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First-Line Systemic Therapy for Metastatic Clear-Cell Renal Cell Carcinoma: Critical Appraisal of Emerging Options

Abstract

Until recently, a dichotomy existed in the front-line approach of metastatic clear-cell renal cell carcinoma (mRCC). Specifically, patients received either targeted therapy or immunotherapy. Targeted therapy entailed use of agents blocking signaling through the vascular endothelial growth factor (VEGF) receptor, such as cabozantinib, sunitinib, or pazopanib. Immunotherapy entailed dual therapy with nivolumab and ipilimumab, both checkpoint inhibitors for intermediate/poor International Metastatic RCC Database Consortium (IMDC)-risk disease patients. Within the past year, two datasets have emerged that led to recent approvals of combined therapy with VEGF and checkpoint inhibitors. These regimens (axitinib with either avelumab or pembolizumab) are among several that have been or will be evaluated for patients with newly diagnosed mRCC. We aim to facilitate treatment decisions through this comprehensive and contextualized overview of recent datasets in this therapeutic space.

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References

  1. 1.

    Choueiri TK, Motzer RJ. Systemic therapy for metastatic renal-cell carcinoma. N Engl J Med. 2017;376:354–66.

    CAS  Article  Google Scholar 

  2. 2.

    Salgia NJ, Dara Y, Bergerot P, et al. The changing landscape of management of metastatic renal cell carcinoma: current treatment options and future directions. Curr Treat Options Oncol. 2019;20:41.

    Article  Google Scholar 

  3. 3.

    Klapper JA, Downey SG, Smith FO, et al. High-dose interleukin-2 for the treatment of metastatic renal cell carcinoma : a retrospective analysis of response and survival in patients treated in the surgery branch at the National Cancer Institute between 1986 and 2006. Cancer. 2008;113:293–301.

    CAS  Article  Google Scholar 

  4. 4.

    Rosenblatt J, McDermott DF. Immunotherapy for renal cell carcinoma. Hematol Oncol Clin N Am. 2011;25:793–812.

    Article  Google Scholar 

  5. 5.

    Singh P, Agarwal N, Pal SK. Sequencing systemic therapies for metastatic kidney cancer. Curr Treat Options Oncol. 2015;16:316.

    Article  Google Scholar 

  6. 6.

    Lalani AA, Li H, Heng DYC, et al. First-line sunitinib or pazopanib in metastatic renal cell carcinoma: the Canadian experience. Can Urol Assoc J. 2017;11:112–7.

    Article  Google Scholar 

  7. 7.

    Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373:1803–13.

    CAS  Article  Google Scholar 

  8. 8.

    Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med. 2018;378:1277–90.

    CAS  Article  Google Scholar 

  9. 9.

    Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007;356:115–24.

    CAS  Article  Google Scholar 

  10. 10.

    Choueiri TK, Halabi S, Sanford BL, et al. Cabozantinib versus sunitinib as initial targeted therapy for patients with metastatic renal cell carcinoma of poor or intermediate risk: the alliance A031203 CABOSUN trial. J Clin Oncol. 2017;35:591–7.

    CAS  Article  Google Scholar 

  11. 11.

    Yip SM, Wells C, Moreira R, et al. Checkpoint inhibitors in patients with metastatic renal cell carcinoma: results from the International Metastatic Renal Cell Carcinoma Database Consortium. Cancer. 2018;124:3677–83.

    CAS  Article  Google Scholar 

  12. 12.

    Amin A, Plimack ER, Ernstoff MS, et al. Safety and efficacy of nivolumab in combination with sunitinib or pazopanib in advanced or metastatic renal cell carcinoma: the CheckMate 016 study. J Immunother Cancer. 2018;6:109.

    Article  Google Scholar 

  13. 13.

    Bergerot P, Burns K, Prajapati D, et al. Advances in the treatment of metastatic renal cell carcinoma. Cancer Treat Res. 2018;175:127–37.

    Article  Google Scholar 

  14. 14.

    Wallin JJ, Bendell JC, Funke R, et al. Atezolizumab in combination with bevacizumab enhances antigen-specific T-cell migration in metastatic renal cell carcinoma. Nat Commun. 2016;7:12624.

    CAS  Article  Google Scholar 

  15. 15.

    Choueiri TK, Larkin J, Oya M, et al. Preliminary results for avelumab plus axitinib as first-line therapy in patients with advanced clear-cell renal-cell carcinoma (JAVELIN Renal 100): an open-label, dose-finding and dose-expansion, phase 1b trial. Lancet Oncol. 2018;19:451–60.

    CAS  Article  Google Scholar 

  16. 16.

    Atkins MB, Plimack ER, Puzanov I, et al. Axitinib in combination with pembrolizumab in patients with advanced renal cell cancer: a non-randomised, open-label, dose-finding, and dose-expansion phase 1b trial. Lancet Oncol. 2018.

