REFERENCES

1. Ferlay J, Colombet M, Soerjomataram I, et al. Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. Int J Cancer 2019;144:1941-53.

2. Padala SA, Barsouk A, Thandra KC, et al. Epidemiology of Renal Cell Carcinoma. World J Oncol 2020;11:79-87.

3. Sorbellini M, Kattan MW, Snyder ME, et al. A postoperative prognostic nomogram predicting recurrence for patients with conventional clear cell renal cell carcinoma. J Urol 2005;173:48-51.

4. Surveillance, Epidemiology, and End Results Program, National Cancer Institute. Cancer stat facts: kidney and renal pelvis cancer. Available from: https://seer.cancer.gov/statfacts/html/kidrp.html [Last accessed on 21 May 2021].

5. Dizman N, Philip EJ, Pal SK. Genomic profiling in renal cell carcinoma. Nat Rev Nephrol 2020;16:435-51.

6. Ricketts CJ, De Cubas AA, Fan H, et al. Cancer Genome Atlas Research Network. The cancer genome atlas comprehensive molecular characterization of renal cell carcinoma. Cell Rep 2018;23:3698.

7. Nickerson ML, Jaeger E, Shi Y, et al. Improved identification of von Hippel-Lindau gene alterations in clear cell renal tumors. Clin Cancer Res 2008;14:4726-34.

8. Shen C, Kaelin WG Jr. The VHL/HIF axis in clear cell renal carcinoma. Semin Cancer Biol 2013;23:18-25.

9. Gossage L, Eisen T, Maher ER. VHL, the story of a tumour suppressor gene. Nat Rev Cancer 2015;15:55-64.

10. Motzer RJ, Hutson TE, Tomczak P, et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol 2009;27:3584-90.

11. Sternberg CN, Davis ID, Mardiak 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.

12. Motzer RJ, Hutson TE, Cella D, et al. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med 2013;369:722-31.

13. 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.

14. Iyer G, Hanrahan AJ, Milowsky MI, et al. Genome sequencing identifies a basis for everolimus sensitivity. Science 2012;338:221.

15. Motzer RJ, Escudier B, McDermott DF, et al. CheckMate 025 investigators. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med 2015;373:1803-13.

16. Motzer RJ, Tannir NM, McDermott DF, et al. CheckMate 214 Investigators. Nivolumab plus Ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med 2018;378:1277-90.

17. Heng DY, Xie W, Regan MM, et al. External validation and comparison with other models of the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model: a population-based study. Lancet Oncol 2013;14:141-8.

18. Motzer RJ, Bacik J, Murphy BA, Russo P, Mazumdar M. Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. J Clin Oncol 2002;20:289-96.

19. Jubb AM, Pham TQ, Hanby AM, et al. Expression of vascular endothelial growth factor, hypoxia inducible factor 1alpha, and carbonic anhydrase IX in human tumours. J Clin Pathol 2004;57:504-12.

20. Goel S, Duda DG, Xu L, et al. Normalization of the vasculature for treatment of cancer and other diseases. Physiol Rev 2011;91:1071-121.

21. Sennino B, McDonald DM. Controlling escape from angiogenesis inhibitors. Nat Rev Cancer 2012;12:699-709.

22. Lai Y, Zhao Z, Zeng T, et al. Crosstalk between VEGFR and other receptor tyrosine kinases for TKI therapy of metastatic renal cell carcinoma. Cancer Cell Int 2018;18:31.

23. 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;32:1412-8.

24. Hudes G, Carducci M, Tomczak P, et al. Global ARCC Trial. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 2007;356:2271-81.

25. Motzer RJ, Barrios CH, Kim TM, et al. Phase II randomized trial comparing sequential first-line everolimus and second-line sunitinib versus first-line sunitinib and second-line everolimus in patients with metastatic renal cell carcinoma. J Clin Oncol 2014;32:2765-72.

26. Motzer RJ, Jonasch E, Boyle S, et al. NCCN Guidelines Insights: Kidney Cancer, Version 1.2021. J Natl Compr Canc Netw 2020;18:1160-70.

27. Zhou L, Liu XD, Sun M, et al. Targeting MET and AXL overcomes resistance to sunitinib therapy in renal cell carcinoma. Oncogene 2016;35:2687-97.

28. Choueiri TK, Hessel C, Halabi S, 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.

29. Motzer R, Alekseev B, Rha SY, et al. CLEAR Trial Investigators. Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma. N Engl J Med 2021;384:1289-300.

30. Hutson TE, Lesovoy V, Al-shukri S, et al. Axitinib versus sorafenib as first-line therapy in patients with metastatic renal-cell carcinoma: a randomised open-label phase 3 trial. Lancet Oncol 2013;14:1287-94.

31. Motzer RJ, Nosov D, Eisen T, et al. Tivozanib versus sorafenib as initial targeted therapy for patients with metastatic renal cell carcinoma: results from a phase III trial. J Clin Oncol 2013;31:3791-9.

