The Search for the Optimal Immunotherapy Sequencing in the Perioperative Setting of RCC

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Neoadjuvant Immunotherapy Treatment of Localized Genitourinary Cancers

Abstract

Based on the S-TRAC study, sunitinib was approved as adjuvant therapy for high-risk renal cell carcinoma after nephrectomy; however, the role of perioperative immunotherapy is less clear. Multiple immunotherapy combinations have shown clinical benefit superior to sunitinib in metastatic renal cell carcinoma, but their role in localized or locally advanced renal cell carcinoma still remains controversial. The importance of neoadjuvant immunotherapy in patients with locally advanced RCC is currently under investigation in a large phase 3 clinical trial (PROSPER RCC) and other phase 2 studies investigating PD-1 inhibitors with or without CTLA-4 inhibitors. Multiple ongoing clinical trials (IMmotion010, KEYNOTE-564, and CheckMate 914) are evaluating the adjuvant role of immunotherapy. For the majority of patients with synchronous metastatic renal cell carcinoma, combinations with immunotherapy are now the preferred initial treatment compared to upfront cytoreductive nephrectomy. The timing and benefit of consolidative nephrectomy following immunotherapy combinations are under investigation. Over the next 5 years, these trials will further elucidate optimal timing of immunotherapy in the perioperative setting.

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References

  1. Miller DC, Ruterbusch J, Colt JS, et al. Contemporary clinical epidemiology of renal cell carcinoma: insight from a population based case-control study. J Urol [Internet]. 2010;184(6):2254–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20952033

    PubMed  Google Scholar 

  2. Ghali F, Patel SH, Derweesh IH. Current status of immunotherapy for localized and locally advanced renal cell carcinoma. J Oncol [Internet]. 2019;2019:7309205. Available from: http://www.ncbi.nlm.nih.gov/pubmed/31057615

    PubMed  Google Scholar 

  3. Chow W-H, Dong LM, Devesa SS. Epidemiology and risk factors for kidney cancer. Nat Rev Urol [Internet]. 2010;7(5):245–57. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20448658

    PubMed  Google Scholar 

  4. Kane CJ, Mallin K, Ritchey J, Cooperberg MR, Carroll PR. Renal cell cancer stage migration: analysis of the National Cancer Data Base. Cancer [Internet]. 2008;113(1):78–83. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18491376

    PubMed  Google Scholar 

  5. Martinez Chanza N, Tripathi A, Harshman LC. Adjuvant therapy options in renal cell carcinoma: where do we stand? Curr Treat Options Oncol [Internet]. 2019;20(5):44. Available from: http://www.ncbi.nlm.nih.gov/pubmed/31054006

    PubMed  Google Scholar 

  6. Berquist SW, Yim K, Ryan ST, et al. Systemic therapy in the management of localized and locally advanced renal cell carcinoma: current state and future perspectives. Int J Urol [Internet]. 2019;26(5):532–42. Available from: http://www.ncbi.nlm.nih.gov/pubmed/30943578

    PubMed  Google Scholar 

  7. Gleeson JP, Motzer RJ, Lee C-H. The current role for adjuvant and neoadjuvant therapy in renal cell cancer. Curr Opin Urol [Internet]. 2019;29(6):636–42. Available from: http://www.ncbi.nlm.nih.gov/pubmed/31348025

    PubMed  Google Scholar 

  8. Harshman LC, Drake CG, Haas NB, et al. Transforming the perioperative treatment paradigm in non-metastatic RCC-A possible path forward. Kidney Cancer [Internet]. 2017;1(1):31–40. Available from: http://www.ncbi.nlm.nih.gov/pubmed/30334002

    CAS  PubMed  Google Scholar 

  9. Shuch B, Riggs SB, LaRochelle JC, et al. Neoadjuvant targeted therapy and advanced kidney cancer: observations and implications for a new treatment paradigm. BJU Int [Internet]. 2008;102(6):692–6. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18410444

    PubMed  Google Scholar 

  10. Griffioen AW, Mans LA, de Graaf AMA, et al. Rapid angiogenesis onset after discontinuation of sunitinib treatment of renal cell carcinoma patients. Clin Cancer Res [Internet]. 2012;18(14):3961–71. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22573349

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Borregales LD, Adibi M, Thomas AZ, Wood CG, Karam JA. The role of neoadjuvant therapy in the management of locally advanced renal cell carcinoma. Ther Adv Urol [Internet]. 2016;8(2):130–41. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27034725

    CAS  PubMed  Google Scholar 

  12. van der Veldt AAM, Meijerink MR, van den Eertwegh AJM, et al. Sunitinib for treatment of advanced renal cell cancer: primary tumor response. Clin Cancer Res [Internet]. 2008;14(8):2431–6. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18413834

    PubMed  Google Scholar 

  13. Thomas AA, Rini BI, Lane BR, et al. Response of the primary tumor to neoadjuvant sunitinib in patients with advanced renal cell carcinoma. J Urol [Internet]. 2009;181(2):518–23; discussion 523. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19100579

    CAS  PubMed  Google Scholar 

  14. Zhang Y, Li Y, Deng J, Ji Z, Yu H, Li H. Sorafenib neoadjuvant therapy in the treatment of high risk renal cell carcinoma. PLoS One [Internet]. 2015;10(2):e0115896. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25647522

    PubMed  Google Scholar 

  15. Field CA, Cotta BH, Jimenez J, et al. Neoadjuvant sunitinib decreases inferior vena caval thrombus size and is associated with improved oncologic outcomes: a multicenter comparative analysis. Clin Genitourin Cancer [Internet]. 2019;17(3):e505–12. Available from: http://www.ncbi.nlm.nih.gov/pubmed/30808547

    PubMed  Google Scholar 

  16. Karam JA, Devine CE, Urbauer DL, et al. Phase 2 trial of neoadjuvant axitinib in patients with locally advanced nonmetastatic clear cell renal cell carcinoma. Eur Urol [Internet]. 2014;66(5):874–80. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24560330

    CAS  PubMed  Google Scholar 

  17. McDonald ML, Lane BR, Jimenez J, et al. Renal functional outcome of partial nephrectomy for complex R.E.N.A.L. score Tumors with or without neoadjuvant sunitinib: a multicenter analysis. Clin Genitourin Cancer [Internet]. 2018;16(2):e289–95. Available from: http://www.ncbi.nlm.nih.gov/pubmed/29113767

    PubMed  Google Scholar 

  18. Silberstein JL, Millard F, Mehrazin R, et al. Feasibility and efficacy of neoadjuvant sunitinib before nephron-sparing surgery. BJU Int [Internet]. 2010;106(9):1270–6. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20394613

    PubMed  Google Scholar 

  19. Rini BI, Plimack ER, Takagi T, et al. A phase II study of pazopanib in patients with localized renal cell carcinoma to optimize preservation of renal parenchyma. J Urol [Internet]. 2015;194(2):297–303. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25813447

    CAS  PubMed  Google Scholar 

  20. Lane BR, Derweesh IH, Kim HL, et al. Presurgical sunitinib reduces tumor size and may facilitate partial nephrectomy in patients with renal cell carcinoma. Urol Oncol [Internet]. 2015;33(3):112.e15–21. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25532471

    CAS  PubMed  Google Scholar 

  21. Cost NG, Delacroix SE, Sleeper JP, et al. The impact of targeted molecular therapies on the level of renal cell carcinoma vena caval tumor thrombus. Eur Urol [Internet]. 2011;59(6):912–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21367518

    CAS  PubMed  Google Scholar 

  22. Bigot P, Fardoun T, Bernhard JC, et al. Neoadjuvant targeted molecular therapies in patients undergoing nephrectomy and inferior vena cava thrombectomy: is it useful? World J Urol [Internet]. 2014;32(1):109–14. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23624719

    CAS  PubMed  Google Scholar 

  23. Lebacle C, Bensalah K, Bernhard J-C, et al. Evaluation of axitinib to downstage cT2a renal tumours and allow partial nephrectomy: a phase II study. BJU Int [Internet]. 2019;123(5):804–10. Available from: http://www.ncbi.nlm.nih.gov/pubmed/30288884

    CAS  PubMed  Google Scholar 

  24. MacFarlane AW, Jillab M, Plimack ER, et al. PD-1 expression on peripheral blood cells increases with stage in renal cell carcinoma patients and is rapidly reduced after surgical tumor resection. Cancer Immunol Res [Internet]. 2014;2(4):320–31. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24764579

    CAS  PubMed  Google Scholar 

  25. Gorin MA, Patel HD, Rowe SP, et al. Neoadjuvant nivolumab in patients with high-risk non-metastatic renal cell carcinoma. Eur Urol Oncol. 2021, S2588–9311(21)0076–6. Epub ahead of print. PMID 34049847.

