Skip to main content
SpringerLink
Log in

Treatment Options for EGFR T790M-Negative EGFR Tyrosine Kinase Inhibitor-Resistant Non-Small Cell Lung Cancer

  • Review Article
  • Published:
Targeted Oncology Aims and scope Submit manuscript

Abstract

The introduction of first- and second-generation EGFR-tyrosine kinase inhibitors (TKIs) (gefitinib, erlotinib and afatinib) for the treatment of advanced EGFR-mutant non-small cell lung cancer (NSCLC) has dramatically improved patients’ prognosis and quality of life (QoL). Unfortunately, after an initial and sometimes durable benefit from EGFR-TKI therapy, all patients with EGFR-mutant lung cancer eventually become resistant to the treatment and experience disease progression. In approximately 50% of these patients, genomic alterations in the EGFR kinase domain resulting in the mutant T790M are responsible for the resistance and this has led to the development of novel EGFR inhibitors active against mutant-T790M EGFR. The remaining 50% of patients with acquired resistance (AR) to EGFR-TKIs do not harbour the T790M mutation. In these cases, other mechanisms are involved in the development of AR such as perturbations of downstream pathways (e.g. K-RAS mutations), activation of alternative bypassing pathways (including c-Met, AXL, PIK3CA, BRAF), or histologic transformation. This review summarizes the main treatment strategies for this particular and heterogeneous group of “T790M-negative” patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Pao W, Kris MG, Iafrate AJ, et al. Integration of molecular profiling into the lung cancer clinic. Clin Cancer Res. 2009;15:5317–22.

    Article  PubMed  Google Scholar 

  2. 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  PubMed  Google Scholar 

  3. Maemondo M, Inoue A, Kobayashi K, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Eng J Med. 2010;362:2380–8.

    Article  CAS  Google Scholar 

  4. 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.

    Article  CAS  PubMed  Google Scholar 

  5. Zhou C, Wu YL, Chen G, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2011;12:735–42.

    Article  CAS  PubMed  Google Scholar 

  6. 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.

    Article  CAS  PubMed  Google Scholar 

  7. Pan Q, Pao W, Ladanyi M, et al. Rapid polymerase chain reaction-based detection of epidermal growth factor receptor gene mutations in lung adenocarcinomas. J Mol Diagn. 2005;7:396–403.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Sharma SV, Bell DW, Settleman J, et al. Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer. 2007;7:169–81.

    Article  CAS  PubMed  Google Scholar 

  9. 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 

  10. Han JY, Park K, Kim SW, et al. First-SIGNAL: first-line single-agent iressa versus gemcitabine and cisplatin trial in never-smokers with adenocarcinoma of the lung. J Clin Oncol. 2012;30:1122–8.

    Article  CAS  PubMed  Google Scholar 

  11. Wu YL, Zhou C, Liam CK, et al. First-line erlotinib versus gemcitabine/cisplatin in patients with advanced EGFR mutation-positive non-small-cell lung cancer: analyses from the phase III, randomized, open-label, ENSURE study. Ann Oncol. 2015;26:1883–9.

    Article  PubMed  Google Scholar 

  12. 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. Lancet Oncol. 2012;13:539–48.

    Article  CAS  PubMed  Google Scholar 

  13. Sequist LV, Yang N, Yamamoto J, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013;31:3327–34.

    Article  CAS  PubMed  Google Scholar 

  14. Yang JC, Hirsh V, Schuler M, et al. Symptom control and quality of life in LUX-Lung 3: a phase III study of afatinib or cisplatin/pemetrexed in patients with advanced lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013;31:3342–50.

    Article  CAS  PubMed  Google Scholar 

  15. Yang JC, Wu Y, Sebastian 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. Lancet Oncol. 2015;16:141–51.

    Article  CAS  PubMed  Google Scholar 

  16. Jackman D, Pao W, Riely GJ, et al. Clinical definition of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer. J Clin Oncol. 2010;28:357–60.

    Article  CAS  PubMed  Google Scholar 

  17. Sequist LV, Waltman BA, Dias-Santagata D, et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med. 2011;3:75ra26. doi:10.1126/scitranslmed.3002003.

