Opinion statement
Epidermal growth factor receptor (EGFR) mutations have been detected in approximately 10 % of North American patients diagnosed with non-small cell lung cancer (NSCLC). Approximately 90 % of these mutations are exon 19 deletions or exon 21 L858R point mutations. First- and second-generation EGFR tyrosine kinase inhibitors (TKIs) are approved as first-line therapy based on clinical trials demonstrating superior response rates, progression free survival (PFS), and overall survival (OS) compared to chemotherapy in patients with EGFR mutation-positive NSCLC treated with an EGFR TKI prior to chemotherapy. However, the majority of patients treated with an EGFR TKI develop resistance to therapy within about 12 months, approximately 50 % of patients due to a second site mutation, the T790M mutation occurring within exon 20. At the time of progression, the EGFR TKI is most commonly discontinued and a different systemic therapy is initiated. However, oncogene addiction persists and recent exciting data with third-generation EGFR TKIs suggests that acquired resistance may be surmountable. The newest EGFR TKIs have shown activity against EGFR-mutant NSCLC after progression on first-generation TKIs, including those with T90M, while sparing wild-type EGFR and hence appear to be both well tolerated and efficacious. At this time, it appears that third-generation EGFR TKIs are effective following first-generation therapy, and determining the most appropriate sequence to maximize overall survival is a matter of ongoing investigation. As the arsenal of active agents in EGFR mutant NSCLC grows, future research into potential combinations, optimal timing, and resistance mechanisms of these new treatments, as well as their possible role in the adjuvant, post-chemoradiation, and neoadjuvant settings holds great promise for this group of patients.
Similar content being viewed by others
References and Recommended Reading
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
Hirsch FR, Bunn Jr PA. EGFR testing in lung cancer is ready for prime time. Lancet Oncol. 2009;10:432–3.
Ladanyi M, Pao W. Lung adenocarcinoma: guiding EGFR-targeted therapy and beyond. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. 2008;21 Suppl 2:S16–22.
Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al. Erlotinib in previously treated non-small-cell lung cancer. The New England journal of medicine. 2005;353:123–32.
Kobayashi S, Boggon TJ, Dayaram T, et al. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. The New England journal of medicine. 2005;352:786–92.
Pao W, Miller VA, Politi KA, et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS medicine. 2005;2:e73.
Bean J, Riely GJ, Balak M, et al. Acquired resistance to epidermal growth factor receptor kinase inhibitors associated with a novel T854A mutation in a patient with EGFR-mutant lung adenocarcinoma. Clinical cancer research : an official journal of the American Association for Cancer Research. 2008;14:7519–25.
Arcila ME, Oxnard GR, Nafa K, et al. Rebiopsy of lung cancer patients with acquired resistance to EGFR inhibitors and enhanced detection of the T790M mutation using a locked nucleic acid-based assay. Clinical cancer research : an official journal of the American Association for Cancer Research. 2011;17:1169–80.
Balak MN, Gong Y, Riely GJ, et al. Novel D761Y and common secondary T790M mutations in epidermal growth factor receptor-mutant lung adenocarcinomas with acquired resistance to kinase inhibitors. Clinical cancer research : an official journal of the American Association for Cancer Research. 2006;12:6494–501.
Thatcher N, Chang A, Parikh P, et al. 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. 2005;366:1527–37.
Janne PA, Wang XF, Socinski MA. Randomized phase II trial of erlotinib (E) alone or in combination with carboplatin/paclitaxel (CP) in never or light former smokers with advanced lung adenocarcinoma: CALGB 30406. J Clin Oncol (Meeting Abstracts). 2010;28:7503.
Maemondo M, Inoue A, Kobayashi K, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. The New England journal of medicine. 2010;362:2380–8.
Mitsudomi T, Morita S, Yatabe Y, 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. Lancet Oncol. 2010;11:121–8.
Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. The New England journal of medicine. 2009;361:947–57.
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.
Seto T, Kato T, Nishio M, et al. Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): an open-label, randomised, multicentre, phase 2 study. The Lancet Oncology. 2014;15:1236–44.
