First- and Second-Generation EGFR-TKIs Are All Replaced to Osimertinib in Chemo-Naive EGFR Mutation-Positive Non-Small Cell Lung Cancer?

Masayuki Takeda, Kazuhiko Nakagawa, Masayuki Takeda, Kazuhiko Nakagawa

Abstract

Activating mutations of the epidermal growth factor receptor gene (EGFR) are a driving force for some lung adenocarcinomas. Several randomized phase III studies have revealed that treatment with first- or second-generation EGFR tyrosine kinase inhibitors (TKIs) results in an improved progression-free survival (PFS) compared to standard chemotherapy in chemonaive patients with advanced non⁻small cell lung cancer (NSCLC), selected based on the presence of EGFR mutations. Patients treated with second-generation EGFR-TKIs have also shown an improved PFS relative to those treated with first-generation EGRF-TKIs. Osimertinib is a third-generation EGFR-TKI that still irreversibly inhibits the activity of EGFR after it has acquired the secondary T790M mutation that confers resistance to first- and second-generation drugs. Its efficacy has been validated for patients whose tumors have developed T790M-mediated resistance, as well as for first-line treatment of those patients with EGFR mutation⁻positive NSCLC. Although there are five EGFR-TKIs (gefitinib, erlotinib, afatinib, dacomitinib, and osimertinib) currently available for the treatment of EGFR-mutated lung cancer, the optimal sequence for administration of these drugs remains to be determined. In this review, we addressed this issue with regard to maximizing the duration of the EGFR-TKI treatment.

Keywords: drug resistance; epidermal growth factor receptor (EGFR); mutation; non–small cell lung cancer (NSCLC); tyrosine kinase inhibitor (TKI).

Conflict of interest statement

K.N. has received honoraria from Astra Zeneca, Chugai, Boehringer Ingelheim, Eli Lilly, and Pfizer. The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Current and potential ideal sequential treatment regimens with EGFR-TKIs in patients with advanced NSCLC harboring EGFR mutations. Median PFS values are indicated.