    Article  PubMed  PubMed Central  Google Scholar 

  18. 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. Clin Cancer Res. 2013;19:2240–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Kobayashi S, Boggon TJ, Dayaram T, et al. EGFR mutation and resistance of non-small-cell lung cancer to gefıtinib. N Engl J Med. 2005;352:786–92.

    Article  CAS  PubMed  Google Scholar 

  20. 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. doi:10.1371/journal.pmed.0020073.

    Article  PubMed  PubMed Central  Google Scholar 

  21. 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 

  22. Jänne PA, Yang JC, Kim D, et al. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med. 2015;372(18):1689–99.

    Article  PubMed  Google Scholar 

  23. Sequist LV, Soria JC, Goldman JW, et al. Rociletinib in EGFR-mutated non-small-cell lung cancer. N Engl J Med. 2015;372(18):1700–9.

    Article  PubMed  Google Scholar 

  24. Chmielecki J, Foo J, Oxnard GR, et al. Optimization of dosing for EGFR-mutant non-small-cell lung cancer with evolutionary cancer modeling. Sci Transl Med. 2011;3:90ra59. doi:10.1126/scitranslmed.3002356.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Oxnard GR, Arcila ME, Sima CS, et al. Acquired resistance to EGFR tyrosine kinase inhibitors in EGFR-mutant lung cancer: distinct natural history of patients with tumors harboring the T790M mutation. Clin Cancer Res. 2011;17:1616–22.

    Article  CAS  PubMed  Google Scholar 

  26. Chmielecki J, Foo J, Somwar R, et al. EGFR T790M decreases growth potential of lung tumor cells with drug-sensitive EGFR mutant alleles in the absence of drug selection. Cancer Res. 2009;69(9 Supplement):Abstract nr 4217.

  27. Hata A, Katakami N, Yoshioka H, et al. Rebiopsy of non-small cell lung cancer patients with acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitor. Cancer. 2013;15:4325–32.

    Article  Google Scholar 

  28. Uramoto H, Yano S, Tanaka F, et al. T790M is associated with a favourable prognosis in Japanese patients treated with an EGFR-TKI. Lung Cancer. 2012;76:129–30.

    Article  PubMed  Google Scholar 

  29. Hata A, Katakami N, Yoshioka H, et al. Prognostic impact of central nervous system metastases after acquired resistance to EGFR-TKI: poorer prognosis associated with T790M-negative status and leptomeningeal metastases. Anticancer Res. 2015;35(2):1025–31.

    PubMed  Google Scholar 

  30. Tokumo M, Toyooka S, Ichihara S, et al. Double mutation and gene copy number of EGFR in gefitinib refractory non-small-cell lung cancer. Lung Cancer. 2006;53:117–21.

    Article  PubMed  Google Scholar 

  31. Shih J, Gow C, Yang P. EGFR mutation conferring primary resistance to gefitinib in non-small-cell lung cancer. N Engl J Med. 2005;353:207–8.

    Article  CAS  PubMed  Google Scholar 

  32. Inukai M, Toyooka S, Ito S, et al. Presence of epidermal growth factor receptor gene T790M mutation as a minor clone in non-small-cell lung cancer. Cancer Res. 2006;66:7854–8.

    Article  CAS  PubMed  Google Scholar 

  33. Lee Y, Lee GK, Lee T, et al. Clinical outcome according to the level of preexisting epidermal growth factor receptor T790M mutation in patients with lung cancer harboring sensitive epidermal growth factor receptor mutations. Cancer. 2014;120:2090–8.

    Article  CAS  PubMed  Google Scholar 

  34. 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. Clin Cancer Res. 2006;12:6494–501.

    Article  CAS  PubMed  Google Scholar 

  35. 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. Clin Cancer Res. 2008;14:7519–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Costa DB, Schumer ST, Tenen DG, et al. Differential responses to erlotinib in epidermal growth factor receptor (EGFR)-mutated lung cancers with acquired resistance to gefitinib carrying the L747S or T790M secondary mutations. J Clin Oncol. 2008;26:1182–4.

