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Meta-analysis of Seven Randomized Control Trials to Assess the Efficacy and Toxicity of Combining EGFR-TKI with Chemotherapy for Patients with Advanced NSCLC who Failed First-Line Treatment

  • Xiao, Bing-Kun (Department of Pharmacochemistry, Institute of Radiation Medicine) ;
  • Yang, Jian-Yun (Department of Pharmacochemistry, Institute of Radiation Medicine) ;
  • Dong, Jun-Xing (Department of Pharmacochemistry, Institute of Radiation Medicine) ;
  • Ji, Zhao-Shuai (Department of Pharmacy, Beijing Tsinghua Changgung Hospital) ;
  • Si, Hai-Yan (Department of Oncology, Chinese PLA General Hospital) ;
  • Wang, Wei-Lan (Department of Pharmaceutical Care, Chinese PLA General Hospital) ;
  • Huang, Rong-Qing (Department of Pharmacochemistry, Institute of Radiation Medicine)
  • 발행 : 2015.04.14

초록

Background: Some recent clinical trials have been conducted to evaluate a combination of EGFR- TKI with chemotherapy for advanced NSCLC patients as second-line therapy, but the results on the efficacy of such trials are inconsistent. The aim of this meta-analysis was to evaluate the efficacy and safety of combination of EGFR-TKI and chemotherapy for patients with advanced NSCLC who failed first-line treatment. Materials and Methods: We searched relative trials from PubMed, EMBASE, ASCO Abstracts, ESMO Abstracts, Cochrane Library and Clinical Trials.gov. Outcomes analyzed were overall response rate (ORR), progression- free survival (PFS), overall survival (OS) and major toxicity. Results: Seven trails eventually were included in this meta-analysis, covering 1,168 patients. The results showed that the combined regimen arm had a significant higher ORR (RR 1.76 [1.16, 2.66], p=0.007) and longer PFS (HR 0.75 [0.66-0.85], p<0.00001), but failed to show effects on OS (HR 0.88 [0.68-1.15], p=0.36). In terms of subgroup results, continuation of EGFR-TKI in addition to chemotherapy after first-line EGFR-TKI resistance confered no improvement in ORR (RR 0.95 [0.68, 1.33], p=0.75) and PFS (HR 0.89[0.69, 1.15], p=0.38), and OS was even shorter (HR1.52 [1.05-2.21], p=0.03). However, combination therapy with EGFR-TKI and chemotherapy after failure of first-line chemotherapy significantly improved the ORR (RR 2.06 [1.42, 2.99], p=0.0002), PFS (HR 0.71 [0.61, 0.82], p<0.00001) and OS (HR 0.74 [0.62-0.88], p=0.0008), clinical benefit being restricted to combining EGFR-TKI with pemetrexed, but not docetaxel. Grade 3-4 toxicity was found at significantly higher incidence in the combined regimen arm. Conclusions: Continuation of EGFR-TKI in addition to chemotherapy after first-line EGFR-TKI resistance should be avoided. Combination therapy of EGFR-TKI and pemetrexed for advanced NSCLC should be further investigated for prognostic and predictive factors to find the group with the highest benefit of the combination strategy.

