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Journal of Hematology & Oncology
Published in: Journal of Hematology & Oncology 1/2016

Open Access 01-12-2016 | Review

Third-generation inhibitors targeting EGFR T790M mutation in advanced non-small cell lung cancer

Published in: Journal of Hematology & Oncology | Issue 1/2016

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Abstract

The tyrosine kinase inhibitors (TKI) against epidermal growth factor receptor (EGFR) are widely used in patients with non-small cell lung cancer (NSCLC). However, EGFR T790M mutation leads to resistance to most clinically available EGFR TKIs. Third-generation EGFR TKIs against the T790M mutation have been in active clinical development. These agents include osimertinib, rociletinib, HM61713, ASP8273, EGF816, and PF-06747775. Osimertinib and rociletinib have shown clinical efficacy in phase I/II trials in patients who had acquired resistance to first- or second-generation TKIs. Osimertinib (AZD9291, TAGRISSO) was recently approved by FDA for metastatic EGFR T790M mutation-positive NSCLC. HM61713, ASP8237, EGF816, and PF-06747775 are still in early clinical development. This article reviews the emerging data regarding third-generation agents against EGFR T790M mutation in the treatment of patients with advanced NSCLC.
Literature
1.
2.
Sharma SV, Bell DW, Settleman J, Haber DA. Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer. 2007;7(3):169–81.CrossRefPubMed
3.
Cataldo VD, Gibbons DL, Perez-Soler R, Quintas-Cardama A. Treatment of non-small-cell lung cancer with erlotinib or gefitinib. N Engl J Med. 2011;364(10):947–55.CrossRefPubMed
4.
Zhong W, Yang X, Yan H, Zhang X, Su J, Chen Z, Liao R, Nie Q, Dong S, Zhou Q, Yang J, Tu H, Wu Y-L. Phase II study of biomarker-guided neoadjuvant treatment strategy for IIIA-N2 non-small cell lung cancer based on epidermal growth factor receptor mutation status. J Hematol Oncol. 2015;8(1):54.CrossRefPubMedPubMedCentral
5.
6.
Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, Sunpaweravong P, Han B, Margono B, Ichinose Y, Nishiwaki Y, Ohe Y, Yang JJ, Chewaskulyong B, Jiang H, Duffield EL, Watkins CL, Armour AA, Fukuoka M. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361(10):947–57.CrossRefPubMed
7.
Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, Palmero R, Garcia-Gomez R, Pallares C, Sanchez JM, Porta R, Cobo M, Garrido P, Longo F, Moran T, Insa A, De Marinis F, Corre R, Bover I, Illiano A, Dansin E, de Castro J, Milella M, Reguart N, Altavilla G, Jimenez U, Provencio M, Moreno MA, Terrasa J, Munoz-Langa J, 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(3):239–46.CrossRefPubMed
8.
Sequist LV, Yang JC, Yamamoto N, O'Byrne K, Hirsh V, Mok T, Geater SL, Orlov S, Tsai CM, Boyer M, Su WC, Bennouna J, Kato T, Gorbunova V, Lee KH, Shah R, Massey D, Zazulina V, Shahidi M, Schuler M. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013;31(27):3327–34.CrossRefPubMed
9.
10.
Sun W, Yuan X, Tian Y, Wu H, Xu H, Hu G, Wu K. Non-invasive approaches to monitor EGFR-TKI treatment in non-small-cell lung cancer. J Hematol Oncol. 2015;8(1):95.CrossRefPubMedPubMedCentral
11.
Lee CK, Wu Y-L, Ding PN, Lord SJ, Inoue A, Zhou C, Mitsudomi T, Rosell R, Pavlakis N, Links M, Gebski V, Gralla RJ, Yang JC-H. Impact of specific epidermal growth factor receptor (EGFR) mutations and clinical characteristics on outcomes after treatment with EGFR tyrosine kinase inhibitors versus chemotherapy in EGFR-mutant lung cancer: a meta-analysis. J Clin Oncol. 2015;33(17):1958–65.CrossRefPubMed
12.
Jia Y, Juarez J, Li J, Manuia M, Niederst MJ, Tompkins C, Timple N, Vaillancourt M-T, Pferdekamper AC, Lockerman EL, Li C, Anderson J, Costa C, Liao D, Murphy E, DiDonato M, Bursulaya B, Lelais G, Barretina J, McNeill M, Epple R, Marsilje TH, Pathan N, Engelman JA, Michellys P-Y, McNamara P, Harris J, Bender S, Kasibhatla S. EGF816 exerts anticancer effects in non-small cell lung cancer by irreversibly and selectively targeting primary and acquired activating mutations in the EGF receptor. Cancer Res. 2016;76: 1591–602. Doi: 10.1158/0008-5472.CAN-1115-2581.
13.
