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A meta-analysis of the comparing of the first-generation and next-generation TKIs in the treatment of NSCLC

1 Department of Respiration, Shaoxing Municipal Hospital, Affiliated Hospital of Shaoxing University, Shaoxing 312000, Zhejiang, China
2 Department of Oncology, The First Hospital of Jiaxing, First Affiliated Hospital of Jiaxing University, Jiaxing 314000, Zhejiang, China
3 Department of Respiration, The First Hospital of Jiaxing, First Affiliated Hospital of Jiaxing University, Jiaxing 314000, Zhejiang, China
4 Division of Science and Education, The First Hospital of Jiaxing, First Affiliated Hospital of Jiaxing University, Jiaxing 314000, Zhejiang, China

Special Issues: Advanced Big Data Analysis for Precision Medicine

Background: The current standard approach to the treatment of patients with non–small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI)—sensitizing mutations has been the treatment with a first-generation EGFR-TKIs. While, with resistance developed against first-generation EGFR-TKIs, second/third-generation TKIs have attracted all the attention, and replaced first-generation EGFR- TKIs upon disease progression due to the greater efficacy and more favorable tolerability. In the past few years, this strategy has been challenged by clinical evidence when next-generation EGFR-TKIs are used in patients with advanced NSCLC. Objective: In this study, we performed a meta- analysis to investigate the efficacy of next-generation TKIs comparison with first-generation TKIs in the treatment of NSCLC. Methods: The multiple databases including Pubmed, Embase, Cochrane library databases were adopted to search for the relevant studies, and full-text articles involving to comparison of next-generation TKIs and first-generation TKIs were reviewed. After rigorous reviewing on quality, the data was extracted from eligible randomized controlled trial (RCT). Meta-analysis Revman 5.3 software was used to analyze the combined pooled ORs with the corresponding 95% confidence interval using fixed- or random-effects models according to the heterogeneity. Results: A total of 5 randomized controlled trials were included in this analysis. The group of next-generation TKIs did achieved benefit in progression-free survival (PFS) (OR = 0.58, 95%CI = 0.45–0.75, P<0.0001), overall survival (OS) (OR = 0.76, 95%CI = 0.65–0.90, P = 0.001) as well with the objective response rate (ORR) (OR = 1.27, 95%CI = 1.01–1.61, P = 0.04), respectively. In the results of subgroup analysis of PFS with EGFR mutations, there is also significant differences with exon 19 deletion (OR = 0.56, 95%CI = 0.41–0.77, P = 0.0003) and exon 21 (L858R) mutation (OR = 0.60, 95%CI = 0.49–0.75, P<=0.00001). While, the treatment-related severe adverse event (SAE) between the next-generation TKIs and first-generation TKIs did not have statistical significance (OR = 1.48, 95%CI = 0.62–3.55, P = 0.38). Conclusion: The next-generation TKIs significantly improved efficacy outcomes in the treatment of EGFR mutation–positive advanced NSCLC compared with the first-generation TKIs, with a manageable safety profile. These results are potentially important for clinical decision making for these patients.
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1. T. J. Lynch, D. W. Bell, R. Sordella, et al., Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib, N. Engl. J. Med., 350 (2004), 2129–2139.

2. Y. L. Wu, W. Z. Zhong, L. Y. Li, et al., Epidermal growth factor receptor mutations and their correlation with gefitinib therapy in patients with non-small cell lung cancer: a meta-analysis based on updated individual patient data from six medical centers in mainland China, J. Thorac. Oncol., 2 (2007), 430–439.

3. R. Rosell, E. Carcereny, R. Gervais, 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., 13 (2012), 239–246.

4. T. S. Mok, Y. L. Wu, S. Thongprasert, et al., Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma, N. Engl. J. Med., 361 (2009), 947–957.

5. L. V. Sequist, J. C. Yang, N. Yamamoto, et al., Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations, J. Clin. Oncol., 31 (2013), 3327–3334.

6. G. Recondo, F. Facchinetti, K. A. Olaussen, et al., Making the first move in EGFR-driven or ALK-driven NSCLC: first-generation or next-generation TKI?, Nat. Rev. Clin. Oncol., 15 (2018), 694–708.

