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Gefitinib

  • Justyna Rawluk
  • Cornelius F. Waller
Chapter
Part of the Recent Results in Cancer Research book series (RECENTCANCER, volume 211)

Abstract

Gefitinib is an orally active selective inhibitor epidermal growth factor receptor (EGFR). The large randomised phase III IPASS study (gefitinib 250 mg, daily vs carboplatin and paclitaxel) showed a beneficial effect on progression-free survival (PFS) and quality of life in selected patient populations under the treatment with gefitinib (HR for TKI 0.74; 95% CI: 0.65–0.85). In the subgroup of patients with EGFR mutation the effect of gefitinib on PFS was notably, PFS HR 0.48; 95% CI: 0.36–0.64, p < 0.001) and the objective response rate (RR) was 71.2% with gefitinib versus 47.3% with chemotherapy. However no significant difference of overall survival was found. Based on this study gefitinib was approved for the first-line treatment of the patients with non-small cell lung cancer (NSCLC) with sensitising EGFR mutations (exon 19 deletion or L858R point mutation). Gefitinib is metabolized in the liver. Most of the adverse effects of gefitinib, such as rash, dry skin and diarrhoe, are mild to moderate in severity and are reversible.

Keywords

Non-small cell lung cancer Epidermal growth factor receptor (EGFR) EGFR mutation Tyrosine kinase inhibitor (TKI) Gefitinib  