Yang G, Yao Y, Zhou J, Zhao Q. Effects of icotinib, a novel epidermal growth factor receptor tyrosine kinase inhibitor, in EGFR-mutated non-small cell lung cancer. Oncology reports. 2012;27:2066–72.
Zhao Q, Shentu J, Xu N, et al. Phase I study of icotinib hydrochloride (BPI-2009H), an oral EGFR tyrosine kinase inhibitor, in patients with advanced NSCLC and other solid tumors. Lung cancer. 2011;73:195–202.
Shi Y, Zhang L, Liu X, et al. Icotinib versus gefitinib in previously treated advanced non-small-cell lung cancer (ICOGEN): a randomised, double-blind phase 3 non-inferiority trial. The Lancet Oncology. 2013;14:953–61.
Gatzemeier U, Pluzanska A, Szczesna A, et al. Phase III study of erlotinib in combination with cisplatin and gemcitabine in advanced non-small-cell lung cancer: the Tarceva Lung Cancer Investigation Trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2007;25:1545–52.
Herbst RS, Prager D, Hermann R, et al. TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2005;23:5892–9.
Giaccone G, Herbst RS, Manegold C, et al. Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase III trial–INTACT 1. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2004;22:777–84.
Herbst RS, Giaccone G, Schiller JH, et al. Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial–INTACT 2. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2004;22:785–94.
Mok TS, Wu YL, Yu CJ, et al. Randomized, placebo-controlled, phase II study of sequential erlotinib and chemotherapy as first-line treatment for advanced non-small-cell lung cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2009;27:5080–7.
Wu YL, Lee JS, Thongprasert S, et al. Intercalated combination of chemotherapy and erlotinib for patients with advanced stage non-small-cell lung cancer (FASTACT-2): a randomised, double-blind trial. The Lancet Oncology. 2013;14:777–86.
Goss GD, O’Callaghan C, Lorimer I, et al. Gefitinib versus placebo in completely resected non-small-cell lung cancer: results of the NCIC CTG BR19 study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2013;31:3320–6.
Kelly K. ANK, Eberhardt W.E.E., O’Brien M.E.R., Spigel D.R., Crino L., Tsai C-M., Kim J-H., Cho E.K., Szczesna W., Burghuber O., Hoffman P.C., Keshavjee S., Orlov S., Serwatowski P., Wang J., Foley M.A., Horan J.D., Park J.W., Shepherd F.A. A randomized, double-blind phase 3 trial of adjuvant erlotinib (E) versus placebo (P) following complete tumor resection with or without adjuvant chemotherapy in patients (pts) with stage IB-IIIA EGFR positive (IHC/FISH) non-small cell lung cancer (NSCLC): RADIANT results. In: American Society of Clinical Oncology; 2014; Chicago, IL; 2014.
Pennell N.A. NJW, Chaft J.E., Azzoli C.G., et al. SELECT: A multicenter phase II trial of adjuvant erlotinib in resected early-stage EGFR mutation-positive NSCLC. In: American Society of Clinical Oncology Annual Meeting; 2014; Chicago, IL: J Clin Oncol; 2014.
Gerber DE, Oxnard GR, Govindan R. ALCHEMIST: bringing genomic discovery and targeted therapies to early-stage lung cancer. Clinical pharmacology and therapeutics. 2015;97:447–50.
Godin-Heymann N, Ulkus L, Brannigan BW, et al. The T790M “gatekeeper” mutation in EGFR mediates resistance to low concentrations of an irreversible EGFR inhibitor. Mol Cancer Ther. 2008;7:874–9.
Miller VA, Hirsh V, Cadranel J, et al. Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial. The Lancet Oncology. 2012;13:528–38.
Goss G. FE, Cobo M., et al. A randomized, open-label, phase III trial of afatinib vs erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung following first-line platinum-based chemotherapy: LUX-Lung 8. In: ESMO; 2014 September 27th, 2014; Madrid, Spain; 2014.
Yang JC, Shih JY, Su WC, et al. Afatinib for patients with lung adenocarcinoma and epidermal growth factor receptor mutations (LUX-Lung 2): a phase 2 trial. The Lancet Oncology. 2012;13:539–48.