32. Motzer RJ, Escudier B, Tomczak P, et al. Axitinib versus sorafenib as second-line treatment for advanced renal cell carcinoma: overall survival analysis and updated results from a randomised phase 3 trial. Lancet Oncol 2013;14:552-62.

33. Rini BI, Pal SK, Escudier BJ, et al. Tivozanib versus sorafenib in patients with advanced renal cell carcinoma (TIVO-3): a phase 3, multicentre, randomised, controlled, open-label study. Lancet Oncol 2020;21:95-104.

34. McDermott DF, Cheng SC, Signoretti S, et al. The high-dose aldesleukin "select" trial: a trial to prospectively validate predictive models of response to treatment in patients with metastatic renal cell carcinoma. Clin Cancer Res 2015;21:561-8.

35. Coppin C, Porzsolt F, Autenrieth M, et al. . Immunotherapy for advanced renal cell cancer. Cochrane database of systematic reviews. Chichester: John Wiley & Sons, Ltd; 1996.

36. Blankenstein T, Coulie PG, Gilboa E, Jaffee EM. The determinants of tumour immunogenicity. Nat Rev Cancer 2012;12:307-13.

37. Kopecky O, Lukesová S, Vroblová V, et al. Phenotype analysis of tumour-infiltrating lymphocytes and lymphocytes in peripheral blood in patients with renal carcinoma. Acta Medica (Hradec Kralove) 2007;50:207.

38. Komohara Y, Hasita H, Ohnishi K, et al. Macrophage infiltration and its prognostic relevance in clear cell renal cell carcinoma. Cancer Sci 2011;102:1424-31.

39. Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity 2013;39:1-10.

40. Walker LS, Sansom DM. The emerging role of CTLA4 as a cell-extrinsic regulator of T cell responses. Nat Rev Immunol 2011;11:852-63.

41. Dong Y, Sun Q, Zhang X. PD-1 and its ligands are important immune checkpoints in cancer. Oncotarget 2017;8:2171.

42. Hammers HJ, Plimack ER, Infante JR, et al. Safety and efficacy of nivolumab in combination with ipilimumab in metastatic renal cell carcinoma: the CheckMate 016 study. J Clin Oncol 2017;35:3851-8.

43. Motzer RJ, Escudier B, McDermott DF, et al. Survival outcomes and independent response assessment with nivolumab plus ipilimumab versus sunitinib in patients with advanced renal cell carcinoma: 42-month follow-up of a randomized phase 3 clinical trial. J Immunother Cancer 2020;8:e000891.

44. Tannir NM, McDermott DF, Escudier B, Hammers HJ, et al. Overall survival and independent review of response in CheckMate 214 with 42-month follow-up: first-line nivolumab + ipilimumab (N+I) versus sunitinib (S) in patients (pts) with advanced renal cell carcinoma (aRCC). J Clin Oncol 2020;38:6_suppl, 609.

45. Tannir NM, Signoretti S, Choueiri TK, et al. Efficacy and Safety of Nivolumab Plus Ipilimumab versus Sunitinib in First-line Treatment of Patients with Advanced Sarcomatoid Renal Cell Carcinoma. Clin Cancer Res 2021;27:78-86.

46. Tykodi SS, Donskov F, Lee JL, Szczylik C, Malik J et al. First-line pembrolizumab (pembro) monotherapy in advanced clear cell renal cell carcinoma (ccRCC): updated results for KEYNOTE-427 cohort A. J Clin Oncol 2019;37:15_suppl, 4570.

47. Atkins MB, Jegede O, Haas NB, et al. Phase II study of nivolumab and salvage nivolumab + ipilimumab in treatment-naïve patients (pts) with advanced renal cell carcinoma (RCC) (HCRN GU16-260). J Clin Oncol 2020;38(15_suppl):5006.

48. US National Library of Medicine. Available from: https://clinicaltrials.gov/ct2/show/NCT03873402 (2021) [Last accessed on 21 May 2021].

49. Guislain A, Gadiot J, Kaiser A, et al. Sunitinib pretreatment improves tumor-infiltrating lymphocyte expansion by reduction in intratumoral content of myeloid-derived suppressor cells in human renal cell carcinoma. Cancer Immunol Immunother 2015;64:1241-50.

50. Kwilas AR, Ardiani A, Donahue RN, Aftab DT, Hodge JW. Dual effects of a targeted small-molecule inhibitor (cabozantinib) on immune-mediated killing of tumor cells and immune tumor microenvironment permissiveness when combined with a cancer vaccine. J Transl Med 2014;12:294.

51. Li YL, Zhao H, Ren XB. Relationship of VEGF/VEGFR with immune and cancer cells: staggering or forward? Cancer Biol Med 2016;13:206-14.

52. Kwilas AR, Donahue RN, Tsang KY, Hodge JW. Immune consequences of tyrosine kinase inhibitors that synergize with cancer immunotherapy. Cancer Cell Microenviron 2015;2:e677.