    Article  PubMed  Google Scholar 

  37. Ohashi K, Sequist LV, Arcila ME, Moran T, Chmielecki J, Lin YL, et al. Lung cancers with acquired resistance to EGFR inhibitors occasionally harbor BRAF mutations but lack mutations in KRAS, NRAS, or MEK1. Proc Natl Acad Sci U S A. 2012;109:E2127–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Engelman JA, Mukohara T, Zejnullahu K, et al. Allelic dilution obscures detection of a biologically significant resistance mutation in EGFR-amplified lung cancer. J Clin Invest. 2006;116:2695–706.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Bean J, Brennan C, Shih JY, Riely G, Viale A, Wang L, 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;104:20932–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. 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. Clin Cancer Res. 2011;17:1169–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Sequist LV, Waltman BA, Dias-Santagata D, et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med. 2011;3:75ra26.

    Article  PubMed  PubMed Central  Google Scholar 

  42. 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. Science. 2007;316:1039–43.

    Article  CAS  PubMed  Google Scholar 

  43. 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 Discov. 2012;2:922–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Zhang Z, Lee JC, Lin L, et al. Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer. Nat Genet. 2012;44:852–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Byers LA, Diao L, Wang J, et al. An epithelial-mesenchymal transition gene signature predicts resistance to EGFR and PI3K inhibitors and identifies Axl as a therapeutic target for overcoming EGFR inhibitor resistance. Clin Cancer Res. 2013;19:279–90.

    Article  CAS  PubMed  Google Scholar 

  46. Ware KE, Hinz TK, Kleczko E, Singleton KR, Marek LA, Helfrich BA, et al. A mechanism of resistance to gefitinib mediated by cellular reprogramming and the acquisition of an FGF2-FGFR1 autocrine growth loop. Oncogenesis. 2013;2:e39. doi:10.1038/oncsis.2013.4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Azuma K, Kawahara A, Sonoda K, et al. FGFR1 activation is an escape mechanism in human lung cancer cells resistant to afatinib, a pan-EGFR family kinase inhibitor. Oncotarget. 2014;5:5908–19.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Terai H, Soejima K, Yasuda H, Nakayama S, Hamamoto J, Arai D, et al. Activation of the FGF2-FGFR1 autocrine pathway: a novel mechanism of acquired resistance to gefitinib in NSCLC. Mol Cancer Res. 2013;11:759–67.

    Article  CAS  PubMed  Google Scholar 

  49. Ware KE, Marshall ME, Heasley LR, et al. Rapidly acquired resistance to EGFR tyrosine kinase inhibitors in NSCLC cell lines through de-repression of FGFR2 and FGFR3 expression. PLoS One. 2010;5:e14117. doi:10.1371/journal.pone.0014117.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Zakowski MF, Ladanyi M, Kris MG. EGFR mutations in small-cell lung cancers in patients who have never smoked. N Engl J Med. 2006;355:213–5.

    Article  CAS  PubMed  Google Scholar 

  51. Riely GJ, Kris MG, Zhao B, Akhurst T, Milton DT, Moore E, et al. 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;13:5150–5.

    Article  CAS  PubMed  Google Scholar 

  52. Chaft JE, Oxnard GR, Miller VA, Kris MG, Sima CS, Riely GJ. Disease flare after tyrosine kinase inhibitor (TKI) discontinuation in patients with EGFR mutant lung cancer and acquired resistance. J Clin Oncol. 2011;29(supplement abstr e18001).

  53. Hosomi Y, Tanai C, Yoh K, et al. Observational study of treatment with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) in activating EGFR-mutation–positive (EGFRm+) advanced or recurrent non-small-cell lung cancer (NSCLC) after radiologic progression to first-line therapy with EGFR-TKI. J Clin Oncol. 2014;32(5, supplement abstr 8071).

  54. Nishie K, Kawaguchi T, Tamiya A, et al. Epidermal growth factor receptor tyrosine kinase inhibitors beyond progressive disease: a retrospective analysis for Japanese patients with activating EGFR mutations. J Thorac Oncol. 2012;7:1722–7.

    Article  CAS  PubMed  Google Scholar 

  55. Gainor JF, Shaw AT. Emerging paradigms in the development of resistance to tyrosine kinase inhibitors in lung cancer. J Clin Oncol. 2013;31:3987–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Schuler MH, Yang C, Park K, et al. Afatinib beyond progression in patients with non-small-cell lung cancer following chemotherapy, erlotinib/gefitinib and afatinib: phase III randomized LUX-Lung 5 trial. Ann Oncol. 2016;27:417–23.

