Skip to main content

Advertisement

Log in

The Changing Landscape of Management of Metastatic Renal Cell Carcinoma: Current Treatment Options and Future Directions

  • Genitourinary Cancers (S Gupta, Section Editor)
  • Published:
Current Treatment Options in Oncology Aims and scope Submit manuscript

Opinion statement

For the practicing clinician, the dilemma becomes how most appropriate to sequence the aforementioned regimens. It is challenging to be dogmatic, as there are no comparative studies juxtaposing novel front-line options directly—all of the available studies utilize a comparator arm of sunitinib. With this in mind, the selection of front-line therapy with a patient with mRCC should involve a thorough discussion of both efficacy and safety of available options. The oncologist must also weigh their ability to manage complex immune-related adverse events that can emerge from checkpoint inhibitors, particularly with dual regimens such as nivolumab/ipilimumab. For the patient with good-risk disease, VEGF-directed therapies should remain a component of treatment. The data from CheckMate-214 does not support the use of nivolumab/ipilimumab in this setting, and in fact suggests superiority with the approach of VEGF-TKIs. Until regulatory decisions have been made around bevacizumab/atezolizumab and axitinib/avelumab, sunitinib and pazopanib remain options for patients with good-risk disease, although cabozantinib should be a consideration as well. Although the CABOSUN study did not include patients with good-risk disease, it is important to bear in mind that this was more of a pragmatic decision—inclusion of these patients in the original design could have potentially lengthened the extent of necessary follow-up. From a mechanistic standpoint, there is no reason to assume that cabozantinib would not also achieve superiority to sunitinib in patients with good-risk disease. For patients with intermediate- and poor-risk disease, cabozantinib and nivolumab/ipilimumab represent the only reasonable options thus far that have achieved regulatory approval. As previously noted, nivolumab/ipilimumab has proven benefit in this setting, but should be used only by the oncologist who has ready access to subspecialists who can aid in managing immune-related adverse events. Prompt recognition of colitis, hepatitis, and other sequelae from these therapies is critical, as these toxicities can be life-threatening. If such resources are not available, then cabozantinib should be considered. Cabozantinib should further be contemplated in the subset of patients with bony metastatic disease, where it appears to offer substantial control. Of course, it also represents an option for those individuals who have contraindications to immunotherapy, such as rheumatologic and autoimmune disorders.

When combinations of VEGF-directed and immunotherapies are approved, the clinician will have an even more complicated dilemma. Regimens such as a bevacizumab/atezolizumab offer an exceptional safety profile, which may weigh heavily in frail patients who cannot tolerate the side effect profile associated with VEGF-TKIs.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Motzer RJ, Mazumdar M, Bacik J, Berg W, Amsterdam A, Ferrara J. Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma. J Clin Oncol. 1999;17(8):2530–40.

    Article  CAS  Google Scholar 

  2. Belldegrun A, Tso CL, Zisman A, Naitoh J, Said J, Pantuck AJ, et al. Interleukin 2 gene therapy for prostate cancer: phase I clinical trial and basic biology. Hum Gene Ther. 2001;12(8):883–92.

    Article  CAS  Google Scholar 

  3. Atzpodien J, Kirchner H, Jonas U, Bergmann L, Schott H, Heynemann H, et al. Interleukin-2- and interferon alfa-2a-based immunochemotherapy in advanced renal cell carcinoma: a prospectively randomized trial of the German Cooperative Renal Carcinoma Chemoimmunotherapy Group (DGCIN). J Clin Oncol. 2004;22(7):1188–94.

  4. Alsharedi M, Katz H. Check point inhibitors a new era in renal cell carcinoma treatment. Med Oncol. 2018;35(6):85.

    Article  Google Scholar 

  5. Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007;356(2):125–34.

    Article  CAS  Google Scholar 

  6. Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet. 2008;372(9637):449–56.

    Article  CAS  Google Scholar 

  7. Dolan DE, Gupta S. PD-1 pathway inhibitors: changing the landscape of cancer immunotherapy. Cancer Control. 2014;21(3):231–7.

    Article  Google Scholar 

  8. Osanto S, van der Hulle T. Cabozantinib in the treatment of advanced renal cell carcinoma in adults following prior vascular endothelial growth factor targeted therapy: clinical trial evidence and experience. Ther Adv Urol. 2018;10(3):109–23.

    Article  CAS  Google Scholar 

  9. Motzer RJ, Tannir NM, McDermott DF, Aren Frontera O, Melichar B, Choueiri TK, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med. 2018;378(14):1277–90.

