Emerging Therapies for Advanced Clear Cell Renal Cell Carcinoma

Main Article Content

Alexander T. Toth
Daniel Cho


Renal Cell Carcinoma, Systemic therapy, Immunotherapy, TKI, HIF


Multiple combinational regimens have recently been approved and are now considered the standard of care for patients with advanced clear cell renal cell carcinoma (RCC). Several additional combinational regimens are deep in clinical assessment and are likely to soon join the crowded front-line therapeutic landscape. Most of these regimens are combinations of agents already approved as single-agents in RCC including tyrosine kinase inhibitors (TKI) and immune checkpoint inhibitors. While these new front-line regimens are associated with reliably high response rates and prolonged survival, complete and durable remissions remain limited to a small subset of patients and the vast majority of patients continue to require subsequent therapy. The need for the continued development of novel agents in RCC persists and efforts have focused on agents targeting the molecular biology of clear cell RCC and novel immunotherapies including cytokines. In this review, we discuss the progress in the development of these novel therapies in the context of the evolving standard of care for patients with advanced clear cell RCC.

Abstract 231 | PDF Downloads 53 XML Downloads 31 HTML Downloads 11


1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020 Jan;70(1):7–30. http://dx.doi.org/10.3322/ caac.21590
2. Lam JS, Belldegrun AS, Pantuck AJ. Long-term outcomes of the surgical management of renal cell carcinoma. World J Urol. 2006 Aug;24(3):255–66. http://dx.doi.org/10.1007/ s00345-006-0055-5
3. Garcia J, Rini BI. Recent progress in the management of advanced renal cell carcinoma. CA Cancer J Clin. 2007 Mar- Apr;57(2):112–25. http://dx.doi.org/10.3322/canjclin.57.2.112
4. Hsieh JJ, Purdue MP, Signoretti S, Swanton C, Albiges L, Schmidinger M, et al. Renal cell carcinoma. Nat Rev Dis Primers. 2017 Mar 9;3:17009. http://dx.doi.org/10.1038/nrdp.2017.9
5. Kovacs G, Akhtar M, Beckwith BJ, Bugert P,  Cooper CS,  Delahunt B, et al. The Heidelberg classification of renal cell tumours. J Pathol. 1997 Oct;183(2):131–3. http://dx.doi. org/10.1002/(SICI)1096-9896(199710)183:2<131::AID-PATH931>3.0.CO;2-G
6. Reuter VE, Presti JC Jr. Contemporary approach to the classification of renal epithelial tumors. Semin Oncol. 2000 Apr;27:124–37. Retrieved from: https://pubmed.ncbi.nlm.nih. gov/10768592/
7. Zbar B, Brauch H, Talmadge C, Linehan WM. Loss of alleles of loci on the short arm of chromosome 3 in renal cell carcinoma. Nature. 1987 Jun–Jul;327(6124):721–4. http://dx.doi. org/10.1038/327721a0
8. Kroeger N, Klatte T, Chamie K, Rao PN, Birkhauser FD, Sonn GA, et al. Deletions of chromosome 3p and 14 q molecularly subclassify clear cell renal cell carcinoma. Cancer. 2013 Apr;119(8):1547–54. http://dx.doi.org/10.1002/cncr.27947
9. Iliopoulos O, Kibel A, Gray S, Kaelin WG Jr. Tumour suppres-sion by the human von Hippel-Lindau gene product. Nat Med. 1995 Oct;1(8):822–6. http://dx.doi.org/10.1038/nm0895-822
10. Ricketts CJ, De Cubas AA, Fan H, Smith CC, Lang M, Reznik E, et al. The Cancer Genome Atlas comprehensive molecular characterization of renal cell carcinoma. Cell Rep. 2018 Apr;23(1):313–26.e5. http://dx.doi.org/10.1016/j. celrep.2018.03.075
11. Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, Gaskell  SJ, et al. Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydrox-ylation. Science. 2001 Apr;292(5516):468–72. http://dx.doi. org/10.1126/science.1059796
12. de Paulsen N, Brychzy A, Fournier MC, Klausner RD, Gnarra  JR, Pause A, et al. Role of transforming growth factor-alpha in von Hippel–Lindau (VHL)(-/-) clear cell renal carcinoma cell proliferation: A possible mechanism coupling VHL tumor suppressor inactivation and tumorigenesis. Proc Natl Acad Sci U S A. 2000 Feb;98(4):1387–92. http://dx.doi. org/10.1073/pnas.031587498
13. Kondo K, Kico J, Nakamura E, Lechpammer M, Kaelin, W. Inhibition of HIF is necessary for tumor suppression by the von Hippel-Lindau protein. Cancer Cell. 2002 Apr;1(3):237–46. http://dx.doi.org/10.1016/s1535-6108(02)00043-0
14. Maranchie JK, Vasselli JR, Riss J, Bonifacino JS, Linehan WM, Klausner RD. The contribution of VHL substrate binding and HIF-1? to the phenotype of VHL loss in renal cell carcinoma. Cancer Cell. 2002 Apr;1(3):247–55. http://dx.doi.org/10.1016/ s1535-6108(02)00044-2
15. Mitchell TJ, Turajlic S, Rowan A, Nicol D, Farmery JHR, O’Brien T, et al. Timing the landmark events in the evolution of clear cell renal cell cancer: TRACERx renal. Cell. 2018 Apr;173(3):611–23.e17. http://dx.doi.org/10.1016/j. cell.2018.02.020
16. Voss MH, Reising A, Cheng Y, Patel P, Marker M, Kuo  F, et al. Genomically annotated risk model for advanced renal-cell carcinoma: A retrospective cohort study. Lancet Oncol. 2018 Dec;19(12):1688–98. http://dx.doi.org/10.1016/ S1470-2045(18)30648-X
17. Hsieh JJ, Chen D, Wang PI, Marker M, Redzematovic A, Chen  YB, et al. Genomic biomarkers of a randomized trial comparing first-line everolimus and sunitinib in patients with metastatic renal cell carcinoma. Eur Urol. 2017 Mar;71(3):405– 14. http://dx.doi.org/10.1016/j.eururo.2016.10.007
18. Liu XD, Kong W, Peterson CB, McGrail DJ, Hoang A, Zhang X, et al. PBRM1 loss defines a nonimmunogenic tumor phenotype associated with checkpoint inhibitor resistance in renal carcinoma. Nat Commn. 2020 May;11(1):2135. http://dx. doi.org/10.1038/s41467-020-15959-6
19. 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 Dec;345(23):1655–9. http://dx.doi. org/10.1056/NEJMoa003013
20. 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 ran-domized clinical trial. JAMA Oncol. 2019 Feb;5(2):164–70. http://dx.doi.org/10.1001/jamaoncol.2018.5543
21. Mejean A, Ravaud A, Thezenas S, Colas S, Beauval JB, Bensalah K, et al. Sunitinib alone or after nephrectomy in meta-static renal-cell carcinoma. N Engl J Med. 2018 Aug;379(5):417– 27. http://dx.doi.org/10.1056/NEJMoa1803675
22. Mejean A, Thezenas S, Chevreau C, Bensalah K, Geoffrols L, Theiry-Vuillemjn, 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 May;37(Suppl 15):4508. http://dx.doi.org/10.1200/ JCO.2019.37.15_suppl.4508
23. 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 Apr;378(14):1277–90. http://dx.doi.org/10.1056/ NEJMoa1712126
24. Motzer RJ, Escudier B, McDermott DF, Arén Frontera O, Melichar B, Powles T, et al. Survival outcomes and independent 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 Jul;8(2):e000891. http://dx.doi.org/10.1136/ jitc-2020-000891