53. Zhang Q, Tian K, Xu J, et al. Synergistic Effects of Cabozantinib and EGFR-Specific CAR-NK-92 Cells in Renal Cell Carcinoma. J Immunol Res 2017;2017:6915912.

54. Bao Y, Wang Z, Liu B, et al. A feed-forward loop between nuclear translocation of CXCR4 and HIF-1α promotes renal cell carcinoma metastasis. Oncogene 2019;38:881-95.

55. Liu XD, Hoang A, Zhou L, et al. Resistance to Antiangiogenic Therapy Is Associated with an Immunosuppressive Tumor Microenvironment in Metastatic Renal Cell Carcinoma. Cancer Immunol Res 2015;3:1017-29.

56. Hipp MM, Hilf N, Walter S, et al. Sorafenib, but not sunitinib, affects function of dendritic cells and induction of primary immune responses. Blood 2008;111:5610-20.

57. 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.

58. 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;393:2404-15.

59. Rini BI, Plimack ER, Stus V, et al. KEYNOTE-426 Investigators. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 2019;380:1116-27.

60. Powles T, Plimack ER, Soulières D, Waddell T, Stus V et al. Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): extended follow-up from a randomized, open-label, phase 3 trial. Lancet Oncol 2020;21:1563-73.

61. 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.

62. Choueiri TK, Motzer RJ, Rini BI, et al. Updated efficacy results from the JAVELIN Renal 101 trial: first-line avelumab plus axitinib versus sunitinib in patients with advanced renal cell carcinoma. Ann Oncol 2020;31:1030-9.

63. Choueiri TK, Powles T, Burotto M, et al. CheckMate 9ER Investigators. Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 2021;384:829-41.

64. Regan MM, Atkins MB, Powles T, Werner L, Mantia C et al. Treatment-free survival, with and without toxicity, as a novel outcome applied to immuno-oncology agents in advanced renal cell carcinoma. Ann Oncol 2019;30:v393-4.

65. Regan M, Jegede OA, Mantia C, Powles T, Werner L et al. 713P Treatment-free survival, with and without toxicity, after immuno-oncology vs targeted therapy for advanced renal cell carcinoma (aRCC): 42-month results of CheckMate 214. Ann Oncol 2020;31:S561.

66. Cella D, Grünwald V, Escudier B, et al. Patient-reported outcomes of patients with advanced renal cell carcinoma treated with nivolumab plus ipilimumab versus sunitinib (CheckMate 214): a randomised, phase 3 trial. Lancet Oncol 2019;20:297-310.

67. Leite KR, Reis ST, Junior JP, et al. PD-L1 expression in renal cell carcinoma clear cell type is related to unfavorable prognosis. Diagn Pathol 2015;10:189.

68. Iacovelli R, Nolè F, Verri E, et al. Prognostic Role of PD-L1 Expression in Renal Cell Carcinoma. A Systematic Review and Meta-Analysis. Target Oncol 2016;11:143-8.

69. Motzer RJ, Banchereau R, Hamidi H, et al. Molecular Subsets in Renal Cancer Determine Outcome to Checkpoint and Angiogenesis Blockade. Cancer Cell 2020;38:803-17.e4.

70. Kapur P, Christie A, Rajaram S, Brugarolas J. What morphology can teach us about renal cell carcinoma clonal evolution. Kidney Cancer J 2020;18:68-75.

71. Gu YF, Cohn S, Christie A, et al. Modeling renal cell carcinoma in mice: Bap1 and Pbrm1 inactivation drive tumor grade. Cancer Discov 2017;7:900-17.

72. Brugarolas J, Rajaram S, Christie A, Kapur P. The Evolution of Angiogenic and Inflamed Tumors: The Renal Cancer Paradigm. Cancer Cell 2020;38:771-3.

73. Flanigan RC, Salmon SE, Blumenstein BA, 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.

74. 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.

75. Méjean 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.

76. Bex A, Mulders P, Jewett M, 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.

77. US National Library of Medicine. Available from: https://clinicaltrials.gov/ct2/show/NCT03977571 (2021) [Last accessed on 21 May 2021].

78. US National Library of Medicine. Available from: https://clinicaltrials.gov/ct2/show/NCT04090710 (2021) [Last accessed on 21 May 2021].

79. US National Library of Medicine. Available from: https://clinicaltrials.gov/ct2/show/NCT04322955 (2021) [Last accessed on 21 May 2021].

80. US National Library of Medicine. Available from: https://clinicaltrials.gov/ct2/show/NCT04510597 (2021) [Last accessed on 21 May 2021].

81. US National Library of Medicine. Available from: https://clinicaltrials.gov/ct2/show/NCT03937219 (2021) [Last accessed on 21 May 2021].

82. US National Library of Medicine. Available from: https://clinicaltrials.gov/ct2/show/NCT03793166 (2021) [Last accessed on 21 May 2021].