Current Treatment Options in Oncology

, Volume 13, Issue 4, pp 516–526 | Cite as

Strategies for Overcoming EGFR Resistance in the Treatment of Advanced-Stage NSCLC

  • Christine M. Lovly
  • Leora HornEmail author
Lung Cancer (HA Wakelee, Section Editor)

Opinion statement

Patients whose tumors harbor somatic-activating mutations within the epidermal growth factor receptor (EGFR) gene define a clinically distinct molecular cohort of lung cancers with increased sensitivity to the EGFR tyrosine kinase inhibitors (TKIs), including the “first-generation” reversible inhibitors, erlotinib and gefitinib, and the “second-generation” irreversible inhibitors, afatinib and dacomitinib. Several, large, phase III studies have shown already that patients with EGFR-mutant tumors display radiographic response rates of >60 % and improved progression free survival (PFS) when treated with an EGFR TKI compared with chemotherapy. Unfortunately, despite these initial responses, patients inevitably develop progressive disease, a concept referred to clinically as acquired resistance. Novel strategies are needed to delay or overcome acquired resistance to EGFR TKIs. These strategies include second-generation EGFR inhibitors, rationale combinations of targeted small molecule inhibitors and/or monoclonal antibodies, and addition of traditional cytotoxic chemotherapy to EGFR TKI therapy at the time of progression. Unfortunately, to date, there is no genotype-specific standard of care, and enrollment of patients with acquired resistance to EGFR TKIs into clinical trials specifically addressed at overcoming resistance is paramount to continue to advance the field and to improve outcomes for these patients.


Non-small cell lung cancer (NSCLC) EGFR Tyrosine kinase inhibitor Erlotinib Gefitinib Afatinib Dacomitinib Acquired resistance T790M 



C.M. Lovly: none; L. Horn: travel/accommodation expenses covered or reimbursed by Boehringer Ingelheim for travel to IASLC South American Regency Meeting.