References

    1. Lynch T.J., Bell D.W., Sordella R., Gurubhagavatula S., Okimoto R.A., Brannigan B.W., Harris P.L., Haserlat S.M., Supko J.G., Haluska F.G., 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;350:2129–2139. doi: 10.1056/NEJMoa040938.
    1. Paez J.G., Janne P.A., Lee J.C., Tracy S., Greulich H., Gabriel S., Herman P., Kaye F.J., Lindeman N., Boggon T.J., et al. EGFR mutations in lung cancer: Correlation with clinical response to gefitinib therapy. Science. 2004;304:1497–1500. doi: 10.1126/science.1099314.
    1. Soda M., Choi Y.L., Enomoto M., Takada S., Yamashita Y., Ishikawa S., Fujiwara S., Watanabe H., Kurashina K., Hatanaka H., et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature. 2007;448:561–566. doi: 10.1038/nature05945.
    1. Maemondo M., Inoue A., Kobayashi K., Sugawara S., Oizumi S., Isobe H., Gemma A., Harada M., Yoshizawa H., Kinoshita I., et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N. Engl. J. Med. 2010;362:2380–2388. doi: 10.1056/NEJMoa0909530.
    1. Mitsudomi T., Morita S., Yatabe Y., Negoro S., Okamoto I., Tsurutani J., Seto T., Satouchi M., Tada H., Hirashima T., 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;11:121–128. doi: 10.1016/S1470-2045(09)70364-X.
    1. Zhou C., Wu Y.L., Chen G., Feng J., Liu X.Q., Wang C., Zhang S., Wang J., Zhou S., Ren S., 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;12:735–742. doi: 10.1016/S1470-2045(11)70184-X.
    1. Rosell R., Carcereny E., Gervais R., Vergnenegre A., Massuti B., Felip E., Palmero R., Garcia-Gomez R., Pallares C., Sanchez J.M., 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;13:239–246. doi: 10.1016/S1470-2045(11)70393-X.
    1. Sequist L.V., Yang J.C., Yamamoto N., O’Byrne K., Hirsh V., Mok T., Geater S.L., Orlov S., Tsai C.M., Boyer M., et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J. Clin. Oncol. 2013;31:3327–3334. doi: 10.1200/JCO.2012.44.2806.
    1. Wu Y.L., Zhou C., Hu C.P., Feng J., Lu S., Huang Y., Li W., Hou M., Shi J.H., Lee K.Y., 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. Lancet Oncol. 2014;15:213–222. doi: 10.1016/S1470-2045(13)70604-1.
    1. Park K., Tan E.H., O’Byrne K., Zhang L., Boyer M., Mok T., Hirsh V., Yang J.C., Lee K.H., Lu S., et al. Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): A phase 2B, open-label, randomised controlled trial. Lancet Oncol. 2016;17:577–589. doi: 10.1016/S1470-2045(16)30033-X.
    1. Wu Y.L., Cheng Y., Zhou X., Lee K.H., Nakagawa K., Niho S., Tsuji F., Linke R., Rosell R., Corral J., et al. Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): A randomised, open-label, phase 3 trial. Lancet Oncol. 2017;18:1454–1466. doi: 10.1016/S1470-2045(17)30608-3.
    1. Furuya N., Fukuhara T., Saito H., Watanabe K., Sugawara S., Iwasawa S., Tsunezuka Y., Yamaguchi O., Okada M., Yoshimori K., et al. Phase III study comparing bevacizumab plus erlotinib to erlotinib in patients with untreated NSCLC harboring activating EGFR mutations: NEJ026. ASCO Ann. Meet. Proc. 2018;27:9006. doi: 10.1200/JCO.2018.36.15_suppl.9006.
    1. Mok T.S., Wu Y.L., Ahn M.J., Garassino M.C., Kim H.R., Ramalingam S.S., Shepherd F.A., He Y., Akamatsu H., Theelen W.S., et al. Osimertinib or Platinum-Pemetrexed in EGFR T790M-Positive Lung Cancer. N. Engl. J. Med. 2017;376:629–640. doi: 10.1056/NEJMoa1612674.
    1. Soria J.C., Ohe Y., Vansteenkiste J., Reungwetwattana T., Chewaskulyong B., Lee K.H., Dechaphunkul A., Imamura F., Nogami N., Kurata T., et al. Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. N. Engl. J. Med. 2018;378:113–125. doi: 10.1056/NEJMoa1713137.
    1. Sequist L.V., Waltman B.A., Dias-Santagata D., Digumarthy S., Turke A.B., Fidias P., Bergethon K., Shaw A.T., Gettinger S., Cosper A.K., 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.
    1. Ohashi K., Maruvka Y.E., Michor F., Pao W. Epidermal growth factor receptor tyrosine kinase inhibitor-resistant disease. J. Clin. Oncol. 2013;31:1070–1080. doi: 10.1200/JCO.2012.43.3912.
    1. Yano S., Yamada T., Takeuchi S., Tachibana K., Minami Y., Yatabe Y., Mitsudomi T., Tanaka H., Kimura T., Kudoh S., et al. Hepatocyte growth factor expression in EGFR mutant lung cancer with intrinsic and acquired resistance to tyrosine kinase inhibitors in a Japanese cohort. J. Thorac. Oncol. 2011;6:2011–2017. doi: 10.1097/JTO.0b013e31823ab0dd.
    1. Kobayashi S., Boggon T.J., Dayaram T., Janne P.A., Kocher O., Meyerson M., Johnson B.E., Eck M.J., Tenen D.G., Halmos B. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N. Engl. J. Med. 2005;352:786–792. doi: 10.1056/NEJMoa044238.
    1. Wu S.G., Liu Y.N., Tsai M.F., Chang Y.L., Yu C.J., Yang P.C., Yang J.C., Wen Y.F., Shih J.Y. The mechanism of acquired resistance to irreversible EGFR tyrosine kinase inhibitor-afatinib in lung adenocarcinoma patients. Oncotarget. 2016;7:12404–12413. doi: 10.18632/oncotarget.7189.