25. Motzer RJ, Jonasch E, Michaelson MD, Nandagopal L, Gore JL, George S, et al. NCCN guidelines insights: kidney cancer, version 2020. J Natl Compr Cancer Netw. 2019 Nov;17(11):1279–85. http://dx.doi.org/10.6004/jnccn.2019.0054
26. Rini BI, Plimack ER, Stus V, Gafanov R, Hawkins R, Nosov D, et al. Renal cell carcinoma. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019 Mar;380(12):1116–27. http://dx.doi.org/10.1056/ NEJMoa1816714
27. 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 Mar;380(12):1103–15. http:// dx.doi.org/10.1056/NEJMoa1816047
28. Choueiri TK, Motzer RJ, Rini BI, Haanen J, Campbell MT, Venugopal B, et al. Updated efficacy results from the JAVELIN Renal 101 trial: First-line avelumab plus axitinib versus suni-tinib in patients with advanced renal cell carcinoma. Ann Oncol. 2020 Aug;31(8):1030–9. http://dx.doi.org/10.1016/j. annonc.2020.04.010
29. Gul A, Stewart TF, Mantia CM, Shah NJ, Gatof ES, Long Y, et al. Salvage ipilimumab and nivolumab in patients with met-astatic renal cell carcinoma after prior immune checkpoint inhibitors. J Clin Oncol. 2020 Sep;38(27):3088–94. http://dx.doi. org/10.1200/JCO.19.03315
30. Vlachostergios PJ. Resistance to pembrolizumab and axitinib in renal cell carcinoma: Clinical and genomic evaluation. J Kidney Cancer VHL. 2020 Jun;7(1):7–11. http://dx.doi.org/10.15586/ jkcvhl.2020.135
31. Bristol Myers Squibb and Exelixis announce positive topline results from pivotal phase 3 checkmate-9ER trial evaluating Opdivo® (nivolumab) in combination with CABOMETYX® (cabozantinib) in previously untreated advanced renal cell carcinoma [Internet]. [cited 2020 April 20]. Available from: https:// bit.ly/2RRBItE
32. Gordan JD, Lal P, Dondeti VR, Letrero R, Parekh KN, Oquendo CE, et al. HIF-alpha effects on c-Myc distinguish two subtypes of sporadic VHL-deficient clear cell renal carcinoma. Cancer Cell. 1999 Dec;14(6):435–46. http://dx.doi.org/10.1016/j. ccr.2008.10.016
33. Kondo K, Kim WY, Lechpammer M, Kaelin WG. Inhibition of HIF2alpha is sufficient to suppress pVHL-defective tumor growth. PLoS Biol. 2003 Dec;1(3):E83. http://dx.doi. org/10.1371/journal.pbio.0000083
34. Zimmer M, Doucette D, Siddiqui N, Iliopoulos O. Inhibition of hypoxia-inducible factor is sufficient for growth suppression of VHL -/- tumors. Mol Cancer Res. 2004 Feb;2(2):89–95. http:// dx.doi.org/10.1017/CBO9781139052443.012
35. Shen C, Beroukhim R, Schumacher SE, Zhou J, Chang M, Signoretti S, et al. Genetic and functional studies implicate HIF1? as a 14q kidney cancer suppressor gene. Cancer Discovery. 2011 Aug;1(3):222–35. http://dx.doi.org/10.1158/ 2159-8290.CD-11-0098
36. Courtney KD, Infante JR, Lam ET, Figlin RA, Rini BI, Brugarolas J, et al. Phase I dose-escalation trial of PT2385, a first-in-class hypoxia inducible factor-2? antagonist in patients with previously treated advanced clear cell renal cell carcinoma. J Clin Oncol. 2017 Mar; 36(9):867–75. http://dx.doi.org/10.1200/ JCO.2017.74.2627
37. Papadopoulos KP, Jonasch E, Zojwalla NJ, Wang K, Bauer TM. A first-in-human phase 1 dose-escalation trial of the oral HIF-2a inhibitor PT2977 in patients with advanced solid tumors. J Clin Oncol. 2018 May;36(Suppl 15):2508. http://dx. doi.org/10.1093/annonc/mdz249