    Article  CAS  PubMed  Google Scholar 

  57. Goldberg SB, Oxnard BR, 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. Oncologist. 2013;18:1214–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Zhao N, Sun Z, Wang Y, et al. Gefitinib-integrated regimen versus chemotherapy alone in heavily pretreated patients with epidermal growth factor receptor-mutated lung adenocarcinoma: a case-control study. Transl Oncol. 2014;7(4):508–12.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Soria JC, Wu YL, Nakagawa K, et al. Gefitinib plus chemotherapy versus placebo plus chemotherapy in EGFR-mutation-positive non-small-cell lung cancer after progression on first-line gefitinib (IMPRESS): a phase 3 randomised trial. Lancet Oncol. 2015;16(8):990–8.

    Article  CAS  PubMed  Google Scholar 

  60. Soria JC, Kim SW, Wu YL, et al. Gefitinib/chemotherapy vs chemotherapy in EGFR mutation-positive NSCLC after progression on 1st line gefitinib (IMPRESS study): final overall survival (OS) analysis. Ann Oncol. 2016;27(6):vi416–54.

    Google Scholar 

  61. Hata A, Katakami N, Kaji R, et al. Does T790M disappear? Successful gefitinib rechallenge after T790M disappearance in a patient with EGFR-mutant non-small-cell lung cancer. J Thorac Oncol. 2013;8(3):e27–9. doi:10.1097/JTO.0b013e318282e047.

    Article  PubMed  Google Scholar 

  62. Chmielecki J, Foo J, Oxnard GR, et al. Optimization of dosing for EGFR-mutant non-small cell lung cancer with evolutionary cancer modeling. Sci Transl Med. 2011;3:90ra59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Oxnard GR, Arcila ME, Chmielecki J, et al. New strategies in overcoming acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in lung cancer. Clin Cancer Res. 2011;17:5530–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Naumov GN, Nilsson MB, Cascone T, et al. Combined vascular endothelial growth factor receptor and epidermal growth factor receptor (EGFR) blockade inhibits tumor growth in xenograft models of EGFR inhibitor resistance. Clin Cancer Res. 2009;15(10):3484–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Otsuka K, Hata A, Takeshita J, et al. EGFR-TKI rechallenge with bevacizumab in EGFR-mutant non-small-cell lung cancer. Cancer Chemother Pharmacol. 2015;76(4):835–41.

    Article  CAS  PubMed  Google Scholar 

  66. Kwak L, Sordella R, Bell DW, et al. Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib. Proc Natl Acad Sci U S A. 2012;21(102):7665–70. 

  67. Clovis Oncology announces regulatory update for rociletinib NDA filing. Business Wire. (http://www.businesswire.com/ news/ home/20151116005513/en/). November 16, 2015

  68. Sequist LV, Soria JC, Camidge DR. Update to rociletinib data with the RECIST confirmed response rate. N Engl J Med. 2016;374(23):2296–7.

    Article  PubMed  Google Scholar 

  69. Goss G, Tsai C-M, Shepherd FA. Osimertinib for pretreated EGFR Thr790Met-positive advanced non-small-cell lung cancer (AURA2): a multicentre, open-label, single-arm, phase 2 study. 2016;17(12):1643–52. doi:10.1016/S1470-2045(16)30508-3.

  70. Janjigian YY, Smit EF, Groen HJ, et al. Dual inhibition of EGFR with afatinib and cetuximab in kinase inhibitor-resistant EGFR-mutant lung cancer with and without T790M mutations. Cancer Discov. 2014;4(9):1036–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Murakami A, Takahashi F, Nurwidya F, et al. Hypoxia increases gefitinib-resistant lung cancer stem cells through the activation of insulin-like growth factor 1 receptor. PLoS One. 2014;9(1):e86459. doi:10.1371/journal.pone.0086459.

    Article  PubMed  PubMed Central  Google Scholar 

  72. Liu SV, Aggarwal C, Brzezniak C, et al. Phase 2 study of tarloxotinib bromide (TRLX) in patients with EGFR-mutant, T790M-negative NSCLC progressing on an EGFR TKI. J Clin Oncol. 2016;34(supplement abstr TPS9100).