References

  1. Arteaga CL, Engelman JA (2014) ERBB receptors: from oncogene discovery to basic science to mechanism-based cancer therapeutics. Cancer Cell 25(3):282–303.  https://doi.org/10.1016/j.ccr.2014.02.025CrossRefPubMedPubMedCentralGoogle Scholar
  2. Baselga J, Rischin D, Ranson M et al (2002) Phase I safety, pharmacokinetic, and pharmacodynamic trial of ZD1839, a selective oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with five selected solid tumor types. J Clin Oncol 20:4292–4302Google Scholar
  3. Bronte G, Rolfo C, Giovannetti E et al (2014) Are erlotinib and gefitinib interchangeable, opposite or complementary for non-small cell lung cancer treatment? Biological, pharmacological and clinical. Crit Rev Oncol/Hematol 89:300–313CrossRefGoogle Scholar
  4. Campbell L, Blackhall F, Thatcher N (2010) Gefitinib for the treatment of non-small-cell lung cancer. Expert Opin Pharmacother 11(8):1343–1357CrossRefPubMedGoogle Scholar
  5. Douillard JY, Shepherd FA, Hirsh V et al (2009) Molecular predictors of outcome with gefitinib and docetaxel in previously treated non-small-cell lung cancer: data from the randomized phase III INTEREST trial. J Clin Oncol 28:744–752CrossRefPubMedGoogle Scholar
  6. Ercan D, Choi HG, Yun CH, Capelletti M, Xie T, Eck MJ, Gray NS, Jänne PA (2015) EGFR mutations and resistance to irreversible pyrimidine-based EGFR inhibitors. Clin Cancer Res 21(17):3913–3923.  https://doi.org/10.1158/1078-0432.ccr-14-2789. Epub 2015 May 6
  7. Fukuoka M, Yano S, Giaccone G et al (2003) A multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small cell lung cancer (the IDEAL 1 trial). J Clin Oncol 21:2237–2246CrossRefPubMedGoogle Scholar
  8. Han JY, Par K, Kim SW et al (2012) First-SIGNAL: first-line single-agent iressa versus gemcitabine and cisplatin trial in never-smokers with adenocarcinoma of the lung. J Clin Oncol 30:1122–1128CrossRefPubMedGoogle Scholar
  9. Herbst R, Giaccone G, Schiller JH et al (2004) Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial—INTACT 2. J Clin Oncol 22:785–794CrossRefPubMedGoogle Scholar
  10. Herbst RS, Maddox A-M, Rothenberg ML et al (2002) Selective oral epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 is generally well-tolerated and has activity in non–small-cell lung cancer and other solid tumors: results of a phase I trial. J Clin Oncol 20(18):3815–3825Google Scholar
  11. Hirsch FR, Varella-Garcia M, Bunn PA Jr et al (2003) Epidermal growth factor receptor in non-small-cell lung carcinomas: correlation between gene copy number and protein expression and impact on prognosis. J Clin Oncol 21:3798–3807CrossRefPubMedGoogle Scholar
  12. Kim ES, Hirsh V, Mok T et al (2008) Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial. Lancet 372:1809–1818CrossRefPubMedGoogle Scholar
  13. Ku GY, Haaland BA, de Lima Lopes Jr G (2011) Gefitinib vs. chemotherapy as first-line therapy in advanced non-small cell lung cancer: meta-analysis of phase III trials. Lung Cancer 74:469–473Google Scholar
  14. Lynch TJ, Bell DW, Sordella R et al (2004) Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350(21):2129–2139CrossRefPubMedGoogle Scholar
  15. Maemondo M, Inoue A, Kobayashi K et al (2010) Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med 362:2380–2388CrossRefPubMedGoogle Scholar
  16. Mitsudomi T, Morita S, Yatabe Y et al (2010) 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. Lancet Oncol 11:121–128CrossRefPubMedGoogle Scholar
  17. Mok TS, Wu YL, Thongprasert S et al (2009) Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 361:947–957CrossRefPubMedGoogle Scholar
  18. Pao W, Miller V, Zakowski M et al (2004) EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci USA 101:13306–13311CrossRefPubMedGoogle Scholar
  19. Paz-Ares L, Tan EH, O’Byrne K, Zhang L, Hirsh V, Boyer M, Yang JC, Mok T, Lee KH, Lu S, Shi Y, Lee DH, Laskin J, Kim DW, Laurie SA, Kölbeck K, Fan J, Dodd N, Märten A, Park K (2017) 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 28(2):270–277.  https://doi.org/10.1093/annonc/mdw611CrossRefPubMedPubMedCentralGoogle Scholar
  20. Shah NT, Kris MG, Pao W et al (2005) Practical management of patients with non-small-cell lung cancer treated with gefitinib. J Clin Oncol 23:165–174CrossRefPubMedGoogle Scholar
  21. Sholl LM, Aisner DL, Varella-Garcia M et al (2015) Multi-institutional oncogenic driver mutation analysis in lung adenocarcinoma the lung cancer mutation consortium experience. J Thorac Oncol 10:768–777CrossRefPubMedPubMedCentralGoogle Scholar
  22. Shigematsu H, Lin L, Takahashi T et al (2005) Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. J Natl Cancer Inst 97(5):339–346Google Scholar
  23. Sordella R, Bell DW, Haber DA, Settleman J (2004) Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways. Science 305(5687):1163–1167CrossRefPubMedGoogle Scholar
  24. Soria JC, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee KH, Dechaphunkul A, Imamura F, Nogami N, Kurata T, Okamoto I, Zhou C, Cho BC, Cheng Y, Cho EK, Voon PJ, Planchard D, Su WC, Gray JE, Lee SM, Hodge R, Marotti M, Rukazenkov Y, Ramalingam SS, FLAURA Investigators (2018) Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med 378(2):113–125.  https://doi.org/10.1056/nejmoa1713137. Epub 2017 Nov 18
  25. Thatcher N, Chang A, Parikh P et al (2005) Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (iressa survival evaluation in lung cancer). Lancet 366:1527–1537CrossRefPubMedGoogle Scholar
  26. Wu YL, Cheng Y, Zhou X, Lee KH, Nakagawa K, Niho S, Tsuji F, Linke R, Rosell R, Corral J, Migliorino MR, Pluzanski A, Sbar EI, Wang T, White JL, Nadanaciva S, Sandin R, Mok TS (2017) Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): a randomised, open-label, phase 3 trial. Lancet Oncol 18(11):1454–1466.  https://doi.org/10.1016/S1470-2045(17)30608-3 Epub 2017 Sep 25CrossRefPubMedGoogle Scholar
  27. Yang C-H, Yu C-J, Shih J-Y et al (2008) Specific EGFR mutations predict treatment outcome of stage IIIB/IV patients with chemotherapy-Naive non–small-Cell lung cancer receiving first-line gefitinib monotherapy. J Clin Oncol 26(16):2745–2753Google Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Haematology, Oncology and Stem Cell Transplantation, University Medical Centre Freiburg, Faculty of MedicineUniversity of FreiburgFreiburgGermany

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