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Published Online:https://doi.org/10.2217/fon.15.250

Non-small-cell lung cancer (NSCLC) patients whose tumors have an EGFR-activating mutation develop acquired resistance after a median of 9–11 months from the beginning of treatment with erlotinib, gefitinib and afatinib. T790M mutation is the cause of this resistance in approximately 60% of cases. AZD9291 is an oral, irreversible, mutant-selective EGF receptor (EGFR) tyrosine kinase inhibitor (TKI) developed to have potency against EGFR mutations, including T790M mutation, while sparing wild-type EGFR. A Phase I trial of AZD9291 in EGFR-mutant NSCLC patients, demonstrated high activity, essentially among T790M-mutant tumors, with a manageable tolerability profile. Ongoing Phase III trials are evaluating AZD9291 in EGFR-mutant patients as first-line treatment compared with erlotinib and gefitinib; and as second-line treatment compared with chemotherapy after progression on EGFR TKI in T790M-mutant tumors. Better identification of T790M-mutant tumors post EGFR TKI relapse and mechanisms of resistance to AZD9291 are the future challenges. This article reviews the emerging data regarding AZD9291 in the treatment of patients with advanced NSCLC.

Papers of special note have been highlighted as: • of interest; •• of considerable interest

References

  • 1 Gahr S, Stoehr R, Geissinger E et al. EGFR mutational status in a large series of Caucasian European NSCLC patients: data from daily practice. Br. J. Cancer. 109(7), 1821–1828 (2013).
  • 2 Kris MG, Johnson BE, Berry LD et al. Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. JAMA 311(19), 1998–2006 (2014).
  • 3 Reguart N, Remon J. Common EGFR-mutated subgroups (Del19/L858R) in advanced non-small-cell lung cancer: chasing better outcomes with tyrosine-kinase inhibitors. Future Oncol. 1(8), 1245–1257 (2015).
  • 4 Sequist LV, Waltman BA, Dias-Santagata D et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci. Transl. Med. 3(75), 75ra26 (2011).•• Initial study demonstrating the main mechanisms of acquired resistance to EGF receptor tyrosine kinase inhibitors in EGFR-mutant patients.
  • 5 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. 17(5), 1169–1180 (2011).
  • 6 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. 19(8), 2240–2247 (2013).
  • 7 Yun C-H, Mengwasser KE, Toms AV et al. The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc. Natl Acad. Sci. USA 105(6), 2070–2075 (2008).
  • 8 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. 3(90), 90ra59 (2011).
  • 9 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: comparison between T790M mutation-positive and mutation-negative populations. Cancer 119(24), 4325–4332 (2013).
  • 10 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. 17(6), 1616–1622 (2011).• Clinical study that describes natural history of acquired T790M mutation in EGFR-mutant non-small-cell lung cancer (NSCLC) patients.
  • 11 Sun J-M, Ahn M-J, Choi Y-L, Ahn JS, Park K. Clinical implications of T790M mutation in patients with acquired resistance to EGFR tyrosine kinase inhibitors. Lung Cancer Amst. Neth. 82(2), 294–298 (2013).
  • 12 Rosell R, Molina MA, Costa C et al. Pretreatment EGFR T790M mutation and BRCA1 mRNA expression in erlotinib-treated advanced non-small-cell lung cancer patients with EGFR mutations. Clin. Cancer Res. 17(5), 1160–1168 (2011).
  • 13 Watanabe M, Kawaguchi T, Isa S-I et al. Ultra-sensitive detection of the pretreatment EGFR T790M mutation in non-small cell lung cancer patients with an EGFR-activating mutation using droplet digital PCR. Clin. Cancer Res. 21(15), 3552–3560 (2015).
  • 14 Yu HA, Arcila ME, Hellmann MD, Kris MG, Ladanyi M, Riely GJ. Poor response to erlotinib in patients with tumors containing baseline EGFR T790M mutations found by routine clinical molecular testing. Ann. Oncol. 25(2), 423–428 (2014).
  • 15 Ding D, Yu Y, Li Z, Niu X, Lu S. The predictive role of pretreatment epidermal growth factor receptor T790M mutation on the progression-free survival of tyrosine-kinase inhibitor-treated non-small cell lung cancer patients: a meta-analysis. Onco Targets Ther. 7, 387–393 (2014).