  17. 17.

    Escudier B, Barthelemy P, Ravaud A, et al. Tivozanib combined with nivolumab: phase Ib/II study in metastatic renal cell carcinoma (mRCC). J Clin Oncol. 2018;36:618.

    Article  Google Scholar 

  18. 18.

    Choueiri TK, Apolo AB, Powles T, et al. A phase 3, randomized, open-label study of nivolumab combined with cabozantinib vs sunitinib in patients with previously untreated advanced or metastatic renal cell carcinoma (RCC; CheckMate 9ER). J Clin Oncol. 2018;36:TPS4598.

    Article  Google Scholar 

  19. 19.

    George S, Rini BI, Hammers HJ. Emerging role of combination immunotherapy in the first-line treatment of advanced renal cell carcinoma: a review. JAMA Oncol. 2018.

  20. 20.

    Flippot R, Escudier B, Albiges L. Immune checkpoint inhibitors: toward new paradigms in renal cell carcinoma. Drugs. 2018;78:1443–57.

    CAS  Article  Google Scholar 

  21. 21.

    Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019;380:1116–27.

    CAS  Article  Google Scholar 

  22. 22.

    Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019;380:1103–15.

    CAS  Article  Google Scholar 

  23. 23.

    Rini BI, Powles T, Atkins MB, et al. Atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (IMmotion151): a multicentre, open-label, phase 3, randomised controlled trial. Lancet. 2019.

  24. 24.

    Tannir NM, Frontera OA, Hammers HJ, et al. Thirty-month follow-up of the phase III CheckMate 214 trial of first-line nivolumab + ipilimumab (N + I) or sunitinib (S) in patients (pts) with advanced renal cell carcinoma (aRCC). J Clin Oncol. 2019;37:547.

    Article  Google Scholar 

  25. 25.

    Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373:1814–23.

    CAS  Article  Google Scholar 

  26. 26.

    Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2016;17:917–27.

    CAS  Article  Google Scholar 

  27. 27.

    Mejean A, Ravaud A, Thezenas S, et al. Sunitinib alone or after nephrectomy in metastatic renal-cell carcinoma. N Engl J Med. 2018;379:417–27.

    CAS  Article  Google Scholar 

  28. 28.

    Vaishampayan U. SWOG PROBE in Pal SK, Editors SWOG Spring meeting. 2019.

  29. 29.

    Motzer RJ, Powles T, Atkins MB, et al. IMmotion151: a randomized phase III study of atezolizumab plus bevacizumab vs sunitinib in untreated metastatic renal cell carcinoma (mRCC). J Clin Oncol. 2018;36:578.

    Article  Google Scholar 

  30. 30.

    Heng DY, Xie W, Regan MM, et al. Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large, multicenter study. J Clin Oncol. 2009;27:5794–9.

    CAS  Article  Google Scholar 

  31. 31.

    Diab A, Tannir NM, Bernatchez C, et al. A phase 1/2 study of a novel IL-2 cytokine, NKTR-214, and nivolumab in patients with select locally advanced or metastatic solid tumors. J Clin Oncol. 2017;35:e14040.

    Article  Google Scholar 

  32. 32.

    ClinicalTrials.gov: A study of NKTR-214 in combination with nivolumab compared with the investigator’s choice of a tyrosine kinase inhibitor (TKI) therapy (Either Sunitinib or Cabozantinib Monotherapy) for advanced metastatic renal cell carcinoma (RCC)—NCT03729245, 2019.

  33. 33.

    Hoerner CR, Chen VJ, Fan AC. The ‘Achilles Heel’ of metabolism in renal cell carcinoma: glutaminase inhibition as a rational treatment strategy. Kidney Cancer. 2019;3:15–29.

    CAS  Article  Google Scholar 

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Correspondence to Sumanta K. Pal.

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No external funding was used in the preparation of this article.

Conflict of interest

Vivian Loo, PharmD, Meghan Salgia, Paulo Bergerot, MD, and Errol J. Philip, PhD declare that they have no conflicts of interest that might be relevant to the contents of this article. Sumanta K. Pal, MD: Honoraria: Novartis, Medivation, Astellas Pharma; Consulting or Advisory Role: Pfizer, Novartis, Aveo, Myriad; Pharmaceuticals, Genentech, Exelixis, Bristol-Myers Squibb, Astellas Pharma; Research Funding: Medivation.

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Loo, V., Salgia, M., Bergerot, P. et al. First-Line Systemic Therapy for Metastatic Clear-Cell Renal Cell Carcinoma: Critical Appraisal of Emerging Options. Targ Oncol 14, 639–645 (2019). https://doi.org/10.1007/s11523-019-00676-y

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