Yu HA, Arcila ME, Rekhtman N, Sima CS, Zakowski MF, Pao W, Kris MG, Miller VA, Ladanyi M, Riely GJ. 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(8):2240–7.CrossRefPubMedPubMedCentral
14.
Sequist LV, Waltman BA, Dias-Santagata D, Digumarthy S, Turke AB, Fidias P, Bergethon K, Shaw AT, Gettinger S, Cosper AK, Akhavanfard S, Heist RS, Temel J, Christensen JG, Wain JC, Lynch TJ, Vernovsky K, Mark EJ, Lanuti M, Iafrate AJ, Mino-Kenudson M, Engelman JA. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med. 2011;3(75):75ra26.PubMedPubMedCentral
15.
Cross DA, Ashton SE, Ghiorghiu S, Eberlein C, Nebhan CA, Spitzler PJ, Orme JP, Finlay MR, Ward RA, Mellor MJ, Hughes G, Rahi A, Jacobs VN, Red Brewer M, Ichihara E, Sun J, Jin H, Ballard P, Al-Kadhimi K, Rowlinson R, Klinowska T, Richmond GH, Cantarini M, Kim DW, Ranson MR, Pao W. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov. 2014;4(9):1046–61.CrossRefPubMedPubMedCentral
16.
Walter AO, Sjin RT, Haringsma HJ, Ohashi K, Sun J, Lee K, Dubrovskiy A, Labenski M, Zhu Z, Wang Z, Sheets M, St Martin T, Karp R, van Kalken D, Chaturvedi P, Niu D, Nacht M, Petter RC, Westlin W, Lin K, Jaw-Tsai S, Raponi M, Van Dyke T, Etter J, Weaver Z, Pao W, Singh J, Simmons AD, Harding TC, Allen A. Discovery of a mutant-selective covalent inhibitor of EGFR that overcomes T790M-mediated resistance in NSCLC. Cancer Discov. 2013;3(12):1404–15.CrossRefPubMedPubMedCentral
17.
Park K, Lee J-S, Lee KH, Kim J-H, Min YJ, Cho JY, Han J-Y, Kim B-S, Kim J-S, Lee DH, Kang JH, Cho EK, Jang I-J, Jung J, Kim H-Y, Sin HJ, Son J, Woo JS, Kim D-W. 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). ASCO Meet Abstr. 2015;33(15):8084.
18.
Ward RA, Anderton MJ, Ashton S, Bethel PA, Box M, Butterworth S, Colclough N, Chorley CG, Chuaqui C, Cross DA, Dakin LA, Debreczeni JE, Eberlein C, Finlay MR, Hill GB, Grist M, Klinowska TC, Lane C, Martin S, Orme JP, Smith P, Wang F, Waring MJ. Structure- and reactivity-based development of covalent inhibitors of the activating and gatekeeper mutant forms of the epidermal growth factor receptor (EGFR). J Med Chem. 2013;56(17):7025–48.CrossRefPubMed
19.
Janne PA, Yang JC, Kim DW, Planchard D, Ohe Y, Ramalingam SS, Ahn MJ, Kim SW, Su WC, Horn L, Haggstrom D, Felip E, Kim JH, Frewer P, Cantarini M, Brown KH, Dickinson PA, Ghiorghiu S, Ranson M. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med. 2015;372(18):1689–99.CrossRefPubMed
20.
Ramalingam SS, Yang J, Lee C, Kurata T, Kim D-W, John T, Nogami N, Ohe Y, Rukazenkov Y, Frewer P, Cantarini M, Ghiorghiu S, Jänne PA. MINI 16.07: AZD9291 in treatment-naïve EGFRm advanced NSCLC: AURA first-Line cohort. J Thoracic Oncol. 2015;10(9_suppl 2):S319.
21.
Eberlein CA, Stetson D, Markovets AA, Al-Kadhimi KJ, Lai Z, Fisher PR, Meador CB, Spitzler P, Ichihara E, Ross SJ, Ahdesmaki MJ, Ahmed A, Ratcliffe LE, O’Brien EL, Barnes CH, Brown H, Smith PD, Dry JR, Beran G, Thress KS, Dougherty B, Pao W, Cross DA. Acquired resistance to the mutant-selective EGFR inhibitor AZD9291 is associated with increased dependence on RAS signaling in preclinical models. Cancer Res. 2015;75(12):2489–500.CrossRefPubMed
22.
23.
Sequist LV, Soria JC, Goldman JW, Wakelee HA, Gadgeel SM, Varga A, Papadimitrakopoulou V, Solomon BJ, Oxnard GR, Dziadziuszko R, Aisner DL, Doebele RC, Galasso C, Garon EB, Heist RS, Logan J, Neal JW, Mendenhall MA, Nichols S, Piotrowska Z, Wozniak AJ, Raponi M, Karlovich CA, Jaw-Tsai S, Isaacson J, Despain D, Matheny SL, Rolfe L, Allen AR, Camidge DR. Rociletinib in EGFR-mutated non-small-cell lung cancer. N Engl J Med. 2015;372(18):1700–9.CrossRefPubMed
24.