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    L1ynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, Harris PL, Haserlat SM, Supko JG, Haluska FG, Louis DN, 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(21):2129–39.PubMedCrossRefGoogle Scholar
  2. 2.
    Kris MG, Johnson BE, Kwiatkowski DJ, et al. Identification of driver mutations in tumor specimens from 1,000 patients with lung adenocarcinoma: the NCI's Lung Cancer Mutation Consortium (LCMC). J Clin Oncol. 2011;29(Suppl; abstr CRA7506).Google Scholar
  3. 3.
    Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, Sunpaweravong P, Han B, Margono B, Ichinose Y, Nishiwaki Y, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361(10):947–57.PubMedCrossRefGoogle Scholar
  4. 4.
    Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Tsurutani J, Seto T, Satouchi M, Tada H, Hirashima T, Asami K, 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(2):121–8.PubMedCrossRefGoogle Scholar
  5. 5.
    Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H, Gemma A, Harada M, Yoshizawa H, Kinoshita I, Fujita Y, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 2010;362(25):2380–8.PubMedCrossRefGoogle Scholar
  6. 6.
    Rosell R, Gervais R, Vergnenegre A, Massuti B, Felip E, Cardenal F, Garcia Gomez R, Pallares C, Sanchez J, Porta R, Cobo M, Di Seri M, Garrido Lopez P, Insa A, De Marinis F, Corre R, Carreras M, Carcereny E, Taron M, Paz-Ares LG. Erlotinib versus chemotherapy (CT) in advanced non-small cell lung cancer (NSCLC) patients (p) with epidermal growth factor receptor (EGFR) mutations: interim results of the European Erlotinib Versus Chemotherapy (EURTAC) phase III randomized trial. J Clin Oncol. 2011;29S(Abstract 7503).Google Scholar
  7. 7.
    Yang JC, Schuler MH, Yamamoto N, O'Byrne KJ, Hirsh V, Mok T, Geater SL, Orlov SV, Tsai CM, Boyer MJ, Su WC, Bennouna J, Kato T, Gorbunova V, Lee KH, Shah R, Massey D, Lorence RM, Shahidi M, Sequist LV. LUX-Lung 3: a randomized, open-label, phase III study of afatinib versus pemetrexed and cisplatin as first-line treatment for patients with advanced adenocarcinoma of the lung harboring EGFR-activating mutations. J Clin Oncol. 2012;30(suppl; abstr LBA7500).Google Scholar
  8. 8.••
    Jackman D, Pao W, Riely GJ, Engelman JA, Kris MG, Janne PA, Lynch T, Johnson BE, Miller VA. Clinical definition of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer. J Clin Oncol. 2010;28(2):357–60.PubMedCrossRefGoogle Scholar
  9. 9.
    Kobayashi S, Boggon TJ, Dayaram T, Janne PA, Kocher O, Meyerson M, Johnson BE, Eck MJ, Tenen DG, Halmos B. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med. 2005;352(8):786–92.PubMedCrossRefGoogle Scholar
  10. 10.
    Pao W, Miller VA, Politi KA, Riely GJ, Somwar R, Zakowski MF, Kris MG, Varmus H. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med. 2005;2(3):e73.PubMedCrossRefGoogle Scholar
  11. 11.
    Daub H, Specht K, Ullrich A. Strategies to overcome resistance to targeted protein kinase inhibitors. Nat Rev Drug Discov. 2004;3(12):1001–10.PubMedCrossRefGoogle Scholar
  12. 12.
    Guida T, Anaganti S, Provitera L, Gedrich R, Sullivan E, Wilhelm SM, Santoro M, Carlomagno F. Sorafenib inhibits imatinib-resistant KIT and platelet-derived growth factor receptor beta gatekeeper mutants. Clin Cancer Res. 2007;13(11):3363–9.PubMedCrossRefGoogle Scholar
  13. 13.
    Balak MN, Gong Y, Riely GJ, Somwar R, Li AR, Zakowski MF, Chiang A, Yang G, Ouerfelli O, Kris MG, Ladanyi M, et al. Novel D761Y and common secondary T790M mutations in epidermal growth factor receptor-mutant lung adenocarcinomas with acquired resistance to kinase inhibitors. Clin Cancer Res. 2006;12(21):6494–501.PubMedCrossRefGoogle Scholar
  14. 14.
