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Efficacy and safety of third-line molecular-targeted therapy in metastatic renal cell carcinoma resistant to first-line vascular endothelial growth factor receptor tyrosine kinase inhibitor and second-line therapy

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Abstract

Background

The number of studies evaluating the efficacy and safety of third-line molecular-targeted therapy for metastatic renal cell carcinoma (mRCC) is limited.

Methods

The data for 48 patients with disease progression after first-line vascular endothelial growth factor receptor tyrosine kinase inhibitor (TKI) and second-line targeted therapy were evaluated. Patients with prior cytokine therapy were excluded. Overall survival (OS) after first- and second-line therapy initiation was compared between patients with and without third-line therapy. In addition, dose-limiting toxicities (DLTs) were evaluated.

Results

Twenty-two of 48 patients (45.8%) received third-line therapy, and TKI and mammalian target of rapamycin inhibitor were each administered in 11 patients (50%). Patients with third-line therapy had significantly longer median OS after first-line therapy (26.6 vs. 14.6 months, p = 0.0010) and second-line therapy (18.2 vs. 7.4 months, p < 0.0001) compared to those without third-line therapy. Multivariate analysis showed that the use of third-line therapy following second-line therapy was an independent prognosticator for longer OS (hazard ratio 0.29, 95% confidence interval 0.14–0.58, p = 0.0005). The median progression-free survival and OS after third-line therapy was 2.76 and 8.71 months, respectively. Although a high frequency of DLTs was observed (n = 10, 45.5%), the frequencies were similar among the sequential therapies.

Conclusions

Third-line therapy has a beneficial therapeutic effect in patients with mRCC that is resistant to previous therapies. However, there is a need to evaluate in detail the high frequency of adverse events, including DLTs.

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References

  1. Figlin R, Sternberg C, Wood CG (2012) Novel agents and approaches for advanced renal cell carcinoma. J Urol 188:707–715

    Article  PubMed  CAS  Google Scholar 

  2. Motzer RJ, Hutson TE, Tomczak P et al (2007) Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 356:115–124

    Article  PubMed  CAS  Google Scholar 

  3. Duran I, Lambea J, Maroto P et al (2017) Resistance to targeted therapies in renal cancer: the importance of changing the mechanism of action. Target Oncol 12:19–35

    Article  PubMed  CAS  Google Scholar 

  4. Seidel C, Busch J, Weikert S et al (2012) Progression free survival of first line vascular endothelial growth factor-targeted therapy is an important prognostic parameter in patients with metastatic renal cell carcinoma. Eur J Cancer (Oxford, England: 1990) 48:1023–1030

    Article  CAS  Google Scholar 

  5. Wells JC, Stukalin I, Norton C et al (2017) Third-line targeted therapy in metastatic renal cell carcinoma: results from the International Metastatic Renal Cell Carcinoma Database Consortium. Eur Urol 71:204–209

    Article  PubMed  Google Scholar 

  6. Ko JJ, Choueiri TK, Rini BI et al (2014) First-, second-, third-line therapy for mRCC: benchmarks for trial design from the IMDC. Br J Cancer 110:1917–1922

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Oudard S, Geoffrois L, Guillot A et al (2016) Clinical activity of sunitinib rechallenge in metastatic renal cell carcinoma—results of the REchallenge with SUnitinib in MEtastatic RCC (RESUME) study. Eur J Cancer (Oxford, England: 1990) 62:28–35

  8. Buchler T, Bortlicek Z, Poprach A et al (2014) Efficacy of everolimus in second- and third-line therapy for metastatic renal cell carcinoma: a registry-based analysis. Urol Oncol 32:569–575

    Article  PubMed  CAS  Google Scholar 

  9. Park I, Lee JL, Ahn JH et al (2015) Vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR-TKI) rechallenge for patients with metastatic renal cell carcinoma after treatment failure using both VEGFR-TKI and mTOR inhibitor. Cancer Chemother Pharmacol 75:1025–1035

    Article  PubMed  CAS  Google Scholar 

  10. Busch J, Seidel C, Erber B et al (2013) Retrospective comparison of triple-sequence therapies in metastatic renal cell carcinoma. Eur Urol 64:62–70

    Article  PubMed  CAS  Google Scholar 

  11. Bedke J, Gauler T, Grunwald V et al (2017) Systemic therapy in metastatic renal cell carcinoma. World J Urol 35:179–188

    Article  PubMed  CAS  Google Scholar 

  12. Escudier B, Michaelson MD, Motzer RJ et al (2014) Axitinib versus sorafenib in advanced renal cell carcinoma: subanalyses by prior therapy from a randomised phase III trial. Br J Cancer 110:2821–2828

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. De Velasco G, Xie W, Donskov F et al (2017) Discontinuing VEGF-targeted therapy for progression versus toxicity affects outcomes of second-line therapies in metastatic renal cell carcinoma. Clin Genitourin Cancer 15(403–410):e402

