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Is There a Survival Benefit of First-Line Epidermal Growth Factor Receptor Tyrosine-Kinase Inhibitor Monotherapy Versus Chemotherapy in Patients with Advanced Non-Small-Cell Lung Cancer?: A Meta-Analysis

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Abstract

Background

Tyrosine-kinase inhibitors (TKIs) markedly improve progression-free survival (PFS) of patients with advanced non-small-cell lung cancer (NSCLC) mutated for epidermal growth factor receptor (EGFR). Results on overall survival (OS) are less clear-cut. We performed a publication-based meta-analysis to address further this issue.

Methods

We did a PubMed query using keywords simultaneously (lung neoplasm, tyrosine kinase inhibitors, epidermal growth factor receptor mutation, survival, and randomized controlled trials). We also searched for relevant abstracts in annual proceedings of ASCO, ESMO, and WCLC meetings. We cross-checked all references from all eligible articles. Only phase III randomized controlled trials comparing TKI monotherapy and platinum-based doublet chemotherapy in first-line treatment of metastatic or advanced NSCLC were included. We used EasyMA software to perform statistical analyses. A random effect model was used in case of heterogeneity between studies (and a fixed effect model in absence of heterogeneity).

Results

The eight eligible studies included 2962 patients (780 males, 2182 females, mostly Asian, median age 60 years), 2909 adenocarcinomas (98 %), 1739 mutated tumors (897 exon 19 deletion, 699 L858 mutation), 448 stage IIIB, and 2222 stage IV (75 %) tumours and 2453 never smokers (83 %). Four studies assessed gefitinib, two studies assessed erlotinib, and two studies assessed afatinib. Chemotherapies were doublets including a platinum salt. All studies included patients with EGFR mutations, but six studies included only EGFR mutated patients. OS was similar among patients who first received TKI or chemotherapy (HR 0.98, 95 % CI 0.87-1.10, fixed effect model). Conversely, compared with chemotherapy, EGFR TKIs significantly improved PFS in patients with EGFR-mutated tumours (HR 0.37, 95 % CI 0.29-0.49, random effect model). Concerning side effects, rash (RR 6.29, 95 % CI 4.05-9.77), diarrhoea (RR 3.51, 95 % CI 2.15-5.75), stomatitis (RR 3.57, 95 % CI 1.81-7.04), and interstitial lung disease (RR 6.07, 95 % CI 1.66-22.2) were significantly more frequent after TKIs. As expected, fatigue (RR 0.38, 95 % CI 0.32-0.45), nausea/vomiting (RR 0.19, 95 % CI 0.11-0.32), and haematological disorders, including thrombocytopenia (RR 0.18, 95 % CI 0.09-0.35), anaemia (RR 0.22, 95 % CI 0.15-0.33), and grade 3-4 neutropenia (RR 0.06, 95 % CI 0.04-0.08), were significantly more frequent after chemotherapy.

Conclusion

The major discrepancy between a similar OS and a markedly improved PFS after first-line TKI compared with chemotherapy could be related to the high level of crossing-over between both groups.

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References

  1. Douillard JY, Shepherd FA, Hirsh V, Mok T et al (2010) Molecular predictors of outcome with gefitinib and docetaxel in previously treated non-small-cell lung cancer: data from the randomized phase III INTEREST trial. J Clin Oncol 28:744–52

    Article  CAS  PubMed  Google Scholar 

  2. Cappuzzo F, Ciuleanu T, Stelmakh L, Cicenas S et al (2010) Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomised, placebo-controlled phase 3 study. Lancet Oncol 11:521–9

    Article  CAS  PubMed  Google Scholar 

  3. Tsao MS, Sakurada A, Cutz JC, Zhu CQ et al (2005) Erlotinib in lung cancer - molecular and clinical predictors of outcome. N Engl J Med 353:133–44

    Article  CAS  PubMed  Google Scholar 

  4. Marchetti A, Felicioni L, Buttitta F (2006) Assessing EGFR mutations. N Engl J Med 354:526–8

    Article  CAS  PubMed  Google Scholar 

  5. Calvo E, Baselga J (2006) Ethnic differences in response to epidermal growth factor receptor tyrosine kinase inhibitors. J Clin Oncol 24:2158–63

    Article  CAS  PubMed  Google Scholar 

  6. Rosell R, Carcereny E, Gervais R, Vergnenegre A et al (2012) 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 13:239–46

    Article  CAS  PubMed  Google Scholar 

  7. Lee JS, Park K, Kim SW A randomized phase III study of gefitinib versus standard chemotherapy (gemcitabin plus cisplatin) as a first-line treatment for neversmokers with advanced or metastatic adenocarcinoma of the lung. 13th World Conference on Lung Cancer 2009; abstr PRS.4

  8. Zhou C, Wu Y, Chen G, Feng J et al (2011) 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 12:735–42

    Article  CAS  PubMed  Google Scholar 

  9. Mitsudomi T, Morita S, Yatabe Y, Negoro S et al (2010) 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 11:121–8

    Article  CAS  PubMed  Google Scholar 

  10. Maemondo M, Inoue A, Kobayashi K, Sugawara S et al (2010) Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med 362:2380–8

    Article  CAS  PubMed  Google Scholar 

  11. Mok TS, Wu Y, Thongprasert S, Yang C et al (2009) Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 361:947–57

    Article  CAS  PubMed  Google Scholar 

  12. Han JY, Park K, Kim SW, Lee DH et al (2012) First-SIGNAL: firstline single-agent iressa versus gemcitabine and cisplatin trial in never-smokers with adenocarcinoma of the lung. J Clin Oncol 30:1122–8