7. K. Park, E. H. Tan, K. O'Byrne, 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., 17 (2016), 577–589.

8. L. Paz-Ares, E. H. Tan, K. O'Byrne, et al., Afatinib versus gefitinib in patients with EGFR mutation-positive advanced non-small-cell lung cancer: overall survival data from the phase IIb LUX-Lung 7 trial, Ann. Oncol., 28 (2017), 270–277.

9. A. R. Jadad, R. A. Moore, D. Carroll, et al., Assessing the quality of reports of randomized clinical trials: is blinding necessary?, Control. Clin. Trials, 17 (1996), 1–12.

10. J. P. Higgins and S. G. Thompson, Quantifying heterogeneity in a meta-analysis, Stat. Med., 21 (2002), 1539–1558.

11. J. P. Higgins, S. G. Thompson, J. J. Deeks, et al., Measuring inconsistency in meta-analyses, BMJ, 327 (2003), 557–560.

12. J. C. Soria, Y. Ohe, J. Vansteenkiste, et al., Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer, N. Engl. J. Med., 378 (2018), 113–125.

13. T. S. Mok, Y. Cheng, X. Zhou, 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., 36 (2018), 2244–2250.

14. Y. L. Wu, Y. Cheng, X. Zhou, 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., 18 (2017), 1454–1466.

15. S. Novello, F. Barlesi, R. Califano, et al., Metastatic non-small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up, Ann. Oncol., 27 (2016), v1–v27.

16. H. A. Yu, M. E. Arcila, N. Rekhtman, 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 (2013), 2240–2247.

17. S. N. Kazaz and I. Oztop, Treatment after first-generation epidermal growth factor receptor tyrosine kinase inhibitor resistance in non-small-cell lung cancer, Turk. Thorac. J., 18 (2017), 66–71.

18. L. V. Sequist, B. A. Waltman, D. Dias-Santagata, et al., Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors, Sci. Transl. Med., 3 (2011), 75ra26.

19. C. H. Yun, K. E. Mengwasser, A. V. Toms, et al., The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP, Proc. Natl. Acad. Sci. USA, 105 (2008), 2070–2075.

20. A. Michalczyk, S. Kluter, H. B. Rode, et al., Structural insights into how irreversible inhibitors can overcome drug resistance in EGFR, Bioorg. Med. Chem., 16 (2008), 3482–3488.

21. M. L. Sos, H. B. Rode, S. Heynck, et al., Chemogenomic profiling provides insights into the limited activity of irreversible EGFR Inhibitors in tumor cells expressing the T790M EGFR resistance mutation, Cancer Res., 70 (2010), 868–874.

22. D. Li, L. Ambrogio, T. Shimamura, et al., BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models, Oncogene, 27 (2008), 4702–4711.

23. F. Solca, G. Dahl, A. Zoephel, et al., Target binding properties and cellular activity of afatinib (BIBW 2992), an irreversible ErbB family blocker, J. Pharmacol. Exp. Ther., 343 (2012), 342–350.

24. D. A. Cross, S. E. Ashton, S. Ghiorghiu, et al., AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer, Cancer Discov., 4 (2014), 1046–1061.

25. Y. L. Wu, M. J. Ahn, M. C. Garassino, et al., CNS efficacy of osimertinib in patients with t790m-positive advanced non-small-cell lung cancer: data from a randomized phase III trial (AURA3), J. Clin. Oncol., 36 (2018), 2702–2709.

26. O. Romanidou, L. Landi, F. Cappuzzo, et al., Overcoming resistance to first/second generation epidermal growth factor receptor tyrosine kinase inhibitors and ALK inhibitors in oncogene-addicted advanced non-small cell lung cancer, Ther. Adv. Med. Oncol., 8 (2016), 176–187.

27. C. Zhou and L. D. Yao, Strategies to Improve Outcomes of Patients with EGRF-Mutant Non-Small Cell Lung Cancer: Review of the Literature, J. Thorac. Oncol., 11 (2016), 174–186.

28. H. Shigematsu, L. Lin, T. Takahashi, et al., Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers, J. Natl. Cancer Inst., 97 (2005), 339–346.

29. C. K. Lee, Y. L. Wu, P. N. Ding, et al., 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., 33 (2015), 1958–1965.

© 2019 the Author(s), licensee AIMS Press. This is an open access article distributed under the terms of the Creative Commons Attribution Licese (http://creativecommons.org/licenses/by/4.0)

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