  • 16 Costa C, Molina MA, Drozdowskyj A et al. The impact of EGFR T790M mutations and BIM mRNA expression on outcome in patients with EGFR-mutant NSCLC treated with erlotinib or chemotherapy in the randomized Phase III EURTAC trial. Clin. Cancer Res. 20(7), 2001–2010 (2014).
  • 17 Janjigian YY, Smit EF, Groen HJM 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. 4(9), 1036–1045 (2014).
  • 18 Park K, Ahn M, Yu C et al. ASPIRATION: first-line erlotinib (E) until and beyond RECIST progression (PD) in Asian patients (pts) with EGFR mutation-positive (mut+) NSCLC. Ann. Oncol. 25(Suppl. 4), iv426–iv470 (2014).
  • 19 Soria J-C, Wu Y-L, 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. 16(8), 990–998 (2015).
  • 20 Weickhardt AJ, Scheier B, Burke JM et al. Local ablative therapy of oligoprogressive disease prolongs disease control by tyrosine kinase inhibitors in oncogene-addicted non-small-cell lung cancer. J. Thorac. Oncol. 7(12), 1807–1814 (2012).
  • 21 Yu HA, Sima CS, Huang J et al. Local therapy with continued EGFR tyrosine kinase inhibitor therapy as a treatment strategy in EGFR-mutant advanced lung cancers that have developed acquired resistance to EGFR tyrosine kinase inhibitors. J. Thorac. Oncol. 8(3), 346–351 (2013).
  • 22 Watanabe S, Tanaka J, Ota T et al. Clinical responses to EGFR-tyrosine kinase inhibitor retreatment in non-small cell lung cancer patients who benefited from prior effective gefitinib therapy: a retrospective analysis. BMC Cancer. 11, 1 (2011).
  • 23 Kaira K, Naito T, Takahashi T et al. Pooled analysis of the reports of erlotinib after failure of gefitinib for non-small cell lung cancer. Lung Cancer Amst. Neth. 68(1), 99–104 (2010).
  • 24 Hata A, Katakami N, Yoshioka H et al. Erlotinib after gefitinib failure in relapsed non-small cell lung cancer: clinical benefit with optimal patient selection. Lung Cancer Amst. Neth. 74(2), 268–273 (2011).
  • 25 Yang JC-H, Wu Y-L, 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. Lancet Oncol. 16(2), 141–151 (2015).
  • 26 Ramalingam SS, Jänne 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. Lancet Oncol. 15(12), 1369–1378 (2014).
  • 27 Eskens FA, Mom CH, Planting AST et al. A Phase I dose escalation study of BIBW 2992 an irreversible dual inhibitor of epidermal growth factor receptor 1 (EGFR) and 2 (HER2) tyrosine kinase in a 2-week on, 2-week off schedule in patients with advanced solid tumours. Br. J. Cancer. 98(1), 80–85 (2008).
  • 28 Sequist LV, Soria J-C, Goldman JW et al. Rociletinib in EGFR-mutated non-small-cell lung cancer. N. Engl. J. Med. 372(18), 1700–1709 (2015).•• Initial Phase I trial demonstrating efficacy of CO1686 (rociletinib) in patients with advanced EGFR-mutant NSCLC.
  • 29 Kim D-W, Lee DH, Kang JH et al. Clinical activity and safety of HM61713, an EGFR-mutant selective inhibitor, in advanced non-small cell lung cancer (NSCLC) patients (pts) with EGFR mutations who had received EGFR tyrosine kinase inhibitors (TKIs). ASCO Meet. Abstr. 32(15 Suppl.), 8011 (2014).
  • 30 Jänne PA, Yang JC-H, Kim D-W et al. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N. Engl. J. Med. 372(18), 1689–1699 (2015).•• Initial Phase I trial demonstrating efficacy of AZD9291 in patients with advanced EGFR-mutant NSCLC.
  • 31 Jänne P, Ahn M, Kim D et al. LBA3: a Phase I study of AZD9291 in patients with EGFR-TKI-resistant advanced NSCLC – updated progression free survival and duration of response data. Ann. Oncol. 26(Suppl. 1), I60 (2015).
  • 32 Cross DAE, Ashton SE, Ghiorghiu S et al. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov. 4(9), 1046–1061 (2014).• Initial discovery of AZD9291 activity in EGFR-mutant NSCLC cell lines and transgenic mouse models
  • 33 Finlay MRV, Anderton M, Ashton S et al. Discovery of a potent and selective EGFR inhibitor (AZD9291) of both sensitizing and T790M resistance mutations that spares the wild type form of the receptor. J. Med. Chem. 57(20), 8249–8267 (2014).