Lee K-O, Cha MY, Kim M, Song JY, Lee J-H, Kim YH, Lee Y-M, Suh KH, Son J. Abstract LB-100: discovery of HM61713 as an orally available and mutant EGFR selective inhibitor. Cancer Res. 2014;74(19 Supplement):LB-100.CrossRef
25.
Sakagami H, Konagai S, Yamamoto H, Tanaka H, Matsuya T, Mori M, Koshio H, Yuri M, Hirano M, Kuromitsu S. Abstract 1728: ASP8273, a novel mutant-selective irreversible EGFR inhibitor, inhibits growth of non-small cell lung cancer (NSCLC) cells with EGFR activating and T790M resistance mutations. Cancer Res. 2014;74(19 Supplement):1728.CrossRef
26.
Konagai S, Sakagami H, Yamamoto H, Tanaka H, Matsuya T, Mimasu S, Tomimoto Y, Mori M, Koshio H, Hirano M, Kuromitsu S, Takeuchi M. Abstract 2586: ASP8273 selectively inhibits mutant EGFR signal pathway and induces tumor shrinkage in EGFR mutated tumor models. Cancer Res. 2015;75(15 Supplement):2586.CrossRef
27.
Goto Y, Nokihara H, Murakami H, Shimizu T, Seto T, Krivoshik AP, Keating AT, Uegaki K, Takeda K, Komatsu K, Morita S, Fukuoka M, Nakagawa K. ASP8273, a mutant-selective irreversible EGFR inhibitor in patients (pts) with NSCLC harboring EGFR activating mutations: preliminary results of first-in-human phase I study in Japan. ASCO Meet Abstr. 2015;33(15_suppl):8014.
28.
Yu HA, Oxnard GR, Spira AI, Horn L, Weiss J, Feng Y, West HJ, Giaccone G, Evans TL, Kelly RJ, Fleege T, Poondru S, Jie F, Aoyama K, Foley MA, Whitcomb D, Keating AT, Krivoshik AP. Phase I dose escalation study of ASP8273, a mutant-selective irreversible EGFR inhibitor, in subjects with EGFR mutation positive NSCLC. ASCO Meet Abstr. 2015;33(15_suppl):8083.
29.
Jia Y, Juarez J, Manuia M, Lelais G, Kasibhatla S, Long O, McNeill M, DiDonato M, Bursulaya B, Liao D, Murphy E, Epple R, Marsilje T, Pathan N, Michellys P-Y, Bender S, Harris J. Abstract 1734: in vitro characterization of EGF816, a third-generation mutant-selective EGFR inhibitor. Cancer Res. 2014;74(19 Supplement):1734.CrossRef
30.
Kasibhatla S, Li J, Tompkins C, Vaillancourt M-T, Anderson J, Pferdekamper AC, Li C, Long O, McNeill M, Epple R, Liao D, Murphy E, Bender S, Jia Y, Lelais G. Abstract 1733: EGF816, a novel covalent inhibitor of mutant-selective epidermal growth factor receptor, overcomes T790M-mediated resistance in NSCLC. Cancer Res. 2014;74(19 Supplement):1733.CrossRef
31.
Lelais G, Epple R, Michellys P-Y, Marsilje TH, Long Y, McNeill M, Chen B, Lu W, Bursulaya B, DiDonato M, Jia Y, Kasibhatla S, Li C, Matushansky I, Bender S. Abstract 2585: discovery of a potent covalent mutant-selective EGFR inhibitor—the journey from high throughput screening to EGF816. Cancer Res. 2015;75(15 Supplement):2585.CrossRef
32.
Tan DS-W, Seto T, Leighl NB, Riely GJ, Sequist LV, Felip E, Wolf J, Yang JC-H, Matushansky I, Yu X, Schmitz S-FH, Cui X, Kim D-W. 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. ASCO Meet Abstr. 2015;33(15_suppl):8013.
33.
Niederst MJ, Hu H, Mulvey HE, Lockerman EL, Garcia AR, Piotrowska Z, Sequist LV, Engelman JA. The allelic context of the C797S mutation acquired upon treatment with third-generation EGFR inhibitors impacts sensitivity to subsequent treatment strategies. Clin Cancer Res. 2015;21(17):3924–33.CrossRefPubMed
34.