    1. Janne P.A., Yang J.C., Kim D.W., Planchard D., Ohe Y., Ramalingam S.S., Ahn M.J., Kim S.W., Su W.C., Horn L., et al. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N. Engl. J. Med. 2015;372:1689–1699. doi: 10.1056/NEJMoa1411817.
    1. Urata Y., Katakami N., Morita S., Kaji R., Yoshioka H., Seto T., Satouchi M., Iwamoto Y., Kanehara M., Fujimoto D., et al. Randomized Phase III Study Comparing Gefitinib with Erlotinib in Patients with Previously Treated Advanced Lung Adenocarcinoma: WJOG 5108L. J. Clin. Oncol. 2016;34:3248–3257. doi: 10.1200/JCO.2015.63.4154.
    1. Nelson V., Ziehr J., Agulnik M., Johnson M. Afatinib: Emerging next-generation tyrosine kinase inhibitor for NSCLC. Onco Targets Ther. 2013;6:135–143.
    1. Engelman J.A., Zejnullahu K., Gale C.M., Lifshits E., Gonzales A.J., Shimamura T., Zhao F., Vincent P.W., Naumov G.N., Bradner J.E., 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;67:11924–11932. doi: 10.1158/0008-5472.CAN-07-1885.
    1. Janne P.A., Ou S.H., Kim D.W., Oxnard G.R., Martins R., Kris M.G., Dunphy F., Nishio M., O’Connell J., Paweletz C., 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. Lancet Oncol. 2014;15:1433–1441. doi: 10.1016/S1470-2045(14)70461-9.
    1. Mok T.S., Cheng Y., Zhou X., Lee K.H., Nakagawa K., Niho S., Lee M., Linke R., Rosell R., Corral J., et al. Improvement in Overall Survival in a Randomized Study That Compared Dacomitinib With Gefitinib in Patients with Advanced Non-Small-Cell Lung Cancer and EGFR-Activating Mutations. J. Clin. Oncol. 2018;36:2244–2250. doi: 10.1200/JCO.2018.78.7994.
    1. Sandler A., Gray R., Perry M.C., Brahmer J., Schiller J.H., Dowlati A., Lilenbaum R., Johnson D.H. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N. Engl. J. Med. 2006;355:2542–2550. doi: 10.1056/NEJMoa061884.
    1. Takeda M., Yamanaka T., Seto T., Hayashi H., Azuma K., Okada M., Sugawara S., Daga H., Hirashima T., Yonesaka K., et al. Bevacizumab beyond disease progression after first-line treatment with bevacizumab plus chemotherapy in advanced nonsquamous non-small cell lung cancer (West Japan Oncology Group 5910L): An open-label, randomized, phase 2 trial. Cancer. 2016;122:1050–1059. doi: 10.1002/cncr.29893.
    1. Seto T., Kato T., Nishio M., Goto K., Atagi S., Hosomi Y., Yamamoto N., Hida T., Maemondo M., Nakagawa K., 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. Lancet Oncol. 2014;15:1236–1244. doi: 10.1016/S1470-2045(14)70381-X.
    1. Ichihara E., Hotta K., Nogami N., Kuyama S., Kishino D., Fujii M., Kozuki T., Tabata M., Harada D., Chikamori K., et al. Phase II trial of gefitinib in combination with bevacizumab as first-line therapy for advanced non-small cell lung cancer with activating EGFR gene mutations: The Okayama Lung Cancer Study Group Trial 1001. J. Thorac. Oncol. 2015;10:486–491. doi: 10.1097/JTO.0000000000000434.
    1. Reck M., Garon E.B., Paz-Ares L., Ponce S., Jaime J.C., Juan O., Nadal E., Kiura K., Widau R.C., He S., et al. Randomized, Double-Blind Phase Ib/III Study of Erlotinib With Ramucirumab or Placebo in Previously Untreated EGFR-Mutant Metastatic Non-Small-Cell Lung Cancer (RELAY): Phase Ib Results. Clin. Lung Cancer. 2018;19:213–220 e4. doi: 10.1016/j.cllc.2017.11.003.
    1. Ramalingam S.S., Yang J.C., Lee C.K., Kurata T., Kim D.W., John T., Nogami N., Ohe Y., Mann H., Rukazenkov Y., et al. Osimertinib As First-Line Treatment of EGFR Mutation-Positive Advanced Non-Small-Cell Lung Cancer. J. Clin. Oncol. 2018;36:841–849. doi: 10.1200/JCO.2017.74.7576.
    1. Ramalingam S.S., Cheng Y., Zhou C., Ohe Y., Imamura F., Cho B.C., Lin M., Majem M., Shah R., Rukazenkov Y., et al. Mechanisms of acquired resistance to first-line osimertinib: Preliminary data from the phase III FLAURA study; Proceedings of the ESMO 2018 Congress; Munich, Germany. 19–23 October 2018.
    1. Planchard D., Boyer M., Lee J.-S., Dechaphunkul A., Cheema P., Takahashi T., Todd A., McKeown A., Rukazenkov Y., Ohe Y. Osimertinib vs. standard of care (SoC) EGFR-TKI as first-line therapy in patients (pts) with untreated EGFRm advanced NSCLC: FLAURA post-progression outcomes. J. Thorac. Oncol. 2018;13:S72–S73. doi: 10.1016/S1556-0864(18)30402-7.
    1. Hochmair M.J., Morabito A., Hao D., Yang C.T., Soo R.A., Yang J.C., Gucalp R., Halmos B., Wang L., Golembesky A., et al. Sequential treatment with afatinib and osimertinib in patients with EGFR mutation-positive non-small-cell lung cancer: An observational study. Future Oncol. 2018;14:2861–2874. doi: 10.2217/fon-2018-0711.
    1. Offin M., Rizvi H., Tenet M., Ni A., Sanchez-Vega F., Li B.T., Drilon A., Kris M.G., Rudin C.M., Schultz N., et al. Tumor Mutation Burden and Efficacy of EGFR-Tyrosine Kinase Inhibitors in Patients with EGFR-Mutant Lung Cancers. Clin. Cancer Res. 2018 doi: 10.1158/1078-0432.CCR-18-1102.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe