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Update on First-Line Combination Treatment Approaches in Metastatic Clear-Cell Renal Cell Carcinoma

  • Genitourinary Cancers (S Gupta, Section Editor)
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Opinion statement

The treatment for metastatic renal cell carcinoma (mRCC) has significantly evolved in recent years with a deeper understanding of the molecular make-up of the disease and the clinical development of therapies with novel mechanisms of action. While some patients with more indolent disease may benefit from local therapy such as metastasectomy or cytoreductive nephrectomy, others may safely embark on an active surveillance program or be offered targeted therapy. Yet, a combination regimen including an ICI is the most effective regimen and should be considered in most mRCC cases. Ongoing studies will help determine which factors can be further used to optimize treatment selection and personalize disease management.

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References and Recommended Reading

  1. Turajlic S, Swanton C, Boshoff C. Kidney cancer: the next decade. J Exp Med. 2018;215:2477–9. https://doi.org/10.1084/jem.20181617.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Barata PC, Rini BI. Treatment of renal cell carcinoma: current status and future directions. CA Cancer J Clin. 2017;67:507–24. https://doi.org/10.3322/caac.21411.

    Article  PubMed  Google Scholar 

  3. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70:7–30. https://doi.org/10.3322/caac.21590.

    Article  Google Scholar 

  4. American Cancer Society. Survival rates for kidney cancer. https://www.cancer.org/cancer/kidney-cancer/detection-diagnosis-staging/survival-rates.html#references. Accessed 22 Apr 2020.

  5. National Cancer Institute. Cancer stat facts: kidney and renal pelvis cancer. https://seer.cancer.gov/statfacts/html/kidrp.html. Accessed 22 Apr 2020.

  6. Störkel S, van den Berg E. Morphological classification of renal cancer. World J Urol. 1995;13:153–8. https://doi.org/10.1007/BF00184870.

    Article  PubMed  Google Scholar 

  7. Srigley JR, Delahunt B, Eble JN, Egevad L, Epstein JI, Grignon D, et al. The International Society of Urological Pathology (ISUP) Vancouver classification of renal neoplasia. Am J Surg Pathol. 2013;37:1469–89. https://doi.org/10.1097/PAS.0b013e318299f2d1.

    Article  PubMed  Google Scholar 

  8. Maxwell PH, Wiesener MS, Chang G-W, Clifford SC, Vaux EC, Cockman ME, et al. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature. 1999;399:271–5. https://doi.org/10.1038/20459.

    Article  CAS  PubMed  Google Scholar 

  9. Clark PE. The role of VHL in clear-cell renal cell carcinoma and its relation to targeted therapy. Kidney Int. 2009;76:939–45. https://doi.org/10.1038/ki.2009.296.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Nickerson ML, Jaeger E, Shi Y, Durocher JA, Mahurkar S, Zaridze D, et al. Improved identification of von Hippel-Lindau gene alterations in clear cell renal tumors. Clin Cancer Res. 2008;14:4726–34. https://doi.org/10.1158/1078-0432.CCR-07-4921.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Brugarolas J. Molecular genetics of clear-cell renal cell carcinoma. J Clin Oncol. 2014;32:1968–76. https://doi.org/10.1200/JCO.2012.45.2003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Thomas GV, Tran C, Mellinghoff IK, Welsbie DS, Chan E, Fueger B, et al. Hypoxia-inducible factor determines sensitivity to inhibitors of mTOR in kidney cancer. Nat Med. 2006;12:122–7. https://doi.org/10.1038/nm1337.

    Article  CAS  PubMed  Google Scholar 

  13. Lebacle C, Pooli A, Bessede T, Irani J, Pantuck AJ, Drakaki A. Epidemiology, biology and treatment of sarcomatoid RCC: current state of the art. World J Urol. 2019;37:115–23. https://doi.org/10.1007/s00345-018-2355-y.

    Article  PubMed  Google Scholar 

  14. Samiei A, Tayshetye P, Sanguino A, Miller R, Lyne J, Cohen J, et al. The clinical outcome of renal cell carcinoma with rhabdoid and sarcomatoid differentiation. J Clin Oncol. 2019;37:e16083. https://doi.org/10.1200/JCO.2019.37.15_suppl.e16083.

    Article  Google Scholar 

  15. Herrera-Caceres JO, Jewett MAS. Roles for active surveillance in renal cancer. Curr Opin Urol. 2018;28:375–82. https://doi.org/10.1097/MOU.0000000000000506.

    Article  PubMed  Google Scholar 

  16. Rini BI, Dorff TB, Elson P, Rodriguez CS, Shepard D, Wood L, et al. Active surveillance in metastatic renal-cell carcinoma: a prospective, phase 2 trial. Lancet Oncol. 2016;17:1317–24. https://doi.org/10.1016/S1470-2045(16)30196-6.

    Article  PubMed  Google Scholar 

  17. Verhoeff S, van Es SC, Elias SG, Gerritse S, Angus L, Oosting S, et al. Prediction of watchful waiting in newly diagnosed metastatic clear cell renal cell carcinoma patients with a good or intermediate prognosis. J Clin Oncol. 2020;38:5079. https://doi.org/10.1200/JCO.2020.38.15_suppl.5079.

    Article  Google Scholar 

  18. Park I, Lee J-L, Ahn J-H, Lee DH, Lee KH, Jeong IG, et al. Active surveillance for metastatic or recurrent renal cell carcinoma. J Cancer Res Clin Oncol. 2014;140:1421–8. https://doi.org/10.1007/s00432-014-1680-9.

    Article  CAS  PubMed  Google Scholar 

  19. Kushnir I, Basappa NS, Ghosh S, Lalani AKA, Soulieres D, Bjarnason GA, et al. Active surveillance in metastatic renal cell carcinoma (mRCC): results from the Canadian Kidney Cancer information system (CKCis). J Clin Oncol. 2019;37:4516. https://doi.org/10.1200/jco.2019.37.15_suppl.4516.

    Article  Google Scholar 

  20. ASCO 2019: Active surveillance in metastatic renal cell carcinoma: results from the Canadian Kidney Cancer information system. https://www.urotoday.com/conference-highlights/asco-2019-annual-meeting/asco-2019-kidney-cancer/113043-asco-2019-active-surveillance-in-metastatic-renal-cell-carcinoma-results-from-the-canadian-kidney-cancer-information-system.html. Accessed 21 May 2020.

  21. Motzer RJ, Russo P. Cytoreductive nephrectomy — patient selection is key. N Engl J Med. 2018;379:481–2. https://doi.org/10.1056/NEJMe1806331.

    Article  PubMed  Google Scholar 

  22. Flanigan RC, Salmon SE, Blumenstein BA, Bearman SI, Roy V, McGrath PC, et al. Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer. N Engl J Med. 2001;345:1655–9. https://doi.org/10.1056/NEJMoa003013.

    Article  CAS  PubMed  Google Scholar 

  23. Mickisch G, Garin A, van Poppel H, de Prijck L, Sylvester R. Radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: a randomised trial. Lancet. 2001;358:966–70. https://doi.org/10.1016/S0140-6736(01)06103-7.

    Article  CAS  PubMed  Google Scholar 

  24. Franklin JR, Figlin R, Rauch J, Gitlitz B, Belldegrun A. Cytoreductive surgery in the management of metastatic renal cell carcinoma: the UCLA experience. Semin Urol Oncol. 1996;14(4):230–6.

  25. Pindoria N, Raison N, Blecher G, Catterwell R, Dasgupta P. Cytoreductive nephrectomy in the era of targeted therapies: a review. BJU Int. 2017;120:320–8. https://doi.org/10.1111/bju.13860.

    Article  PubMed  Google Scholar 

  26. Grant M, Szabados B, Kuusk T, Powles T, Bex A. Cytoreductive nephrectomy: does CARMENA (Cancer du Rein Metastatique Nephrectomie et Antiangiogéniques) change everything? Curr Opin Urol. 2019;30:36–40. https://doi.org/10.1097/mou.0000000000000696.

    Article  Google Scholar 

  27. Kokorovic A, Rendon RA. Cytoreductive nephrectomy in metastatic kidney cancer: what do we do now? Curr Opin Support Palliat Care. 2019. https://doi.org/10.1097/SPC.0000000000000433.

  28. Alhalabi O, Karam JA, Tannir NM. Evolving role of cytoreductive nephrectomy in metastatic renal cell carcinoma of variant histology. Curr Opin Urol. 2019. https://doi.org/10.1097/MOU.0000000000000661.

  29. Graham J, Bhindi B, Heng DYC. The evolving role of cytoreductive nephrectomy in metastatic renal cell carcinoma. Curr Opin Urol. 2019. https://doi.org/10.1097/mou.0000000000000657.

  30. Méjean A, Ravaud A, Thezenas S, Colas S, Beauval JB, Bensalah K, et al. Sunitinib alone or after nephrectomy in metastatic renal-cell carcinoma. N Engl J Med. 2018;379:417–27. https://doi.org/10.1056/NEJMoa1803675.

    Article  PubMed  Google Scholar 

  31. Hsiang WR, Kenney PA, Leapman MS. Redefining the role of surgical management of metastatic renal cell carcinoma. Curr Oncol Rep. 2020;22:35. https://doi.org/10.1007/s11912-020-0895-y.

    Article  PubMed  Google Scholar 

  32. Mejean A, Thezenas S, Chevreau C, Bensalah K, Geoffrois L, Thiery-Vuillemin A, et al. Cytoreductive nephrectomy (CN) in metastatic renal cancer (mRCC): update on Carmena trial with focus on intermediate IMDC-risk population. J Clin Oncol. 2019;37:4508. https://doi.org/10.1200/jco.2019.37.15_suppl.4508.

    Article  Google Scholar 

  33. Lázaro M, Valderrama BP, Suárez C, de-Velasco G, Beato C, Chirivella I, et al. SEOM clinical guideline for treatment of kidney cancer (2019). Clin Transl Oncol. 2020;22:256–69. https://doi.org/10.1007/s12094-019-02285-7.

    Article  CAS  PubMed  Google Scholar 

  34. Massari F, Di Nunno V, Gatto L, et al. Should CARMENA really change our attitude towards cytoreductive nephrectomy in metastatic renal cell carcinoma? A systematic review and meta-analysis evaluating cytoreductive nephrectomy in the era of targeted therapy. Target Oncol. 2018;13:705–14. https://doi.org/10.1007/s11523-018-0601-2.

    Article  PubMed  Google Scholar 

  35. ASCO 2019: Update on the CARMENA trial with focus on intermediate IMDC-risk population: cytoreductive nephrectomy in metastatic renal cancer. https://www.urotoday.com/conference-highlights/asco-2019-annual-meeting/asco-2019-kidney-cancer/113069-asco-2019-cytoreductive-nephrectomy-in-metastatic-renal-cancer-update-on-carmena-trial-with-focus-on-intermediate-imdc-risk-population.html. Accessed 21 May 2020.

  36. Immediate surgery or surgery after sunitinib malate in treating patients with metastatic kidney cancer - ClinicalTrials.gov. 2017; https://www.clinicaltrials.gov/ct2/show/NCT01099423?term=surtime&rank=1. Accessed 22 Apr 2020.

  37. Zequi SC. Editorial comment: comparison of immediate vs deferred cytoreductive nephrectomy in patients with synchronous metastatic renal cell carcinoma receiving sunitinib: the SURTIME randomized clinical trial. Int Braz J Urol. 2020. https://doi.org/10.1590/S1677-5538.IBJU.2020.03.12.

  38. Bex A, Mulders P, Jewett M, Wagstaff J, van Thienen JV, Blank CU, et al. Comparison of immediate vs deferred cytoreductive nephrectomy in patients with synchronous metastatic renal cell carcinoma receiving sunitinib: the SURTIME randomized clinical trial. JAMA Oncol. 2019;5:164–70. https://doi.org/10.1001/jamaoncol.2018.5543.

    Article  PubMed  Google Scholar 

  39. Heng DYC, Wells JC, Rini BI, Beuselinck B, Lee JL, Knox JJ, et al. Cytoreductive nephrectomy in patients with synchronous metastases from renal cell carcinoma: results from the international metastatic renal cell carcinoma database consortium. Eur Urol. 2014;66:704–10. https://doi.org/10.1016/j.eururo.2014.05.034.

    Article  PubMed  Google Scholar 

  40. Choueiri TK, Xie W, Kollmannsberger C, North S, Knox JJ, Lampard JG, et al. The impact of cytoreductive nephrectomy on survival of patients with metastatic renal cell carcinoma receiving vascular endothelial growth factor targeted therapy. J Urol. 2011;185:60–6. https://doi.org/10.1016/j.juro.2010.09.012.

    Article  PubMed  Google Scholar 

  41. ASCO GU 2020: Cytoreductive nephrectomy for metastatic renal cell carcinoma treated with immune checkpoint inhibitors or targeted therapy. https://www.urotoday.com/conference-highlights/asco-gu-2020/asco-gu-2020-kidney-cancer/119346-asco-gu-2020-cytoreductive-nephrectomy-for-metastatic-renal-cell-carcinoma-treated-with-immune-checkpoint-inhibitors-or-targeted-therapy.html. Accessed 22 Apr 2020.

  42. Alnimer YM, Qasrawi A, Katato K. The role of cytoreductive nephrectomy in metastatic renal cell carcinoma. J Clin Oncol. 2020. https://doi.org/10.1200/JCO.2020.38.15_suppl.e17080.

  43. Ornstein MC, Wood LS, Hobbs BP, Allman KD, Martin A, Bevan M, et al. A phase II trial of intermittent nivolumab in patients with metastatic renal cell carcinoma (mRCC) who have received prior anti-angiogenic therapy. J Immunother Cancer. 2019;7:127. https://doi.org/10.1186/s40425-019-0615-z.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Kim HL, Mayerson E, Lara PN, Messing E, Tangen C, Shuch BM, et al. Considerations for the next clinical trial evaluating the role of cytoreductive nephrectomy for metastatic renal cell carcinoma. EU Focus. 2019;5:927–9. https://doi.org/10.1016/j.euf.2019.05.006.

    Article  PubMed  Google Scholar 

  45. Deferred cytoreductive nephrectomy in synchronous metastatic renal cell carcinoma: the NORDIC-SUN-Trial - ClinicalTrials.gov. 2020; https://clinicaltrials.gov/ct2/show/NCT03977571. Accessed 22 May 2020.

  46. Kavolius JP, Mastorakos DP, Pavlovich C, Russo P, Burt ME, Brady MS. Resection of metastatic renal cell carcinoma. J Clin Oncol. 1998;16:2261–6. https://doi.org/10.1200/JCO.1998.16.6.2261.

    Article  CAS  PubMed  Google Scholar 

  47. Alt AL, Boorjian SA, Lohse CM, Costello BA, Leibovich BC, Blute ML. Survival after complete surgical resection of multiple metastases from renal cell carcinoma. Cancer. 2011;117:2873–82. https://doi.org/10.1002/cncr.25836.

    Article  PubMed  Google Scholar 

  48. You D, Lee C, Jeong IG, Song C, Lee JL, Hong B, et al. Impact of metastasectomy on prognosis in patients treated with targeted therapy for metastatic renal cell carcinoma. J Cancer Res Clin Oncol. 2016;142:2331–8. https://doi.org/10.1007/s00432-016-2217-1.

    Article  CAS  PubMed  Google Scholar 

  49. Palumbo C, Pecoraro A, Knipper S, et al. Survival and complication rates of metastasectomy in patients with metastatic renal cell carcinoma treated exclusively with targeted therapy: a combined population-based analysis. Anticancer Res. 2019. https://doi.org/10.21873/anticanres.13604.

  50. Ouzaid I, Capitanio U, Staehler M, Wood CG, Leibovich BC, Ljungberg B, et al. Surgical metastasectomy in renal cell carcinoma: a systematic review. Eur Urol Oncol. 2019;2:141–9. https://doi.org/10.1016/j.euo.2018.08.028.

    Article  PubMed  Google Scholar 

  51. Appleman LJ, Puligandla M, Pal SK, Harris W, Agarwal N, Costello BA, et al. Randomized, double-blind phase III study of pazopanib versus placebo in patients with metastatic renal cell carcinoma who have no evidence of disease following metastasectomy: a trial of the ECOG-ACRIN cancer research group (E2810). J Clin Oncol. 2019;37:4502. https://doi.org/10.1200/JCO.2019.37.15_suppl.4502.

    Article  Google Scholar 

  52. Procopio G, Apollonio G, Cognetti F, Miceli R, Milella M, Mosca A, et al. Sorafenib versus observation following radical metastasectomy for clear-cell renal cell carcinoma: results from the phase 2 randomized open-label RESORT study. Eur Urol Oncol. 2019;2:699–707. https://doi.org/10.1016/j.euo.2019.08.011.

    Article  PubMed  Google Scholar 

  53. Lee CC, Tey JCS, Cheo T, Lee CH, Wong A, Kumar N, et al. Outcomes of patients with spinal metastases from renal cell carcinoma treated with conventionally-fractionated external beam radiation therapy. Medicine (Baltimore). 2020;99:e19838. https://doi.org/10.1097/md.0000000000019838.

    Article  CAS  Google Scholar 

  54. DiBiase SJ, Valicenti RK, Schultz D, et al. Palliative irradiation for focally symptomatic metastatic renal cell carcinoma. J Urol. 1997;158:746–9. https://doi.org/10.1097/00005392-199709000-00013.

    Article  CAS  PubMed  Google Scholar 

  55. Klausner G, Troussier I, Biau J, Jacob J, Schernberg A, Canova CH, et al. Stereotactic radiation therapy for renal cell carcinoma brain metastases in the tyrosine kinase inhibitors era: outcomes of 120 patients. Clin Genitourin Cancer. 2019;17:191–200. https://doi.org/10.1016/j.clgc.2019.02.007.

    Article  PubMed  Google Scholar 

  56. Taunk NK, Spratt DE, Bilsky M, Yamada Y. Spine radiosurgery in the management of renal cell carcinoma metastases. JNCCN. 2015. https://doi.org/10.6004/jnccn.2015.0093.

  57. Zaorsky NG, Lehrer EJ, Kothari G, Louie AV, Siva S. Stereotactic ablative radiation therapy for oligometastatic renal cell carcinoma (SABR ORCA): a meta-analysis of 28 studies. Eur Urol Oncol. 2019;2:515–23. https://doi.org/10.1016/j.euo.2019.05.007.

    Article  PubMed  Google Scholar 

  58. Dengina N, Mitin T, Gamayunov S, Safina S, Kreinina Y, Tsimafeyeu I. Stereotactic body radiation therapy in combination with systemic therapy for metastatic renal cell carcinoma: a prospective multicentre study. ESMO Open. 2019;4:e000535. https://doi.org/10.1136/esmoopen-2019-000535.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Barata PC, Mendiratta P, Kotecha R, Gopalakrishnan D, Juloori A, Chao ST, et al. Effect of switching systemic treatment after stereotactic radiosurgery for oligoprogressive, metastatic renal cell carcinoma. Clin Genitourin Cancer. 2018;16:413–419.e1. https://doi.org/10.1016/j.clgc.2018.07.018.

    Article  PubMed  Google Scholar 

  60. ASCO GU 2020: Combined dual checkpoint inhibition and stereotactic body radiotherapy in the metastatic renal cell carcinoma Setting (RADVAX RCC). https://www.urotoday.com/conference-highlights/asco-gu-2020/asco-gu-2020-kidney-cancer/119323-asco-gu-2020-combined-dual-checkpoint-inhibition-and-stereotactic-body-radiotherapy-in-the-metastatic-renal-cell-carcinoma-setting-radvax-rcc.html. Accessed 28 Apr 2020.

  61. Twyman-Saint Victor C, Rech AJ, Maity A, Rengan R, Pauken KE, Stelekati E, et al. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature. 2015;520:373–7. https://doi.org/10.1038/nature14292.

    Article  CAS  PubMed  Google Scholar 

  62. ASCO GU 2020: Nivolumab in combination with stereotactic body radiotherapy in pre-treated patients with metastatic renal cell carcinoma (NIVES). https://www.urotoday.com/conference-highlights/asco-gu-2020/asco-gu-2020-kidney-cancer/119278-asco-gu-2020-nivolumab-in-combination-with-stereotactic-body-radiotherapy-in-pre-treated-patients-with-metastatic-renal-cell-carcinoma-nives.html. Accessed 28 Apr 2020.

  63. Motzer RJ, Rini BI, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial. Lancet Oncol. 2019;20:1370–85. https://doi.org/10.1016/S1470-2045(19)30413-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Garcia JA, Rini BI. Recent progress in the management of advanced renal cell carcinoma. CA Cancer J Clin. 2007;57:112–25. https://doi.org/10.3322/canjclin.57.2.112.

    Article  PubMed  Google Scholar 

  65. Choueiri TK, Motzer RJ. Systemic therapy for metastatic renal-cell carcinoma. N Engl J Med. 2017;376:354–66. https://doi.org/10.1056/NEJMra1601333.

    Article  CAS  PubMed  Google Scholar 

  66. Allard CB, Gelpi-Hammerschmidt F, Harshman LC, Choueiri TK, Faiena I, Modi P, et al. Contemporary trends in high-dose interleukin-2 use for metastatic renal cell carcinoma in the United States. Urol Oncol Semin Orig Investig. 2015;33:496.e11–6. https://doi.org/10.1016/j.urolonc.2015.06.014.

    Article  CAS  Google Scholar 

  67. Negrier S, Escudier B, Lasset C, Douillard JY, Savary J, Chevreau C, et al. Recombinant human interleukin-2, recombinant human interferon alfa-2a, or both in metastatic renal-cell carcinoma. N Engl J Med. 1998;338:1272–8. https://doi.org/10.1056/NEJM199804303381805.

    Article  CAS  PubMed  Google Scholar 

  68. Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007;356:2271–81. https://doi.org/10.1056/NEJMoa066838.

    Article  CAS  PubMed  Google Scholar 

  69. 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;356:125–34. https://doi.org/10.1056/NEJMoa060655.

    Article  CAS  PubMed  Google Scholar 

  70. Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007;356:115–24. https://doi.org/10.1056/NEJMoa065044.

    Article  CAS  PubMed  Google Scholar 

  71. Roskoski R. Vascular endothelial growth factor (VEGF) and VEGF receptor inhibitors in the treatment of renal cell carcinomas. Pharmacol Res. 2017;120:116–32. https://doi.org/10.1016/j.phrs.2017.03.010.

    Article  CAS  PubMed  Google Scholar 

  72. Sternberg CN, Davis ID, Mardiak J, Szczylik C, Lee E, Wagstaff J, et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol. 2010;28:1061–8. https://doi.org/10.1200/JCO.2009.23.9764.

    Article  CAS  PubMed  Google Scholar 

  73. Frampton JE, Keating GM. Bevacizumab: in first-line treatment of advanced and/or metastatic renal cell carcinoma. BioDrugs. 2008;22:113–20. https://doi.org/10.2165/00063030-200822020-00004.

    Article  CAS  PubMed  Google Scholar 

  74. Motzer RJ, Hutson TE, Cella D, Reeves J, Hawkins R, Guo J, et al. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med. 2013;369:722–31. https://doi.org/10.1056/NEJMoa1303989.

    Article  CAS  PubMed  Google Scholar 

  75. Escudier B, Porta C, Bono P, et al. Randomized, controlled, double-blind, cross-over trial assessing treatment preference for pazopanib versus sunitinib in patients with metastatic renal cell carcinoma: PISCES study. J Clin Oncol. 2014. https://doi.org/10.1200/JCO.2013.50.8267.

  76. 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;35:591–7. https://doi.org/10.1200/JCO.2016.70.7398.

    Article  CAS  PubMed  Google Scholar 

  77. Wiechno P, Kucharz J, Sadowska M, Michalski W, Sikora-Kupis B, Jonska-Gmyrek J, et al. Contemporary treatment of metastatic renal cell carcinoma. Med Oncol. 2018;35:156. https://doi.org/10.1007/s12032-018-1217-1.

    Article  PubMed  Google Scholar 

  78. Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373:1803–13. https://doi.org/10.1056/NEJMoa1510665.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Atkins MB, Tannir NM. Current and emerging therapies for first-line treatment of metastatic clear cell renal cell carcinoma. Cancer Treat Rev. 2018;70:127–37. https://doi.org/10.1016/j.ctrv.2018.07.009.

    Article  CAS  PubMed  Google Scholar 

  80. Ornstein MC, Rini BI. Radical shifts in the first-line management of metastatic renal cell carcinoma. Nat Rev Clin Oncol. 2019;16:71–2. https://doi.org/10.1038/s41571-018-0146-4.

    Article  PubMed  Google Scholar 

  81. Hahn AW, Klaassen Z, Agarwal N, Haaland B, Esther J, Ye XY, et al. First-line treatment of metastatic renal cell carcinoma: a systematic review and network meta-analysis. Eur Urol Oncol. 2019;2:708–15. https://doi.org/10.1016/j.euo.2019.09.002.

    Article  PubMed  Google Scholar 

  82. Yasuda S, Sho M, Yamato I, Yoshiji H, Wakatsuki K, Nishiwada S, et al. Simultaneous blockade of programmed death 1 and vascular endothelial growth factor receptor 2 (VEGFR2) induces synergistic anti-tumour effect in vivo. Clin Exp Immunol. 2013;172:500–6. https://doi.org/10.1111/cei.12069.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Dirkx AEM, oude Egbrink MGA, Castermans K, et al. Anti-angiogenesis therapy can overcome endothelial cell anergy and promote leukocyte-endothelium interactions and infiltration in tumors. FASEB J. 2006. https://doi.org/10.1096/fj.05-4493com.

  84. Plimack ER, Rini BI, Stus V, Gafanov R, Waddell T, Nosov D, et al. Pembrolizumab plus axitinib versus sunitinib as first-line therapy for advanced renal cell carcinoma (RCC): updated analysis of KEYNOTE-426. J Clin Oncol. 2020;38:5001. https://doi.org/10.1200/jco.2020.38.15_suppl.5001.

    Article  Google Scholar 

  85. Rini BI, Plimack ER, Stus V, Gafanov R, Hawkins R, Nosov D, et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019;380:1116–27. https://doi.org/10.1056/NEJMoa1816714.

    Article  CAS  Google Scholar 

  86. Motzer RJ, Penkov K, Haanen J, Rini B, Albiges L, Campbell MT, et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019;380:1103–15. https://doi.org/10.1056/NEJMoa1816047.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Rini BI, Powles T, Atkins MB, Escudier B, McDermott DF, Suarez C, 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;393:2404–15. https://doi.org/10.1016/S0140-6736(19)30723-8.

    Article  PubMed  Google Scholar 

  88. Pichler R, Compérat E, Klatte T, Pichler M, Loidl W, Lusuardi L, et al. Renal cell carcinoma with sarcomatoid features: finally new therapeutic hope? Cancers (Basel). 2019;11. https://doi.org/10.3390/cancers11030422.

  89. Rini BI, Plimack ER, Stus V, Gafanov R, Hawkins R, Nosov D, et al. Pembrolizumab (pembro) plus axitinib (axi) versus sunitinib as first-line therapy for metastatic renal cell carcinoma (mRCC): outcomes in the combined IMDC intermediate/poor risk and sarcomatoid subgroups of the phase 3 KEYNOTE-426 study. J Clin Oncol. 2019;37:4500. https://doi.org/10.1200/jco.2019.37.15_suppl.4500.

    Article  Google Scholar 

  90. Lee J-L, Ziobro M, Gafanov R, Matveev VB, Suarez C, Donskov F, et al. KEYNOTE-427 cohort B: first-line pembrolizumab (pembro) monotherapy for advanced non–clear cell renal cell carcinoma (NCC-RCC). J Clin Oncol. 2019;37:4569. https://doi.org/10.1200/jco.2019.37.15_suppl.4569.

    Article  Google Scholar 

  91. McDermott DF, Choueiri TK, Motzer RJ, et al. CheckMate 214 post-hoc analyses of nivolumab plus ipilimumab or sunitinib in IMDC intermediate/poor-risk patients with previously untreated advanced renal cell carcinoma with sarcomatoid features. J Clin Oncol. 2019;37:4513. https://doi.org/10.1200/jco.2019.37.15_suppl.4513.

    Article  Google Scholar 

  92. Rini BI, Motzer RJ, Powles T, McDermott DF, Escudier B, Donskov F, et al. Atezolizumab (atezo) + bevacizumab (bev) versus sunitinib (sun) in pts with untreated metastatic renal cell carcinoma (mRCC) and sarcomatoid (sarc) histology: IMmotion151 subgroup analysis. J Clin Oncol. 2019;37:4512. https://doi.org/10.1200/jco.2019.37.15_suppl.4512.

    Article  Google Scholar 

  93. Bristol Myers Squibb and Exelixis announce positive topline results from pivotal phase 3 CheckMate -9ER trial evaluating - Bloomberg. https://www.bloomberg.com/press-releases/2020-04-20/bristol-myers-squibb-and-exelixis-announce-positive-topline-results-from-pivotal-phase-3-checkmate-9er-trial-evaluating. Accessed 18 Jul 2020.

  94. 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;378:1277–90. https://doi.org/10.1056/NEJMoa1712126.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Grünwald V, Powles T, Choueiri TK, Hutson TE, Porta C, Eto M, et al. Lenvatinib plus everolimus or pembrolizumab versus sunitinib in advanced renal cell carcinoma: study design and rationale. Future Oncol. 2019;15:929–41. https://doi.org/10.2217/fon-2018-0745.