    Bean J, Riely GJ, Balak M, Marks JL, Ladanyi M, Miller VA, Pao W. Acquired resistance to epidermal growth factor receptor kinase inhibitors associated with a novel T854A mutation in a patient with EGFR-mutant lung adenocarcinoma. Clin Cancer Res. 2008;14(22):7519–25.PubMedCrossRefGoogle Scholar
  15. 15.
    Engelman JA, Zejnullahu K, Mitsudomi T, Song Y, Hyland C, Park JO, Lindeman N, Gale CM, Zhao X, Christensen J, Kosaka T, et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science. 2007;316(5827):1039–43.PubMedCrossRefGoogle Scholar
  16. 16.
    Bean J, Brennan C, Shih JY, Riely G, Viale A, Wang L, Chitale D, Motoi N, Szoke J, Broderick S, Balak M, et al. MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proc Natl Acad Sci U S A. 2007;104(52):20932–7.PubMedCrossRefGoogle Scholar
  17. 17.••
    Sequist LV, Waltman BA, Dias-Santagata D, Digumarthy S, Turke AB, Fidias P, Bergethon K, Shaw AT, Gettinger S, Cosper AK, Akhavanfard S, et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med. 2011;3(75):75ra26.PubMedCrossRefGoogle Scholar
  18. 18.
    Kawano O, Sasaki H, Endo K, Suzuki E, Haneda H, Yukiue H, Kobayashi Y, Yano M, Fujii Y. PIK3CA mutation status in Japanese lung cancer patients. Lung Cancer. 2006;54(2):209–15.PubMedCrossRefGoogle Scholar
  19. 19.
    Sun Y, Ren Y, Fang Z, Li C, Fang R, Gao B, Han X, Tian W, Pao W, Chen H, Ji H. Lung Adenocarcinoma From East Asian Never-Smokers Is a Disease Largely Defined by Targetable Oncogenic Mutant Kinases. J Clin Oncol. 2010;28:4616–20.PubMedCrossRefGoogle Scholar
  20. 20.•
    Chaft JE, Oxnard GR, Sima CS, Kris MG, Miller VA, Riely GJ. Disease flare after tyrosine kinase inhibitor discontinuation in patients with EGFR-mutant lung cancer and acquired resistance to erlotinib or gefitinib: implications for clinical trial design. Clin Cancer Res. 2011;17(19):6298–303.PubMedCrossRefGoogle Scholar
  21. 21.
    Chmielecki J, Foo J, Oxnard GR, Hutchinson K, Ohashi K, Somwar R, Wang L, Amato KR, Arcila M, Sos ML, Socci ND, et al. Optimization of dosing for EGFR-mutant non-small cell lung cancer with evolutionary cancer modeling. Sci Transl Med. 2011;3(90):90ra59.PubMedCrossRefGoogle Scholar
  22. 22.
    Oxnard GR, Lo P, Jackman DM, Butaney M, Heon S, Johnson BE, Sequist LV, Janne PA. Delay of chemotherapy through use of post-progression erlotinib in patients with EGFR-mutant lung cancer. J Clin Oncol. 2012;30(suppl; abstr 7547).Google Scholar
  23. 23.
    Goldberg SB, Oxnard GR, Digumarthy S, Muzikansky A, Jackman DM, Lennes IT, Sequist LV. Chemotherapy with erlotinib or chemotherapy alone in advanced NSCLC with acquired resistance to EGFR tyrosine kinase inhibitors (TKI). J Clin Oncol. 2012;30(suppl; abstr 7524).Google Scholar
  24. 24.
    Ou SH. Second-generation irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs): a better mousetrap? A review of the clinical evidence. Crit Rev Oncol Hematol. 2012.Google Scholar
  25. 25.
    Kwak EL, Sordella R, Bell DW, Godin-Heymann N, Okimoto RA, Brannigan BW, Harris PL, Driscoll DR, Fidias P, Lynch TJ, Rabindran SK, et al. Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib. Proc Natl Acad Sci U S A. 2005;102(21):7665–70.PubMedCrossRefGoogle Scholar
  26. 26.
    Sequist LV, Besse B, Lynch TJ, Miller VA, Wong KK, Gitlitz B, Eaton K, Zacharchuk C, Freyman A, Powell C, Ananthakrishnan R, 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. J Clin Oncol. 2010;28(18):3076–83.PubMedCrossRefGoogle Scholar
  27. 27.
    Engelman JA, Zejnullahu K, Gale CM, Lifshits E, Gonzales AJ, Shimamura T, Zhao F, Vincent PW, Naumov GN, Bradner JE, Althaus IW, 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 Res. 2007;67(24):11924–32.PubMedCrossRefGoogle Scholar
  28. 28.
    Kris MG, Mok T, Ou SHI, Martins R, Kim DW, Goldberg Z, Zhang H, Taylor I, Letrent SP, Janne PA. First-line dacomitinib (PF-00299804), an irreversible pan-HER tyrosine kinase inhibitor, for patients with EGFR-mutant lung cancers. J Clin Oncol. 2012;30(suppl; abstr 7530).Google Scholar