Wu YL, Zhou C, Hu CP, et al. 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. The Lancet Oncology. 2014;15:213–22.
Sequist LV, Yang JC, Yamamoto N, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2013;31:3327–34.
Yang JC, Wu YL, Schuler M, et al. Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials. The Lancet Oncology. 2015;16:141–51. This combined analysis of LUX-Lung 3 (afatinib vs. pemetrexed-cisplatin) and LUX-Lung 6 (afatinib vs. gemcitabine-cisplatin) in the first-line setting stratified patients by EGFR mutation (exon 19 deletion, L858R mutation, or other). While no overall survival benefit was seen in either trial individual, pre-planned combined analysis of patients with exon 19 deletions found improvement in overall survival favoring afatinib, suggesting that response to EGFR TKI therapy may depend upon the type of EGFR mutation present.
Kwak EL, Sordella R, Bell DW, et al. Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib. Proceedings of the National Academy of Sciences of the United States of America. 2005;102:7665–70.
Wong KK, Fracasso PM, Bukowski RM, et al. A phase I study with neratinib (HKI-272), an irreversible pan ErbB receptor tyrosine kinase inhibitor, in patients with solid tumors. Clinical cancer research : an official journal of the American Association for Cancer Research. 2009;15:2552–8.
Sequist LV, Besse B, Lynch TJ, et al. Neratinib, an irreversible pan-ErbB receptor tyrosine kinase inhibitor: results of a phase II trial in patients with advanced non-small-cell lung cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2010;28:3076–83.
Engelman JA, Zejnullahu K, Gale CM, et al. PF00299804, an irreversible pan-ERBB inhibitor, is effective in lung cancer models with EGFR and ERBB2 mutations that are resistant to gefitinib. Cancer research. 2007;67:11924–32.
Janne PA, Boss DS, Camidge DR, et al. Phase I dose-escalation study of the pan-HER inhibitor, PF299804, in patients with advanced malignant solid tumors. Clinical cancer research : an official journal of the American Association for Cancer Research. 2011;17:1131–9.
Ellis PM, Shepherd FA, Millward M, et al. Dacomitinib compared with placebo in pretreated patients with advanced or metastatic non-small-cell lung cancer (NCIC CTG BR.26): a double-blind, randomised, phase 3 trial. The Lancet Oncology. 2014;15:1379–88.
Janne PA, Ou SH, Kim DW, et al. Dacomitinib as first-line treatment in patients with clinically or molecularly selected advanced non-small-cell lung cancer: a multicentre, open-label, phase 2 trial. The lancet oncology. 2014;15:1433–41.
Ramalingam SS, Janne PA, Mok T, et al. Dacomitinib versus erlotinib in patients with advanced-stage, previously treated non-small-cell lung cancer (ARCHER 1009): a randomised, double-blind, phase 3 trial. The lancet oncology. 2014;15:1369–78.
Kobayashi S, Boggon TJ, Dayaram T, et al. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. The New England journal of medicine. 2005;352:786–92.
Pao W, Miller VA, Politi KA, et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med. 2005;2:e73.
Sequist LV, Waltman BA, Dias-Santagata D, et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Science translational medicine 2011;3:75ra26.
Yu HA, Arcila ME, Rekhtman N, et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clinical cancer research : an official journal of the American Association for Cancer Research. 2013;19:2240–7.
Engelman JA, Janne PA. Mechanisms of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer. Clinical cancer research : an official journal of the American Association for Cancer Research. 2008;14:2895–9.
Gandara DR, Li T, Lara PN, et al. Acquired resistance to targeted therapies against oncogene-driven non-small-cell lung cancer: approach to subtyping progressive disease and clinical implications. Clinical lung cancer. 2014;15:1–6.
Goldberg SB, Oxnard GR, Digumarthy S, et al. Chemotherapy with Erlotinib or chemotherapy alone in advanced non-small cell lung cancer with acquired resistance to EGFR tyrosine kinase inhibitors. The oncologist. 2013;18:1214–20.