    Article  CAS  PubMed  Google Scholar 

  13. Inoue A, Kobayashi K, Maemondo M, Sugawara S et al (2013) Updated overall survival results from a randomized phase III trial comparing gefitinib with carboplatin-paclitaxel for chemo-naïve non-small cell lung cancer with sensitive EGFR gene mutations (NEJ002). Ann Oncol 24:54–9

    Article  CAS  PubMed  Google Scholar 

  14. Fukuoka M, Wu YL, Thongprasert S, Sunpaweravong P et al (2011) Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS). J Clin Oncol 21:2866–74

    Article  Google Scholar 

  15. Zhou C, Wu YL, Liu X, Wang C, et al Overall survival (OS) results from OPTIMAL (CTONG0802), a phase III trial of erlotinib (E) versus carboplatin plus gemcitabine (GC) as first-line treatment for Chinese patients with EGFR mutation-positive advanced non-small cell lung cancer (NSCLC). ASCO MEETING ABSTRACTS May 30, 2012:7520

  16. Sequist LV, Yang JC, Yamamoto N, O’Byrne K et al (2013) Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol 31:3327–34

    Article  CAS  PubMed  Google Scholar 

  17. Wu YL, Zhou C, Hu CP, Feng JF, et al LUX-Lung 6: a randomized, open-label, Phase III study of afatinib (A) vs gemcitabine/cisplatin (GC) as first-line treatment for Asian patients (pts) with EGFR mutation-positive (EGFR M+) advanced adenocarcinoma of the lung. ASCO Annual Meeting 2013. Abstract 8016

  18. Yang JC, Wu YL, Schuler M, Sebastian M et al (2015) 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 16:141–51

    Article  CAS  PubMed  Google Scholar 

  19. Yoshioka H, Mitsudomi T, Morita S, Yatabe Y et al (2014) Final overall survival results of WJTOG 3405, a randomized phase 3 trial comparing gefitinib (G) with cisplatin plus docetaxel (CD) as the first-line treatment for patients with non-small cell lung cancer (NSCLC) harboring mutations of the epidermal growth factor receptor (EGFR). Proc Am Soc Clin Oncol 32(suppl):8117, abstr

    Google Scholar 

  20. Zhou C, Wu YL, Liu X, Wang C et al (2012) Overall survival (OS) results from OPTIMAL (CTONG0802), a phase III trial of erlotinib (E) versus carboplatin plus gemcitabine (GC) as fi rst-line treatment for Chinese patients with EGFR mutation-positive advanced non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 30(suppl):7520, abstr

    Google Scholar 

  21. Leon LF, Golsorkhi A, Liu S, Drozdowskyj A, et al Overall survival analyses of first-line erlotinib versus chemotherapy in the EURTAC study population controlling for the use of post-study therapy. ESMO 2014; 1273(P)

  22. Lee CK, Brown C, Gralla RJ, Hirsh V et al (2013) Impact of EGFR inhibitor in non-small cell lung cancer on progression-free and overall survival: a meta-analysis. J Natl Cancer Inst 105:595–605

    Article  CAS  PubMed  Google Scholar 

  23. Gao G, Ren S, Li A, Xu J et al (2012) Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR TKI) therapy is effective as first-line treatment of advanced non-small-cell lung cancer with mutated EGFR: A meta-analysis from 6 phase III randomized controlled trials. Int J Cancer 131:822–9

    Article  Google Scholar 

  24. Popat S, Mok T, Yang JC, Wu YL et al (2014) Afatinib in the treatment of EGFR mutation-positive NSCLC–a network meta-analysis. Lung Cancer 85:230–8

    Article  PubMed  Google Scholar 

  25. Haaland B, Tan PS, de Castro G, Jr LG (2014) Meta-analysis of first-line therapies in advanced non-small-cell lung cancer harboring EGFR-activating mutations. J Thorac Oncol 9:805–11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Rosell R, Perez-Roca L, Sanchez JJ, Cobo M et al (2009) Customized treatment in non-small-cell lung cancer based on EGFR mutations and BRCA1 mRNA expression. PLoS One 4:5133

    Article  Google Scholar 

  27. Sharma SV, Bell DW, Settleman J, Haber DA (2007) Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer 7:169–81

    Article  CAS  PubMed  Google Scholar 

  28. Kancha RK, von Bubnoff N, Peschel C, Duyster J (2009) Functional analysis of epidermal growth factor receptor (EGFR) mutations and potential implications for EGFR targeted therapy. Clin Cancer Res 15:460–7

    Article  CAS  PubMed  Google Scholar 

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Conflict of Interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Oncology, Avicenne Hospital, HUPSSD, AP-HP, 125 route de Stalingrad, 93009, Bobigny, France

    Gaetan Des Guetz, Kader Chouahnia & Jean-François Morere

  2. Unité de Coordination en Onco-Gériatrie (UCOG), HUPSSD, AP-HP, Sevran, France

    Thierry Landre

  3. Department of Pharmacology, Avicenne Hospital, HUPSSD, AP-HP, Bobigny, France

    Bernard Uzzan & Patrick Nicolas

  4. Department of Geriatric Oncology, René Muret hospital, HUPSSD, AP-HP, Avenue du Dr Schaeffner, 93270, Sevran, France

    Thierry Landre

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  1. Gaetan Des Guetz
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Correspondence to Thierry Landre.

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Guetz, G.D., Landre, T., Uzzan, B. et al. Is There a Survival Benefit of First-Line Epidermal Growth Factor Receptor Tyrosine-Kinase Inhibitor Monotherapy Versus Chemotherapy in Patients with Advanced Non-Small-Cell Lung Cancer?: A Meta-Analysis. Targ Oncol 11, 41–47 (2016). https://doi.org/10.1007/s11523-015-0373-x

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  • DOI: https://doi.org/10.1007/s11523-015-0373-x

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