Song HN, Jung KS, Yoo KH, Cho J, Lee JY, Lim SH, Kim HS, Sun JM, Lee SH, Ahn JS, Park K, Choi YL, Park W, Ahn MJ. Acquired C797S mutation upon treatment with a T790M-specific third-generation EGFR inhibitor (HM61713) in non-small cell lung cancer. J Thorac Oncol. 2016. doi:10.​1016/​j.​jtho.​2015.​1012.​1093.
35.
Thress KS, Paweletz CP, Felip E, Cho BC, Stetson D, Dougherty B, Lai Z, Markovets A, Vivancos A, Kuang Y, Ercan D, Matthews SE, Cantarini M, Barrett JC, Janne PA, Oxnard GR. Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M. Nat Med. 2015;21(6):560–2.CrossRefPubMedPubMedCentral
36.
Yu HA, Tian SK, Drilon AE, Borsu L, Riely GJ, Arcila ME, Ladanyi M. Acquired resistance of EGFR-mutant lung cancer to a T790M-specific EGFR inhibitor: emergence of a third mutation (C797S) in the EGFR tyrosine kinase domain. JAMA Oncol. 2015;1(7):982–4.CrossRefPubMedPubMedCentral
37.
Costa DB, Kobayashi SS. Whacking a mole-cule: clinical activity and mechanisms of resistance to third generation EGFR inhibitors in EGFR mutated lung cancers with EGFR-T790M. Transl Lung Cancer Res. 2015;4(6):809–15.PubMedPubMedCentral
38.
Sequist LV, von Pawel J, Garmey EG, Akerley WL, Brugger W, Ferrari D, Chen Y, Costa DB, Gerber DE, Orlov S, Ramlau R, Arthur S, Gorbachevsky I, Schwartz B, Schiller JH. Randomized phase II study of erlotinib plus tivantinib versus erlotinib plus placebo in previously treated non-small-cell lung cancer. J Clin Oncol. 2011;29(24):3307–15.CrossRefPubMed
39.
Shaw AT. Combining inhibitors of ALK and ROS1 with other agents for the treatment of non-small cell lung cancer. Clin Adv Hematol Oncol. 2015;13(5):282–4.PubMed
40.
Shaw AT, Gandhi L, Gadgeel S, Riely GJ, Cetnar J, West H, Camidge DR, Socinski MA, Chiappori A, Mekhail T, Chao BH, Borghaei H, Gold KA, Zeaiter A, Bordogna W, Balas B, Puig O, Henschel V, Ou SI, study i. Alectinib in ALK-positive, crizotinib-resistant, non-small-cell lung cancer: a single-group, multicentre, phase 2 trial. Lancet Oncol. 2015;17(2):234–42.CrossRefPubMed
41.
42.
Shaw AT, Kim DW, Mehra R, Tan DS, Felip E, Chow LQ, Camidge DR, Vansteenkiste J, Sharma S, De Pas T, Riely GJ, Solomon BJ, Wolf J, Thomas M, Schuler M, Liu G, Santoro A, Lau YY, Goldwasser M, Boral AL, Engelman JA. Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J Med. 2014;370(13):1189–97.CrossRefPubMedPubMedCentral
43.
Iragavarapu C, Mustafa M, Akinleye A, Furqan M, Mittal V, Cang S, Liu D. Novel ALK inhibitors in clinical use and development. J Hematol Oncol. 2015;8(1):17.CrossRefPubMedPubMedCentral
44.
Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, Chow LQ, Vokes EE, Felip E, Holgado E, Barlesi F, Kohlhäufl M, Arrieta O, Burgio MA, Fayette J, Lena H, Poddubskaya E, Gerber DE, Gettinger SN, Rudin CM, Rizvi N, Crinò L, Blumenschein GRJ, Antonia SJ, Dorange C, Harbison CT, Graf Finckenstein F, Brahmer JR. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015;373(17):1627–39.CrossRefPubMed
45.
Brahmer J, Reckamp KL, Baas P, Crinò L, Eberhardt WEE, Poddubskaya E, Antonia S, Pluzanski A, Vokes EE, Holgado E, Waterhouse D, Ready N, Gainor J, Arén Frontera O, Havel L, Steins M, Garassino MC, Aerts JG, Domine M, Paz-Ares L, Reck M, Baudelet C, Harbison CT, Lestini B, Spigel DR. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 2015;373(2):123–35.CrossRefPubMed
46.
Davar D, Socinski MA, Dacic S, Burns TF. Near complete response after single dose of nivolumab in patient with advanced heavily pre-treated KRAS mutant pulmonary adenocarcinoma. Exp Hematol Oncol. 2015;4(1):34.CrossRefPubMedPubMedCentral
Metadata
Title
Third-generation inhibitors targeting EGFR T790M mutation in advanced non-small cell lung cancer
Publication date
01-12-2016
Published in
Journal of Hematology & Oncology / Issue 1/2016
Electronic ISSN: 1756-8722
DOI
https://doi.org/10.1186/s13045-016-0268-z

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