Mok TS WY, Nakagawa K, Kim S, Yang J, Ahn M, Wang J, Yang JC, Lu Y, Atagi S, Ponce S, Shi X, Webster A, Jiang H, Soria J. Gefitinib/chemotherapy vs chemotherapy in epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC) after progression on first-line gefitinib: the phase III, randomised IMPRESS study. In: European Society of Medical Oncology Annual Meeting; 2014: Annals of Oncology; 2014.
Park K. AM, Yu C., Kim S., Lin M., Sriuranpong V., Tsai C., Lee J., Kang J., Perez-Moreno P., Button P., Gregory D., Mok T.S.K. ASPIRATION: first-line erlotinib (E) until and beyond RECIST progression (PD) in Asian patients (pts) with EGFR mutation-positive (mut+) NSCLC. In: European Society of Medical Oncology Annual Meeting; 2014; Madrid, Spain; 2014.
Cross DA, Ashton SE, Ghiorghiu S, et al. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer discovery. 2014;4:1046–61.
Janne PA, Yang JC, Kim DW, et al. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. The New England journal of medicine. 2015;372:1689–99. This Phase 1/2 study of AZD9291 in patients with EGFR-mutated NSCLC progressive after a first-generation EGFR TKI showed that this agent was both active, with ORR 51%, and well tolerated with few of the dermatologic and gastrointestinal toxicities associated with first generation EGFR TKIs. Response rates were higher in patients with the T790M resistance mutation than in those without.
Walter AO, Sjin RT, Haringsma HJ, et al. Discovery of a mutant-selective covalent inhibitor of EGFR that overcomes T790M-mediated resistance in NSCLC. Cancer discovery. 2013;3:1404–15.
Sequist LV, Soria JC, Goldman JW, et al. Rociletinib in EGFR-mutated non-small-cell lung cancer. The New England journal of medicine. 2015;372:1700–9. This Phase 1/2 study of Rociletinib in patients with EGFR-mutated NSCLC associated with the T790M resistance mutation demonstrated significant activity and a promising response rate of 59% in this previously treated patient population, with the primary toxicity being hyperglycemia. The response rate was higher in patients harboring the T790M resistance mutation than in those with T790M-negative NSCLC.
Murakami H NH, Shimizu T, et al. Antitumour activity of ASP8273, an irreversible mutant selective EGFR-TKI, in NSCLC patients with tumours harbouring EGFR activating mutations and T790M resistance mutation. In: 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics; 2014 November 18–24, 2014; Barcelona, Spain: Europ J Cancer; 2014. p. 198.
Tan D. S-W. ST, Leighi N.B., et al. First-in-human phase I study of EGF816, a third generation, mutant-selective EGFR tyrosine kinase inhibitor, in advanced non-small cell lung cancer (NSCLC) harboring T790M. In: American Society of Clinical Oncology (ASCO) Annual Meeting; 2015; Chicago, IL: J Clin Oncol; 2015.
Park K. LJ-S, Lee K.H., Kim J-H et al. Updated safety and efficacy results from phase I/II study of HM61713 in patients (pts) with EGFR mutation positive non-small cell lung cancer (NSCLC) who failed previous EGFR-tyrosine kinase inhibitor (TKI). In: American Society of Clinical Oncology Annual Meeting; 2015; Chicago, IL: J Clin Oncol; 2015.
Compliance with Ethics Guidelines
Conflict of Interest
Emily Castellanos declares that she has no conflict of interest.
Leora Horn has received compensation from Genentech and Merck for service on advisory boards, has served on an unpaid advisory board for Bristol-Myers Squibb, as an unpaid consultant for Xcovery, and as an unpaid steering committee member for Bayer.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Author information
Authors and Affiliations
Corresponding author
Additional information
This article is part of the Topical Collection on Lung Cancer
Rights and permissions
About this article
Cite this article
Castellanos, E.H., Horn, L. Generations of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors: Perils and Progress. Curr. Treat. Options in Oncol. 16, 51 (2015). https://doi.org/10.1007/s11864-015-0365-1
Published:
DOI: https://doi.org/10.1007/s11864-015-0365-1