키워드

참고문헌

  1. Aerts JG, Codrington H, Lankheet NA, et al (2013). A randomized phase II study comparing erlotinib versus erlotinib with alternating chemotherapy in relapsed non-small-cell lung cancer patients: the NVALT-10 study. Ann Oncol, 24, 2860-5. https://doi.org/10.1093/annonc/mdt341
  2. Auliac JB, Chouaid C, Greiller L, et al (2014). Randomized open-label non-comparative multicenter phase II trial of sequential erlotinib and docetaxel versus docetaxel alone in patients with non-small-cell lung cancer after failure of first-line chemotherapy: GFPC 10.02 study. Lung Cancer, 85, 415-19. https://doi.org/10.1016/j.lungcan.2014.07.006
  3. Aydiner A, Yildiz I, Seyidova A (2013). Clinical outcomes and prognostic factors associated with the response to erlotinib in non-small cell lung cancer patients with unknown EGFR mutational status. Asian Pac J Cancer Prev, 14, 3255-61. https://doi.org/10.7314/APJCP.2013.14.5.3255
  4. Dahabreh IJ, Linardou H, Siannis F, et al (2010).Somatic EGFR mutation and gene copy gain as predictive biomarkers for response to tyrosine kinase inhibitors in non-small cell lung cancer. Clin Cancer Res, 16, 291-303. https://doi.org/10.1158/1078-0432.CCR-09-1660
  5. Di Maio M, Chiodini P, Georgoulias V, et al (2009). Metaanalysis of single-agent chemotherapy compared with combination chemotherapy as second-line treatment of advanced non-small cell lung cancer. J Clin Oncol, 27, 1836-43. https://doi.org/10.1200/JCO.2008.17.5844
  6. Dittrich C, Papai-Szekely Z, Vinolas N, et al (2014).A randomized phase II study of pemetrexed versus pemetrexed+erlotinib as second-line treatment for locally advanced or metastatic non-squamous non-small cell lung cancer. Eur J Cancer, 50, 1571-80. https://doi.org/10.1016/j.ejca.2014.03.007
  7. Gandara DR, Mack PC, Li T, Lara PN Jr, Herbst RS (2009). Evolving treatment algorithms for advanced non-small-cell lung cancer: 2009 looking towards 2012. Clin Lung Cancer, 10, 392-4. https://doi.org/10.3816/CLC.2009.n.074
  8. Giovannetti E, Lemos C, Tekle C, et al (2008). Molecular mechanisms underlying the synergistic interaction of erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor, with the multitargeted antifolate pemetrexed in non-small-cell lung cancer cells. Mol Pharmacol, 73, 1290-300. https://doi.org/10.1124/mol.107.042382
  9. Goldberg SB, Oxnard GR, Digumarthy S, et al (2013). Chemotherapy with erlotinib or chemotherapy alone in advanced non-small cell lung cancer with acquired resistance to EGFR tyrosine kinase inhibitors. Oncologist, 18, 1214-20. https://doi.org/10.1634/theoncologist.2013-0168
  10. Halmos B, Pennell NA, Otterson GA, et al (2013). Erlotinib beyond progression study: Randomized phase II study comparing chemotherapy plus erlotinib with chemotherapy alone in EGFR TKI-responsive, advanced non-small cell lung cancer (NSCLC) that subsequently progresses. J Clin Oncol, 31, (suppl; abstr 8114).
  11. Hanna N, Shepherd F, Fossella F, et al (2004). Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol, 22, 1589-97. https://doi.org/10.1200/JCO.2004.08.163
  12. Herbst RS, Giaccone G, Schiller JH, et al (2004). Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial-INTACT 2. J Clin Oncol, 22, 785-94. https://doi.org/10.1200/JCO.2004.07.215
  13. Herbst RS, Prager D, Hermann R, et al (2005). TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol, 23, 5892-9. https://doi.org/10.1200/JCO.2005.02.840
  14. Higgins JP, Thompson SG, Deeks JJ, et al (2003). Measuring inconsistency in meta-analyses. BJM, 327, 557-60. https://doi.org/10.1136/bmj.327.7414.557
  15. Hirsch FR, Kabbinavar F, Eisen T, et al (2011). A randomized, phase II, biomarker-selected study comparing erlotinib to erlotinib intercalated with chemotherapy in first-line therapy for advanced non-small-cell lung cancer. J Clin Oncol, 29, 3567-73. https://doi.org/10.1200/JCO.2010.34.4929
  16. Jadad AR, Moore RA, Carroll D, et al (1996). Assessing the quality of reports of randomized clinical trials: Is blinding necessary? Control Clin Trials, 17, 1-12. https://doi.org/10.1016/0197-2456(95)00134-4
  17. Janne PA, Wang X, Socinski MA, et al (2012). Randomized phase II trial of erlotinib alone or with carboplatin and paclitaxel in patients who were never or light former smokers with advanced lung adenocarcinoma: CALGB 30406 trial. J Clin Oncol, 30, 2063-9. https://doi.org/10.1200/JCO.2011.40.1315
