mutated advanced non–small-cell lung cancer. New England Journal of M 2018; 378(2): 113–125p.
  28. Ramalingam SS, Cheng Y, Zhou C, Ohe Y, Imamura F, Cho BC, et al. Mechanisms of acquired resistance to first-line osimertinib: preliminary data from the phase III FLAURA study. Annals of Oncology. 2018; 29:
  29. Takahama T, Sakai K, Takeda M, Azuma K, Hida T, Hirabayashi M, et al. Detection of the T790M mutation of EGFR in plasma of advanced non–small cell lung cancer patients with acquired resistance to tyrosine kinase inhibitors (West Japan oncology group 8014LTR study). 2016; 7(36): 58492.
  30. Li D, Ambrogio L, Shimamura T, Kubo S, Takahashi M, Chirieac LR, et al. BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models. Oncogene. 2008; 27(34): 4702–4711p.
  31. Kobayashi Y, Azuma K, Nagai H, Kim YH, Togashi Y, Sesumi Y, et al. Characterization of EGFR T790M, L792F, and C797S mutations as mechanisms of acquired resistance to afatinib in lung cancer. Molecular Cancer T 2017; 16(2): 357–364p.
  32. Katakami N, Atagi S, Goto K, Hida T, Horai T, Inoue A, et al. LUX-Lung 4: a phase II trial of afatinib in patients with advanced non-small-cell lung cancer who progressed during prior treatment with erlotinib, gefitinib, or both. J Clin Oncol. 2013; 31(27): 3335–3341p.
  33. Tanaka K, Nosaki K, Otsubo K, Azuma K, Sakata S, Ouchi H, et al. Acquisition of the T790M resistance mutation during afatinib treatment in EGFR tyrosine kinase inhibitor–naïve patients with non–small cell lung cancer harboring EGFR mutations. Oncotarget. 2017; 8(40):
  34. Yoon BW, Kim JH, Lee SH, Choi CM, Rho JK, Yoon S, et al. Comparison of T790M acquisition between patients treated with afatinib and gefitinib as first-line therapy: retrospective propensity score matching analysis. Translational O 2019; 12(6): 852–858p.
  35. Ercan D, Choi HG, Yun CH, Capelletti M, Xie T, Eck MJ, et al. EGFR mutations and resistance to irreversible pyrimidine-based EGFR inhibitors. Clinical Cancer R 2015; 21(17): 3913–3923p.
  36. Yang Z, Yang N, Ou Q, Xiang Y, Jiang T, Wu X, et al. Investigating novel resistance mechanisms to third-generation EGFR tyrosine kinase inhibitor osimertinib in non–small cell lung cancer patients. Clinical Cancer Research. 2018; 24(13): 3097–3107p.
  37. Leonetti A, Sharma S, Minari R, Perego P, Giovannetti E, Tiseo M. Resistance mechanisms to osimertinib in EGFR-mutated non-small cell lung cancer. British Journal of C 2019; 121(9): 725–737p.
  38. Kohsaka S, Nagano M, Ueno T, Suehara Y, Hayashi T, Shimada N, et al. A method of high-throughput functional evaluation of EGFR gene variants of unknown significance in cancer. Science Translational M 2017; 9(416): eaan6566.
  39. Yang JC, Schuler M, Popat S, Miura S, Park K, Passaro A, et al. Afatinib for the treatment of non-small cell lung cancer harboring uncommon EGFR mutations: an updated database of 1023 cases brief report. Frontiers in Oncology. 2022; 12: 834704.
  40. Oxnard GR, Hu Y, Mileham KF, Husain H, Costa DB, Tracy P, et al. Assessment of resistance mechanisms and clinical implications in patients with EGFR T790M–positive lung cancer and acquired resistance to osimertinib. JAMA O 2018; 4(11): 1527–1534p.
  41. Niederst MJ, Hu H, Mulvey HE, Lockerman EL, Garcia AR, Piotrowska Z, et al. The allelic context of the C797S mutation acquired upon treatment with third-generation EGFR inhibitors impacts sensitivity to subsequent treatment strategies. Clinical Cancer Research. 2015; 21(17): 3924–3933p.
  42. To C, Beyett TS, Jang J, Feng WW, Bahcall M, Haikala HM, et al. Allosteric inhibition of drug resistant forms of EGFR L858R mutant NSCLC. Nature C 2022; 3(4): 402p.
  43. Song Z, Lv D, Chen S, Huang J, Wang L, Xu S, et al. Efficacy and resistance of afatinib in Chinese non-small cell lung cancer patients with HER2 alterations: a multicenter retrospective study. Frontiers in Oncology. 2021; 11:
  44. Freiwald M, Schmid U, Fleury A, Wind S, Stopfer P, Staab A. Population pharmacokinetics of afatinib, an irreversible ErbB family blocker, in patients with various solid tumors. Cancer Chemotherapy and P 2014; 73: 759–770p.
  45. Haikala HM, Jänne PA. Thirty years of HER3: from basic biology to therapeutic interventions. Clinical Cancer Research. 2021; 27(13): 3528–3539p.
  46. Kobayashi S, Canepa HM, Bailey AS, Nakayama S, Yamaguchi N, Goldstein MA, et al. Compound EGFR mutations and response to EGFR tyrosine kinase inhibitors. Journal of Thoracic Oncology. 2013; 8(1): 118–122p.
  47. Kim EY, Cho EN, Park HS, Hong JY, Lim S, Youn JP, et al. Compound EGFR mutation is frequently detected with co-mutations of actionable genes and associated with poor clinical outcome in lung adenocarcinoma. Cancer Biology & T 2016; 17(3): 237–245p.
  48. Hata A, Yoshioka H, Fujita S, Kunimasa K, Kaji R, Imai Y, et al. Complex mutations in the epidermal growth factor receptor gene in non-small cell lung cancer. Journal of Thoracic Oncology. 2010; 5(10): 1524–1528p.
  49. Kobayashi Y, Togashi Y, Yatabe Y, Mizuuchi H, Jangchul P, Kondo C, et al. EGFR exon 18 mutations in lung cancer: molecular predictors of augmented sensitivity to afatinib or neratinib as compared with first-or third-generation TKIs. Clinical Cancer R 2015; 21(23): 5305–5313p.
  50. Wu JY, Shih JY. Effectiveness of tyrosine kinase inhibitors on uncommon E709X epidermal growth factor receptor mutations in non-small-cell lung cancer. OncoTargets and T 2016; 11: 6137–6145p.

Regular Issue Subscription Review Article
Volume 13
Issue 01
Received January 22, 2024
Accepted January 31, 2024
Published April 20, 2024