    Google Scholar 

  26. Patel HD, Puligandla M, Shuch BM, et al. The future of perioperative therapy in advanced renal cell carcinoma: how can we PROSPER? Future Oncol [Internet]. 2019;15(15):1683–95. Available from: http://www.ncbi.nlm.nih.gov/pubmed/30968729

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Ravaud A, Motzer RJ, Pandha HS, et al. Adjuvant sunitinib in high-risk renal-cell carcinoma after nephrectomy. N Engl J Med [Internet]. 2016;375(23):2246–54. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27718781

    CAS  PubMed  Google Scholar 

  28. Woo S-R, Turnis ME, Goldberg MV, et al. Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape. Cancer Res [Internet]. 2012;72(4):917–27. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22186141

    CAS  PubMed  Google Scholar 

  29. Choueiri TK, Tomczak P, Park SH, et al. Adjuvant pembrolizumab after nephrectomy in renal-cell carcinoma. N Engl J Med. 2021;385(8):683–94. PMID: 34407342.

    Google Scholar 

  30. Bex A, Russo P, Tomita Y, et al. A phase III, randomized, placebo-controlled trial of nivolumab or nivolumab plus ipilimumab in patients with localized renal cell carcinoma at high-risk of relapse after radical or partial nephrectomy (CheckMate 914). J Clin Oncol [Internet]. 2020;38(15_suppl):TPS5099. Available from: https://ascopubs.org/doi/abs/10.1200/JCO.2020.38.15_suppl.TPS5099

    Google Scholar 

  31. Zhang T, Hwang JK, George DJ, Pal SK. The landscape of contemporary clinical trials for untreated metastatic clear cell renal cell carcinoma. Cancer Treat Res Commun [Internet]. 2020;24:100183. Available from: http://www.ncbi.nlm.nih.gov/pubmed/32563923

    PubMed  Google Scholar 

  32. 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 [Internet]. 2001;345(23):1655–9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/11759643

    CAS  PubMed  Google Scholar 

  33. Mickisch GH, Garin A, van Poppel H, de Prijck L, Sylvester R. European Organisation for Research and Treatment of Cancer (EORTC) genitourinary group. Radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: a randomised trial. Lancet (London, England) [Internet]. 2001;358(9286):966–70. Available from: http://www.ncbi.nlm.nih.gov/pubmed/11583750

    CAS  Google Scholar 

  34. Choueiri TK, Motzer RJ. Systemic therapy for metastatic renal-cell carcinoma. N Engl J Med [Internet]. 2017;376(4):354–66. Available from: http://www.ncbi.nlm.nih.gov/pubmed/28121507

    CAS  PubMed  Google Scholar 

  35. Heng DYC, **e 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 [Internet]. 2013;14(2):141–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23312463

    PubMed  Google Scholar 

  36. 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 [Internet]. 2019;5(2):164–70. Available from: http://www.ncbi.nlm.nih.gov/pubmed/30543350

    PubMed  Google Scholar 

  37. Méjean A, Ravaud A, Thezenas S, et al. Sunitinib alone or after nephrectomy in metastatic renal-cell carcinoma. N Engl J Med [Internet]. 2018;379(5):417–27. Available from: http://www.ncbi.nlm.nih.gov/pubmed/29860937

    PubMed  Google Scholar 

  38. Gao J, Karam JA, Tannir NM, et al. A pilot randomized study evaluating nivolumab (nivo) or nivo + bevacizumab (bev) or nivo + ipilimumab (ipi) in patients with metastatic renal cell carcinoma (MRCC) eligible for cytoreductive nephrectomy, metastasectomy or post-treatment biopsy (Bx). J Clin Oncol [Internet]. 2019;37(15_suppl):4501. Available from: https://ascopubs.org/doi/abs/10.1200/JCO.2019.37.15_suppl.4501

    Google Scholar 

  39. DiNatale RG, **e W, Becerra MF, et al. The association between small primary tumor size and prognosis in metastatic renal cell carcinoma: insights from two independent cohorts of patients who underwent cytoreductive nephrectomy. Eur Urol Oncol [Internet]. 2020;3(1):47–56. Available from: http://www.ncbi.nlm.nih.gov/pubmed/31735646

    PubMed  Google Scholar 

  40. Zhang T, Ballman KV, Choudhury AD, et al. PDIGREE: an adaptive phase III trial of PD-inhibitor nivolumab and ipilimumab (IPI-NIVO) with VEGF TKI cabozantinib (CABO) in metastatic untreated renal cell cancer (Alliance A031704). J Clin Oncol [Internet]. 2020;38(15_suppl):TPS5100. Available from: https://ascopubs.org/doi/abs/10.1200/JCO.2020.38.15_suppl.TPS5100