  18. Jemal A, Siegel R, Xu J, Ward E (2010). Cancer statistics, 2010. CA Cancer J Clin, 60, 277-300. https://doi.org/10.3322/caac.20073
  19. Kim ES, Hirsh V, Mok T, et al (2008). Gefitinib versus docetaxel in previously treated on-small-cell lung cancer (INTEREST): a randomized phase III trial. Lancet, 372, 809-18.
  20. Lee DH, Lee JS, Kim SW, et al (2013). Three-arm randomized controlled phase 2 study comparing pemetrexed and erlotinib to as second-line treatment for never-smokers with nonsquamous non-small cell lung cancer. Eur J Cancer, 49, 3111-21. https://doi.org/10.1016/j.ejca.2013.06.035
  21. Linardou H, Dahabreh IJ, Bafaloukos D, Kosmidis P, Murray S (2009). Somatic EGFR mutations and efficacy of tyrosine kinase inhibitors in NSCLC. Nat Rev Clin Oncol, 6, 352-66. https://doi.org/10.1038/nrclinonc.2009.62
  22. Li TH, Piperdi B, Walsh WV, et al (2013). Randomized phase II study of pharmacodynamic separation (PDS) of pemetrexed (Pem) and erlotinib (Erl) versus pem alone in patients (pts) with advanced non-small cell lung cancer (NSCLC). J Clin Oncol, 31, 8097.
  23. Mahaffey CM, Davies AM, Lara PN Jr, et al (2007). Scheduledependent apoptosis in K-ras mutant non-small-cell lung cancer cell lines treated with docetaxel and erlotinib: rationale for pharmacodynamic separation. Clin Lung Cancer, 8, 548-53. https://doi.org/10.3816/CLC.2007.n.041
  24. Massarelli E, Herbst RS (2006). Use of novel second-line targeted therapies in non-small cell lung cancer. Semin Oncol, 33, 9-16.
  25. Mok TS, Wu YL, Nakagawa K, et al (2014). Gefitinib/chemotherapy vs chemotherapy in epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC) after progression on first-line gefitinib: the Phase III, randomised IMPRESS study. Abstract #LBA2_PR presented at the European Society for Medical Oncology (ESMO) 2014 Congress. Available: http://www.esmo.org. Accessed 26-30 September 2014.
  26. OuYang PY, Su Z, Mao YP, Deng W, Xie FY (2013). Combination of EGFR-TKIs and chemotherapy as first-line therapy for advanced NSCLC: a meta-analysis. PLoS One, 13, 79000.
  27. Remon J, Morán T, Majem M, et al (2014). Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in EGFR-mutant non-small cell lung cancer: a new era begins. Cancer Treat Rev, 40, 93-101. https://doi.org/10.1016/j.ctrv.2013.06.002
  28. Schiller JH, Harrington D, Belani CP, et al (2002). Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med, 346, 92-8. https://doi.org/10.1056/NEJMoa011954
  29. Shepherd FA, Dancey J, Ramlau R, et al (2000). Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol, 18, 2095-103.
  30. Song T, Yu W, Wu SX (2014). Subsequent treatment choices with acquired resistance to EGFR-TKIs in non-small cell lung cancer: restore after a drug holiday or switch to another EGFR-TKI? Asian Pac J Cancer Prev, 15, 205-13. https://doi.org/10.7314/APJCP.2014.15.1.205
  31. Stinchcombe TE, Socinski MA (2009). Current treatments for advanced stage non-small cell lung cancer. Proc Am Thorac Soc, 6, 233-41. https://doi.org/10.1513/pats.200809-110LC
  32. Takezawa K, Okamoto I, Tanizaki J, et al (2010). Enhanced anticancer effect of the combination of BIBW2992 and thymidylate synthase-targeted agents in non-small cell lung cancer with the T790M mutation of epidermal growth factor receptor. Mol Cancer Ther, 9, 1647-56. https://doi.org/10.1158/1535-7163.MCT-09-1009
  33. Tsai CM, Chen JT, Chiu CH, et al (2013). Combined epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor and chemotherapy in non-small-cell lung cancer: chemorefractoriness of cells harboringsensitizing-EGFR mutations in the presence of gefitinib. Lung Cancer, 82, 305-12. https://doi.org/10.1016/j.lungcan.2013.08.028
  34. Tsai CM, Chen JT, Stewart DJ, et al (2011). Antagonism between gefitinib and cisplatin in non-small cell lung cancer cells: why randomized trials failed? J Thorac Oncol, 6, 559-68. https://doi.org/10.1097/JTO.0b013e3182021ff5
  35. Tsai CM, Chiu CH, Chang KT, et al (2012). Gefitinib enhances cytotoxicities of antimicrotubule agents in non-small-cell lung cancer cells exhibiting no sensitizing epidermal growth factor receptor mutation. J Thorac Oncol, 7, 1218-27. https://doi.org/10.1097/JTO.0b013e318258cf17

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