    Article  CAS  Google Scholar 

  10. •• Motzer RJ, Tannir NM, McDermott DF, Arén Frontera O, Melichar B, Choueiri TK, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med. 2018;378(14):1277–90. Large scale clinical trial exploring dual checkpoint inhibition in treatment of RCC.

    Article  CAS  Google Scholar 

  11. Hammers HJ, Plimack ER, Infante JR, Rini BI, McDermott DF, Lewis LD, et al. Safety and efficacy of nivolumab in combination with ipilimumab in metastatic renal cell carcinoma: the CheckMate 016 study. J Clin Oncol. 2017;35(34):3851–8.

    Article  CAS  Google Scholar 

  12. Heng DY, Xie W, Regan MM, Warren MA, Golshayan AR, Sahi C, 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(34):5794–9.

    Article  CAS  Google Scholar 

  13. • Choueiri TK, Hessel C, Halabi S, Sanford B, Michaelson MD, Hahn O, et al. Cabozantinib versus sunitinib as initial therapy for metastatic renal cell carcinoma of intermediate or poor risk (Alliance A031203 CABOSUN randomised trial): progression-free survival by independent review and overall survival update. Eur J Cancer. 2018;94:115–25. Clinical trial evaluating use of multikinase inhibitor, cabozantinib, targeting VEGF receptors, MET, and AXL.

    Article  CAS  Google Scholar 

  14. Choueiri TK, Halabi S, Sanford BL, Hahn O, Michaelson MD, Walsh MK, 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(6):591–7.

  15. • Motzer RJ, Powles T, Atkins MB, Escudier B, McDermott DF, Suarez C, 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(6_suppl):578. Large clinical trial reporting efficacy of combined VEGF- and checkpoint inhibitor therapies.

    Article  Google Scholar 

  16. • Motzer RJ, Penkov K, Haanen JBAG, Rini BI, Albiges L, Campbell MT, et al. LBA6_PRJAVELIN renal 101: a randomized, phase III study of avelumab + axitinib vs sunitinib as first-line treatment of advanced renal cell carcinoma (aRCC). Ann Oncol. 2018;29(suppl_8):mdy424.036.Large clinical trial reporting efficacy of combined VEGF- and checkpoint inhibitor therapies.

  17. Press Release: Merck’s KEYTRUDA® (pembrolizumab) in combination with Pfizer’s Inlyta® (axitinib) significantly improved overall survival (OS) and progression-free survival (PFS) as first-line therapy for advanced or metastatic renal cell carcinoma (Available at: https://investors.merck.com/news/press-release-details/2018/Mercks-KEYTRUDA-pembrolizumab-in-Combination-with-Pfizers-Inlyta-axitinib-Significantly-Improved-Overall-Survival-OS-and-Progression-free-Survival-PFS-as-First-Line-Therapy-for-Advanced-or-Metastatic-Renal-Cell-Carcinoma/default.aspx; last accessed 21 Dec 2018.

  18. McDermott DF, Huseni MA, Atkins MB, Motzer RJ, Rini BI, Escudier B, et al. Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma. Nat Med. 2018;24(6):749–57.

    Article  CAS  Google Scholar 

  19. Derosa L, Hellmann MD, Spaziano M, Halpenny D, Fidelle M, Rizvi H, et al. Negative association of antibiotics on clinical activity of immune checkpoint inhibitors in patients with advanced renal cell and non-small-cell lung cancer. Ann Oncol. 2018;29(6):1437–44.

    Article  CAS  Google Scholar 

  20. Routy B, Le Chatelier E, Derosa L, Duong CPM, Alou MT, Daillere R, et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science. 2018;359(6371):91–7.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Sumanta K. Pal MD.

Ethics declarations

Conflict of Interest

Nicholas J. Salgia declares that he has no conflict of interest. Yash Dara declares that he has no conflict of interest. Paulo Bergerot declares that he has no conflict of interest. Meghan Salgia declares that she has no conflict of interest. Sumanta K. Pal has received compensation from Genentech, Aveo, Eisai, Roche, Pfizer, Novartis, Exelixis, Ipsen, Bristol-Myers Squibb, and Astellas for service as a consultant.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Genitourinary Cancers

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Salgia, N.J., 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 in Oncol. 20, 41 (2019). https://doi.org/10.1007/s11864-019-0638-1

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11864-019-0638-1

Keywords

Navigation