  29. 29.
    Miller VA, Hirsh V, Cadranel J, Chen YM, Park K, Kim SW, Zhou C, Su WC, Wang M, Sun Y, Heo DS, 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. Lancet Oncol. 2012;13(5):528–38.PubMedCrossRefGoogle Scholar
  30. 30.
    Yang JC, Shih JY, Su WC, Hsia TC, Tsai CM, Ou SH, Yu CJ, Chang GC, Ho CL, Sequist LV, Dudek AZ, et al. Afatinib for patients with lung adenocarcinoma and epidermal growth factor receptor mutations (LUX-Lung 2): a phase 2 trial. Lancet Oncol. 2012;13(5):539–48.PubMedCrossRefGoogle Scholar
  31. 31.
    Walter AO, Tjin R, Haringsma H, et al. CO-1686, an orally available, mutant-selective inhibitor of the epidermal growth factor receptor (EGFR), causes tumor shrinkage in non-small cell lung cancer (NSCLC) with T790M mutations. Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics: AACR. Mol Cancer Ther. 2011;10(11 Suppl). Abstract C189.Google Scholar
  32. 32.
    Neal JW, Heist RS, Fidias P, Temel JS, Huberman M, Marcoux JP, Muzikansky A, Lynch TJ, Sequist LV. Cetuximab monotherapy in patients with advanced non-small cell lung cancer after prior epidermal growth factor receptor tyrosine kinase inhibitor therapy. J Thorac Oncol. 2010;5(11):1855–8.PubMedCrossRefGoogle Scholar
  33. 33.••
    Janjigian YY, Azzoli CG, Krug LM, Pereira LK, Rizvi NA, Pietanza MC, Kris MG, Ginsberg MS, Pao W, Miller VA, Riely GJ. Phase I/II trial of cetuximab and erlotinib in patients with lung adenocarcinoma and acquired resistance to erlotinib. Clin Cancer Res. 2011;17(8):2521–7.PubMedCrossRefGoogle Scholar
  34. 34.
    Horn L, Groen HJ, Smit EF, et al. Activity and tolerability of combined EGFR targeting with afatinib (BIBW 2992) and cetuximab in T790M+ non-small cell lung cancer patients. 14th World Conference on Lung Cancer. 2011.Google Scholar
  35. 35.
    Soria JC, Shepherd FA, Douillard JY, Wolf J, Giaccone G, Crino L, Cappuzzo F, Sharma S, Gross SH, Dimitrijevic S, Di Scala L, et al. Efficacy of everolimus (RAD001) in patients with advanced NSCLC previously treated with chemotherapy alone or with chemotherapy and EGFR inhibitors. Ann Oncol. 2009;20(10):1674–81.PubMedCrossRefGoogle Scholar
  36. 36.
    Riely GJ, Kris MG, Zhao B, Akhurst T, Milton DT, Moore E, Tyson L, Pao W, Rizvi NA, Schwartz LH, Miller VA. Prospective assessment of discontinuation and reinitiation of erlotinib or gefitinib in patients with acquired resistance to erlotinib or gefitinib followed by the addition of everolimus. Clin Cancer Res. 2007;13(17):5150–5.PubMedCrossRefGoogle Scholar
  37. 37.
    Sequist LV, Gettinger S, Senzer NN, Martins RG, Janne PA, Lilenbaum R, Gray JE, Iafrate AJ, Katayama R, Hafeez N, Sweeney J, et al. Activity of IPI-504, a novel heat-shock protein 90 inhibitor, in patients with molecularly defined non-small-cell lung cancer. J Clin Oncol. 2010;28(33):4953–60.PubMedCrossRefGoogle Scholar
  38. 38.
    Garon EB, Moran T, Barlesi F, Gandhi L, Sequist LV, Kim SW, Groen HJM, Besse B, Smit EF, Kim DW, Akimov M, Avsar E, Bailey S, Felip E, Geffen D. Phase II study of the HSP90 inhibitor AUY922 in patients with previously treated, advanced non-small cell lung cancer (NSCLC). J Clin Oncol. 2012;30(suppl; abstr 7543).Google Scholar
  39. 39.
    Johnson ML, Yu HA, Hart EM, Worden R, Rademaker A, Gupta R, Miller C, Patel JD, Kris MG, Miller VA, Riely GJ. A phase I dose-escalation study of the HSP90 inhibitor AUY922 and erlotinib for patients with EGFR-mutant lung cancer with acquired resistance (AR) to EGFR tyrosine kinase inhibitors (EGFR TKIs). J Clin Oncol. 2012;30(suppl; abstr 3083).Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Vanderbilt Ingram Cancer CenterVanderbilt University Medical CenterNashvilleUSA

Personalised recommendations