38. Choueiri TK, Plimack ER, Bauer TM, Merchan J, Papadopoulos KP, McDermott DF, et al. Phase I/II study of the oral HIF-2? inhibitor MK-6482 in patients with advanced clear cell renal cell carcinoma (RCC). J Clin Oncol. 2020 Feb;38(Suppl 6):611. http://dx.doi.org/10.1200/JCO.2020.38.6_suppl.611
39. Jonasch E, Donskov F, Iliopoulos O, Rathmell WK, Narayan V, Maughan BL, et al. Phase II study of the oral HIF-2? inhibitor MK-6482 for von Hippel-Lindau disease–associated renal cell carcinoma. J Clin Oncol. 2020 May;38(Suppl 15):5003. http:// dx.doi.org/10.1200/JCO.2020.38.15_SUPPL.5003
40. Wetterstein HI, Aboud OA, Lara PN, Weiss RH. Metabolic reprogramming in clear cell renal cell carcinoma. Nat Rev Urol. 2017 Jul;13(7):410–19. http://dx.doi.org/10.1038/nrneph.2017.59
41. Mullen AR, Wheaton WW, Jin ES, Chen PH, Sullivan LB, Cheng T, et al. Reductive carboxylation supports growth in tumor cells with defective mitochondria. Nature. 2012 Nov;481(7381):385–8. http://dx.doi.org/10.1038/nature10642
42. Tannir NM, Fan AC, Lee RJ, Carthon BC, Iliopoulos O, Mier  JW, et al. Phase 1 study of glutaminase (GLS) inhibitor CB-839 combined with either everolimus (E) or cabozantinib (Cabo) in patients (pts) with clear cell (cc) and papillary (pap) metastatic renal cell cancer (mRCC). J Clin Oncol. 2018 Feb;36 (Suppl 6):603. http://dx.doi.org/10.1200/JCO.2018.36.6_suppl.603
43. Meric-Bernstam F, Lee RJ, Carthon BC, Iliopoulos O, Mier JW, Patel MR, et al. CB-839, a glutaminase inhibitor, in combination with cabozanitinb in patients with clear cell and papillary metastatic renal cell carcinoma (mRCC): Results of a phase I study. J Clin Oncol. 2019 Feb;37(Suppl 7):549. http://dx.doi. org/10.1200/JCO.2019.37.7_suppl.549
44. Young A, Ngiow SF, Gao Y, Patch AM, Barkauskas DS, Messaoudene M, et al. A2AR adenosine signaling suppresses natural killer cell maturation in the tumor microenvironment. Cancer Res. 2018 Feb;78(4):1003–16. http://dx.doi. org/10.1158/0008-5472.CAN-17-2826
45. Cekic C, Linden J. Adenosine A2A receptors intrinsically regulate CD8+ T cells in the tumor microenvironment. Cancer Res. 2014 Dec;74(24):7239–49. http://dx.doi.org/10.1158/0008-5472. CAN-13-3581
46. Maj T, Wang W, Crespo J, Zhang H, Wang W, Wei S, et al. Oxidative stress controls regulatory T cell apoptosis and suppressor activity and PD-L1 blockade resistance in tumor. Nat Immunol. 2017 Dec;18(12):1332–41. http://dx.doi.org/10.1038/ ni.3868
47. Beavis PA, Milenkovski N, Henderson MA, John LB, Allard B, Loi S, et al. Adenosine receptor 2A blockade increases efficacy of anti-PD1 through enhanced antitumor T-cell response. Cancer Immunol Res. 2015 May;3(5):506–17. http://dx.doi. org/10.1158/2326-6066.CIR-14-0211
48. Fong L, Hotson A, Powderly JD, Sznol M, Heist RS, Choueiri  TK, et al. Adenosine 2A receptor blockade as an immunotherapy for treatment-refractory renal cell carci-noma. Cancer Discov. 2019 Jan;10(1):40–53. http://dx.doi. org/10.1158/2159-8290.CD-19-0980
49. Bentebibel SE, Hurwitz ME, Benatchez C, Haymaker C, Hudgens CW, Kluger HM, et al. A first-in-human study and biomarker analysis of NKTR-214, a novel IL2R??-biased cytokine, in patients with advanced or metastatic solid tumors. Cancer Discov. 2019 Jun;9(6):711–21. http://dx.doi.org/10.1158/2159-8290.CD-18-1495