  • 34 Planchard D, Dickinson PA, Brown KH, Kim D, Kim S, Ohe Y, Felip E, Leese P, Cantarini M, Ranson M. Preliminary AZD9291 western and Asian clinical pharmacokinetics (PK) in patients (pts) and healthy volunteers (HV): Implications for formulation. Dose and dosing frequency in pivotal clinical studies. Ann. Oncol. 25(Suppl. 4), iv146–iv164 (2014).
  • 35 Mitsudomi T, Tsai Ch, Shepeherd F et al. AZD9291 in pre-treated T790M positive advanced NSCLC: AURA2 Phase II study. J. Thorac. Oncol. 10(9 Suppl. 2), MINI16.08 (2015).
  • 36 Eberlein CA, Stetson D, Markovets AA et al. Acquired resistance to the mutant-selective EGFR inhibitor AZD9291 is associated with increased dependence on RAS signaling in preclinical models. Cancer Res. 75(12), 2489–2500 (2015).
  • 37 Ramalingam SS, Yang JC-H, Lee CK et al. AZD9291 in treatment naïve EGFR mutant advanced NSCLC: AURA first-line cohort. J. Thorac. Oncol. 10(9 Suppl. 2), MINI16.07 (2015).
  • 38 Schouten LJ, Rutten J, Huveneers HAM, Twijnstra A. Incidence of brain metastases in a cohort of patients with carcinoma of the breast, colon, kidney, and lung and melanoma. Cancer 94(10), 2698–2705 (2002).
  • 39 Mujoomdar A, Austin JHM, Malhotra R et al. Clinical predictors of metastatic disease to the brain from non-small cell lung carcinoma: primary tumor size, cell type, and lymph node metastases. Radiology 242(3), 882–888 (2007).
  • 40 Rangachari D, Yamaguchi N, VanderLaan PA et al. Brain metastases in patients with EGFR-mutated or ALK-rearranged non-small-cell lung cancers. Lung Cancer Amst. Neth. 88(1), 108–111 (2015).
  • 41 Hendriks LEL, Smit EF, Vosse BA et al. EGFR mutated non-small cell lung cancer patients: more prone to development of bone and brain metastases? Lung Cancer Amst. Neth. 84(1), 86–91 (2014).
  • 42 Doebele RC, Lu X, Sumey C et al. Oncogene status predicts patterns of metastatic spread in treatment-naive nonsmall cell lung cancer. Cancer 118(18), 4502–4511 (2012).
  • 43 Matsumoto S, Takahashi K, Iwakawa R et al. Frequent EGFR mutations in brain metastases of lung adenocarcinoma. Int. J. Cancer 119(6), 1491–1494 (2006).
  • 44 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. 35(2), 1025–1031 (2015).
  • 45 Lee Y, Lee GK, Hwang J-A, Yun T, Kim HT, Lee JS. Clinical likelihood of sporadic primary EGFR T790M mutation in EGFR-mutant lung cancer. Clin. Lung Cancer 16(1), 46–50 (2015).
  • 46 Jamal-Hanjani M, Spicer J. Epidermal growth factor receptor tyrosine kinase inhibitors in the treatment of epidermal growth factor receptor-mutant non-small cell lung cancer metastatic to the brain. Clin. Cancer Res. 18(4), 938–944 (2012).
  • 47 Omuro AMP, Kris MG, Miller VA et al. High incidence of disease recurrence in the brain and leptomeninges in patients with nonsmall cell lung carcinoma after response to gefitinib. Cancer 103(11), 2344–2348 (2005).
  • 48 Lee YJ, Choi HJ, Kim SK et al. Frequent central nervous system failure after clinical benefit with epidermal growth factor receptor tyrosine kinase inhibitors in Korean patients with nonsmall-cell lung cancer. Cancer 116(5), 1336–1343 (2010).
  • 49 Hoffknecht P, Tufman A, Wehler T et al. Efficacy of the irreversible ErbB family blocker afatinib in epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)-pretreated non-small-cell lung cancer patients with brain metastases or leptomeningeal disease. J. Thorac. Oncol. 10(1), 156–163 (2015).
  • 50 Kim D, Yang J, Cross D et al. Preclinical evidence and clinical cases of AZD9291 activity in EGFR-mutant non-small cell lung cancer (NSCLC) brain metastases (BM). Ann. Oncol. 25(Suppl. 4), iv146–iv164 (2014).