    Google Scholar 

  14. Ishihara H, Kondo T, Yoshida K et al (2017) Time to progression after first-line tyrosine kinase inhibitor predicts survival in patients with metastatic renal cell carcinoma receiving second-line molecular-targeted therapy. Urol Oncol 35(9):542.e1–542.e9

  15. Ishihara H, Yagisawa T, Kondo T et al (2017) Effect of the timing of best tumor shrinkage on survival of patients with metastatic renal cell carcinoma who received first-line tyrosine kinase inhibitor therapy. Int J Clin Oncol 22:126–135

    Article  PubMed  CAS  Google Scholar 

  16. Motzer RJ, Bacik J, Schwartz LH et al (2004) Prognostic factors for survival in previously treated patients with metastatic renal cell carcinoma. J Clin Oncol 22:454–463

    Article  PubMed  Google Scholar 

  17. Fernandez-Pello S, Hofmann F, Tahbaz R et al (2017) A systematic review and meta-analysis comparing the effectiveness and adverse effects of different systemic treatments for non-clear cell renal cell carcinoma. Eur Urol 71:426–436

    Article  PubMed  Google Scholar 

  18. Kroeger N, Xie W, Lee JL et al (2013) Metastatic non-clear cell renal cell carcinoma treated with targeted therapy agents: characterization of survival outcome and application of the International mRCC Database Consortium criteria. Cancer 119:2999–3006

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Alimohamed N, Lee JL, Srinivas S et al (2014) A population-based overview of sequences of targeted therapy in metastatic renal cell carcinoma. Clin Genitourin Cancer 12:e127–e131

    Article  PubMed  Google Scholar 

  20. Geynisman DM, Hu JC, Liu L et al (2015) Treatment patterns and costs for metastatic renal cell carcinoma patients with private insurance in the United States. Clin Genitourin Cancer 13:e93–e100

    Article  PubMed  Google Scholar 

  21. Motzer RJ, Escudier B, McDermott DF et al (2015) Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med 373:1803–1813

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Acknowledgements

The authors thank Editage for English language editing and Nobuko Hata for secretarial support.

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Authors and Affiliations

  1. Department of Urology, Kidney Center, Tokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan

    Hiroki Ishihara, Toshio Takagi, Kazuhiko Yoshida, Kenji Omae, Junpei Iizuka, Hirohito Kobayashi & Kazunari Tanabe

  2. Department of Urology, Tokyo Women’s Medical University Medical Center East, 2-1-10 Nishiogu, Arakawa-ku, Tokyo, 116-8567, Japan

    Tsunenori Kondo & Hidekazu Tachibana

  3. Department of Healthcare Epidemiology, Kyoto University Graduate School of Medicine/School of Public Health, Yoshida Konoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan

    Kenji Omae

  4. Center for Innovative Research for Communities and Clinical Excellence, Fukushima Medical University, 1 Hikarigaoka, Fukushima City, Fukushima, 960-1295, Japan

    Kenji Omae

Authors
  1. Hiroki Ishihara
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  2. Toshio Takagi
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  3. Tsunenori Kondo
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  4. Hidekazu Tachibana
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  5. Kazuhiko Yoshida
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  6. Kenji Omae
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  7. Junpei Iizuka
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  8. Hirohito Kobayashi
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  9. Kazunari Tanabe
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Corresponding author

Correspondence to Hiroki Ishihara.

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Conflict of interest

Tsunenori Kondo received honoraria from Pfizer, Bayer, and Novartis. None of the other authors have any conflicts of interest to declare.

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Fig.

 S1a–b. Overall survival after first- and second-line therapy according to the use of third-line therapy in 34 patients with a diagnosis of clear-cell carcinoma. Patients with third-line therapy (n = 16) had a significantly longer overall survival after first- and second-line therapy than those without third-line therapy. a Median overall survival after first-line therapy: 30.6 vs. 18.5 months, p = 0.0110. b Median overall survival after second-line therapy: 21.8 vs. 8.34 months, p = 0.0013. (TIFF 138 kb)

Fig.

 S2. Waterfall plot analysis. The waterfall plot analysis shows the objective response rate according to the third-line agents used in each patient. mTORi mammalian target of rapamycin inhibitor (TIFF 69 kb)

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Ishihara, H., Takagi, T., Kondo, T. et al. Efficacy and safety of third-line molecular-targeted therapy in metastatic renal cell carcinoma resistant to first-line vascular endothelial growth factor receptor tyrosine kinase inhibitor and second-line therapy. Int J Clin Oncol 23, 559–567 (2018). https://doi.org/10.1007/s10147-018-1241-3

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  • DOI: https://doi.org/10.1007/s10147-018-1241-3

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