    Article  CAS  PubMed  Google Scholar 

  96. Hatton W, Basu A, Koshkin VS, Kilari D, Jaeger E, Ledet EM, et al. First-line PD-1/PD-L1 inhibitor monotherapy for advanced renal cell carcinoma (aRCC): a multi-institutional cohort. J Clin Oncol. 2020;38:e17109. https://doi.org/10.1200/jco.2020.38.15_suppl.e17109.

    Article  Google Scholar 

  97. Escudier B, Bellmunt J, Négrier S, Bajetta E, Melichar B, Bracarda S, et al. Phase III trial of bevacizumab plus interferon alfa-2a in patients with metastatic renal cell carcinoma (AVOREN): final analysis of overall survival. J Clin Oncol. 2010;28:2144–50. https://doi.org/10.1200/JCO.2009.26.7849.

    Article  CAS  PubMed  Google Scholar 

  98. Sternberg CN, Hawkins RE, Wagstaff J, Salman P, Mardiak J, Barrios CH, et al. A randomised, double-blind phase III study of pazopanib in patients with advanced and/or metastatic renal cell carcinoma: final overall survival results and safety update. Eur J Cancer. 2013;49:1287–96. https://doi.org/10.1016/j.ejca.2012.12.010.

    Article  CAS  PubMed  Google Scholar 

  99. 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. https://doi.org/10.1016/j.ejca.2018.02.012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Nivolumab plus cabozantinib improves OS in CheckMate-9ER frontline RCC trial | OncLive. https://www.onclive.com/view/nivolumab-plus-cabozantinib-improves-os-in-checkmate9er-frontline-rcc-trial. Accessed 18 Jul 2020.

  101. Tannir NM, Agarwal N, Pal SK, Cho DC, Formiga M, Guo J, et al. PIVOT-09: a phase III randomized open-label study of bempegaldesleukin (NKTR-214) plus nivolumab versus sunitinib or cabozantinib (investigator’s choice) in patients with previously untreated advanced renal cell carcinoma (RCC). J Clin Oncol. 2020;38:TPS763. https://doi.org/10.1200/jco.2020.38.6_suppl.tps763.

    Article  Google Scholar 

  102. Exelixis initiating phase 3 pivotal trial (COSMIC-313) of cabozantinib in combination with nivolumab and ipilimumab versus nivolumab and ipilimumab in previously untreated advanced renal cell carcinoma | Exelixis, Inc. https://ir.exelixis.com/news-releases/news-release-details/exelixis-initiating-phase-3-pivotal-trial-cosmic-313. Accessed 18 Jul 2020.

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Authors and Affiliations

  1. Tulane University School of Medicine, 1415 Tulane Ave, New Orleans, LA, 70112, USA

    Bryce R. Christensen MD, MBA, Yasmin M. Hajja MD & Pedro C. Barata MD, MSc

  2. Department of Internal Medicine, Brooke Army Medical Center, San Antonio, TX, USA

    Bryce R. Christensen MD, MBA

  3. Tulane Cancer Center, New Orleans, LA, USA

    Yasmin M. Hajja MD & Pedro C. Barata MD, MSc

  4. University of California, 1825 Fourth St Sixth Floor, San Francisco, CA, 94158, USA

    Vadim Koshkin MD

  5. Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA, 70112, USA

    Pedro C. Barata MD, MSc

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Correspondence to Pedro C. Barata MD, MSc.

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Bryce R. Christensen declares that he has no conflict of interest.

Yasmin M. Hajja declares that she has no conflict of interest.

Vadim Koshkin has received compensation from Pfizer, Janssen, Dendreon, and AstraZeneca for participation on advisory boards.

Pedro C. Barata has received research funding from Blue Earth Diagnostics, Inc. and EMD Serono; and has received honoraria (paid to his institution) from Pfizer, Dendreon, Astellas, Clovis Oncology, Bayer, Eisai, Janssen, Bristol Myers Squibb, and Caris Life Sciences for service as a consultant (paid to his institution).

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Christensen, B.R., Hajja, Y.M., Koshkin, V. et al. Update on First-Line Combination Treatment Approaches in Metastatic Clear-Cell Renal Cell Carcinoma. Curr. Treat. Options in Oncol. 22, 15 (2021). https://doi.org/10.1007/s11864-020-00814-z

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