  • 51 Thress KS, Paweletz CP, Felip E et al. Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M. Nat. Med. 21(6), 560–562 (2015).•• Initial report about the mechanisms of acquired resistance on AZD9291 treatment in EGFR-mutant patients.
  • 52 Ercan D, Choi HG, Yun C-H et al. EGFR mutations and resistance to Irreversible pyrimidine based EGFR inhibitors. Clin. Cancer Res. 21(17), 3913–3923 (2015).
  • 53 Niederst MJ, Hu H, Mulvey HE et al. The allelic context of the C797S mutation acquired upon treatment with third generation EGFR inhibitors impacts sensitivity to subsequent treatment strategies. Clin. Cancer Res. 21(17), 3924–3933 (2015).
  • 54 Oxnard GR, Thress C, Paweletz C et al. Mechanisms of acquired resistance to AZD9291 in EGFR T790M positive lung cancer. J. Thoracic. Oncol. 10(9 Suppl. 2), ORAL17.07 (2015).
  • 55 Niederest MJ, Hu H, Mulvey HE et al. The allelic context of the C797S mutation acquired upon treatment with third-generation EGFR inhibitors impacts sensitivity to subsequent treatment strategies. Clin. Cancer Res. 21(17), 3924–3933 (2015).
  • 56 Tricker EM, Xu C, Uddin S et al. Combined EGFR/MEK inhibition prevents the emergence of resistance in EGFR-mutant lung cancer. Cancer Discov. 5(9), 960–971 (2015).
  • 57 Planchard D, Loriot Y, André F et al. EGFR independent mechanisms of acquired resistance to AZD9291 in EGFR T790M-positive NSCLC patients. Ann. Oncol. doi:10.1093/annonc/mdv319 (2015) (Epub ahead of print).
  • 58 Oxnard GR, Ramalingam SS, Ahn M-J 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. 33(15 Suppl.), Abstract 2509 (2015).
  • 59 Regales L, Gong Y, Shen R et al. Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutant lung cancer. J. Clin. Invest. 119(10), 3000–3010 (2009).
  • 60 Meador CB, Jin H, de Stanchina E et al. Optimizing the sequence of anti-EGFR-targeted therapy in EGFR-mutant lung cancer. Mol. Cancer Ther. 14(2), 542–552 (2015).
  • 61 Bosc C, Ferretti GR, Cadranel J et al. Rebiopsy during disease progression in patients treated by TKI for oncogene-addicted NSCLC. Target. Oncol. 10(2), 247–253 (2015).
  • 62 Del Re M, Vasile E, Falcone A, Danesi R, Petrini I. Molecular analysis of cell-free circulating DNA for the diagnosis of somatic mutations associated with resistance to tyrosine kinase inhibitors in non-small-cell lung cancer. Expert Rev. Mol. Diagn. 14(4), 453–468 (2014).
  • 63 Murtaza M, Dawson S-J, Tsui DWY et al. Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA. Nature 497(7447), 108–112 (2013).
  • 64 Nakamura T, Sueoka-Aragane N, Iwanaga K et al. A noninvasive system for monitoring resistance to epidermal growth factor receptor tyrosine kinase inhibitors with plasma DNA. J. Thorac. Oncol. 6(10), 1639–1648 (2011).
  • 65 Kuang Y, Rogers A, Yeap BY et al. Noninvasive detection of EGFR T790M in gefitinib or erlotinib resistant non-small cell lung cancer. Clin. Cancer Res. 15(8), 2630–2636 (2009).
  • 66 Thress K, Yang J, Ahn M et al. Levels of EGFR T790M in plasma DNA as a predictive biomarker for response to AZD9291, a mutant-selective EGFR kinase inhibitor. Ann. Oncol. 25(Suppl. 4), iv426–iv470 (2014).
  • 67 Lindeman NI, Cagle PT, Beasley MB et al. Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. J. Mol. Diagn. 15(4), 415–453 (2013).
  • 68 Sequist LV, Goldman JW, Wakelee HA et al. Efficacy of rociletinib (CO-1686) in plasma-genotyped T790M-positive non-small cell lung cancer (NSCLC) patients (pts). J. Clin. Oncol. 33(15 Suppl.), Abstract 8001 (2015).
  • 69 Diaz LA, Bardelli A. Liquid biopsies: genotyping circulating tumor DNA. J. Clin. Oncol. 32(6), 579–586 (2014).
  • 70 Bean J, Brennan C, Shih J-Y 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. USA 104(52), 20932–20937 (2007).