50. Diab, A, Tannir NM, Bentebibel SE, Hwu P, Papadimitrakopoulou V, Haymaker C, et al. Bempegaldesleukin (NKTR-214) plus nivolumab in patients with advanced solid tumors: Phase I dose-escalation study of safety, efficacy, and immune activation (PIVOT-02). Cancer Discov. 2020 Aug;10(8):1158–73. http://dx.doi.org/10.1158/2159-8290. CD-19-1510
51. Vaishampayan UN, Fishman MN, Cho DC, Holmes CJ, Velcheti  V, McDermott DF, et al. Intravenous administration of ALKS 4230 as monotherapy and in combination with pembrolizumab in a phase I study of patients with advanced solid tumors. J Clin Oncol. 2019 May;37(Suppl 15):2649. http://dx. doi.org/10.1200/JCO.2019.37.15_suppl.TPS2649
52. Waldman TA. The shared and contrasting roles of IL-2 and IL-15 in the life and death of normal and neoplastic lymphocytes: Implications for cancer therapy. Cancer Immunol Res. 2015 Mar;3(3):219–27. http://dx.doi.org/10.1158/2326-6066. CIR-15-0009
53. Margolin K,  Morishima C,  Velcheti V,  Miller JS,  Lee SM, Silk AW, et al. Phase I trial of ALT-803, a novel recombinant IL-15 complex, in patients with advanced solid tumors. Clin Cancer Res. 2018; 24(22):5552–61. http://dx.doi. org/10.1158/1078-0432.CCR-18-0945
54. Wrangle JM, Velcheti V, Patel MR, Garrett-Mayer E, Hill EG, Ravenel JG, et al. ALT-803, an IL-15 superagonist, in combi-nation with nivolumab in patients with metastatic non-small cell lung cancer: A non-randomised, open-label, phase 1b trial. Lancet Oncol. 2018 May;19(5):694–704. http://dx.doi. org/10.1016/S1470-2045(18)30148-7
55. Trinchieri G. Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat Rev Immunol. 2003 Feb;133(2):133–46. http://dx.doi.org/10.1038/nri1001.
56. Del Vecchio M, Bajetta E, Canova S, Lotze MT, Wesa A, Parmiani G, et al. IL-12: Biological properties and clinical application. Clin Cancer Res. 2007 Aug;13(16):4677–85. http://dx. doi.org/10.1158/1078-0432.CCR-07-0776
57. Strauss J, Heery CR, Kim JW, Jochems C, Donahue RN, Montgomery AS, et al. First-in-human phase I trial of a tumor-targeted cytokine (NHS-IL12) in subjects with metastatic solid tumors. Clin Cancer Res. 2018 Jan;25(1):99–109. http://dx. doi.org/10.1158/1078-0432.CCR-18-1512
58. Tolcher AW, Sznol M, Hu-Lieskovan S, Papadopoulos KP, Patnaik A, Rasco DW, et al. Phase Ib study of utomilumab (PF-05082566), a 4-1BB/CD137 agonist, in combination with pembrolizumab (MK-3475) in patients with advanced solid tumors. Clin Cancer Res. 2017 Sep;23(18):5349–57. http://dx. doi.org/10.1158/1078-0432.CCR-17-1243
59. Zelba H, Bedke J, Hennenlotter J, Mostböck S, Zettl M, Zichner  T, et al. PD-1 and LAG-3 dominate checkpoint receptor–mediated t-cell inhibition in renal cell carcinoma. Cancer Immunol Res. 2019 Nov;7(11):1891–9. http://dx.doi. org/10.1158/2326-6066.CIR-19-0146
60. Ascierto PA, Merlero I, Shailender B, et al. Initial efficacy of anti-lymphocyte activation gene-3 (anti–LAG-3; BMS-986016) in combination with nivolumab (nivo) in pts with melanoma (MEL) previously treated with anti–PD-1/PD-L1 therapy. J Clin Oncol. 2017 May;35(Suppl 15):9520. http://dx.doi.org/10.1200/ JCO.2017.35.15_suppl.9520