  73. Akbay EA, Koyama S, Carretero J, et al. Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors. Cancer Discov. 2013;3(12):1355–63.

    Article  CAS  PubMed  Google Scholar 

  74. Herbst RS, Baas P, Kim DW, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016;387:1540–50.

    Article  CAS  PubMed  Google Scholar 

  75. Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015;373:1627–39.

    Article  CAS  PubMed  Google Scholar 

  76. Rizvi N, Chow L, Borghaei H, et al. Safety and response with nivolumab (anti-PD-1; BMS-936558, ONO- 4538) plus erlotinib in patients (Pts) with epidermalgrowth factor receptor mutant (EGFR Mt) advanced NSCLC. J Clin Oncol. 2014;32(5, supplement abstr 8022).

  77. Reckamp KL, Frankel PH, Mack PC, et al. Phase II trial of XL184 (cabozantinib) plus erlotinib in patients (pts) with advanced EGFR-mutant non-small-cell lung cancer (NSCLC) with progressive disease (PD) on epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy: a California Cancer Consortium phase II trial (NCI 9303). J Clin Oncol. 2014;32(5, supplement abstr 8014).

  78. Wu Y-L, Yang JC-H, Kim D-W, et al. Safety and efficacy of INC280 in combination with gefitinib (gef) in patients with EGFR-mutated (mut), MET-positive NSCLC: a single-arm phase lb/ll study. J Clin Oncol. 2014;32(5, supplement abstr 8017).

  79. Lara P, Longmate J, Mack PC, et al. Phase II study of the AKT inhibitor MK-2206 plus erlotinib (E) in patients (pts) with advanced non-small-cell lung cancer (NSCLC) who progressed on prior erlotinib: a California cancer consortium phase II trial (NCI 8698). J Clin Oncol. 2014;32(5, supplement abstr 8015).

  80. Vansteenkiste JF, Canon JL, Braud FD, et al. Safety and efficacy of buparlisib (BKM120) in patients with PI3K pathway-activated non-small-cell lung cancer: results from the phase II BASALT-1 study. J Thorac Oncol. 2015;10(9):1319–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Oxnard GR, Ramalingam SS, Ahn M, et al. Preliminary results of TATTON, a multi-arm phase Ib trial of AZD9291 combined with MEDI4736, AZD6094 or selumetinib in EGFR-mutant lung cancer. J Clin Oncol. 2015;33(supplement abstr 2509).

  82. Reck M, Popat S, Reinmuth N. Metastatic non-small-cell lung cancer (NSCLC): ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014;25(3):iii27–39.

    Article  PubMed  Google Scholar 

  83. Scagliotti GV, Parikh P, von Pawel J, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non–small-cell lung cancer. J Clin Oncol. 2008;26(21):3543–51.

  84. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: non-small-cell lung cancer, version 4.2016. Available at: http://www.nccn.org.

Download references

Acknowledgements

Salvatore Corallo and Ettore D’Argento have equally contributed to this work

Author information

Authors and Affiliations

  1. Department of Medical Oncology, Fondazione Policlinico Universitario Agostino Gemelli, Università Cattolica del Sacro Cuore, Largo A. Gemelli, 8, 00168, Rome, Italy

    Salvatore Corallo, Ettore D’Argento, Antonia Strippoli, Michele Basso, Santa Monterisi, Alessandra Cassano & Carlo M. Barone

  2. Department of Medical Oncology, Humanitas Clinical and Research Center, Via Manzoni, 56, 20089, Rozzano, MI, Italy

    Sabrina Rossi

Authors
  1. Salvatore Corallo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ettore D’Argento
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Antonia Strippoli
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Michele Basso
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Santa Monterisi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sabrina Rossi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Alessandra Cassano
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Carlo M. Barone
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ettore D’Argento.

Ethics declarations

Funding

None

Conflict of Interest

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Corallo, S., D’Argento, E., Strippoli, A. et al. Treatment Options for EGFR T790M-Negative EGFR Tyrosine Kinase Inhibitor-Resistant Non-Small Cell Lung Cancer. Targ Oncol 12, 153–161 (2017). https://doi.org/10.1007/s11523-017-0479-4

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11523-017-0479-4

Keywords

Search

Navigation