    Google Scholar 

  41. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med [Internet]. 2015;373(1):23–34. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26027431

    PubMed  Google Scholar 

  42. Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med [Internet]. 2015;373(17):1627–39. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26412456

    CAS  PubMed  Google Scholar 

  43. Zhang T, Gong J, Maia MC, Pal SK. Systemic therapy for non–clear cell renal cell carcinoma. Am Soc Clin Oncol Educ Book [Internet]. 2017;37:337–42. Available from: http://ascopubs.org/doi/10.1200/EDBK_175572

    PubMed  Google Scholar 

  44. Gulati S, Philip E, Salgia S, Pal SK. Evolving treatment paradigm in metastatic non clear cell renal cell carcinoma. Cancer Treat Res Commun [Internet]. 2020;23:100172. Available from: http://www.ncbi.nlm.nih.gov/pubmed/32252014

    PubMed  Google Scholar 

  45. Aizer AA, Urun Y, McKay RR, Kibel AS, Nguyen PL, Choueiri TK. Cytoreductive nephrectomy in patients with metastatic non-clear-cell renal cell carcinoma (RCC). BJU Int [Internet]. 2014;113(5b):E67–74. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24053727

    PubMed  Google Scholar 

  46. Choueiri TK, **e W, Kollmannsberger C, 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 [Internet]. 2011;185(1):60–6. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21074201

    PubMed  Google Scholar 

  47. Kassouf W, Sanchez-Ortiz R, Tamboli P, et al. Cytoreductive nephrectomy for metastatic renal cell carcinoma with nonclear cell histology. J Urol [Internet]. 2007;178(5):1896–900. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17868729

    PubMed  Google Scholar 

  48. Chahoud J, Msaouel P, Campbell MT, et al. Nivolumab for the treatment of patients with metastatic non-clear cell renal cell carcinoma (nccRCC): a single-institutional experience and literature meta-analysis. Oncologist [Internet]. 2020;25(3):252–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/32162795

    CAS  PubMed  Google Scholar 

  49. Gupta R, Ornstein MC, Li H, et al. Clinical activity of ipilimumab plus nivolumab in patients with metastatic non-clear cell renal cell carcinoma. Clin Genitourin Cancer [Internet]. 2020;18(6):429–35. Available from: http://www.ncbi.nlm.nih.gov/pubmed/32800717

    PubMed  Google Scholar 

  50. Koshkin VS, Barata PC, Zhang T, et al. Clinical activity of nivolumab in patients with non-clear cell renal cell carcinoma. J Immunother cancer [Internet]. 2018;6(1):9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/29378660

    PubMed  Google Scholar 

  51. McKay RR, Bossé D, **e W, et al. The clinical activity of PD-1/PD-L1 inhibitors in metastatic non-clear cell renal cell carcinoma. Cancer Immunol Res [Internet]. 2018;6(7):758–65. Available from: http://www.ncbi.nlm.nih.gov/pubmed/29748390

    CAS  PubMed  Google Scholar 

  52. McGregor BA, McKay RR, Braun DA, et al. Results of a multicenter phase II study of atezolizumab and bevacizumab for patients with metastatic renal cell carcinoma with variant histology and/or sarcomatoid features. J Clin Oncol [Internet]. 2020;38(1):63–70. Available from: https://ascopubs.org/doi/10.1200/JCO.19.01882

    CAS  PubMed  Google Scholar 

  53. Powles T, Larkin JMG, Patel P, et al. A phase II study investigating the safety and efficacy of savolitinib and durvalumab in metastatic papillary renal cancer (CALYPSO). J Clin Oncol [Internet]. 2019;37(7_suppl):545. Available from: https://ascopubs.org/doi/abs/10.1200/JCO.2019.37.7_suppl.545

    Google Scholar 

  54. Lee J-L, Ziobro M, Gafanov R, et al. KEYNOTE-427 cohort B: first-line pembrolizumab (pembro) monotherapy for advanced non–clear cell renal cell carcinoma (NCC-RCC). J Clin Oncol [Internet]. 2019;37(15_suppl):4569. Available from: http://ascopubs.org/doi/10.1200/JCO.2019.37.15_suppl.4569

    Google Scholar 

  55. Vogelzang NJ, McFarlane JJ, Kochenderfer MD, et al. Efficacy and safety of nivolumab in patients with non-clear cell renal cell carcinoma (RCC): results from the phase IIIb/IV CheckMate 374 study. J Clin Oncol. 2019;37(7_suppl):562. Available from: https://ascopubs.org/doi/10.1200/JCO.2019.37.7_suppl.562

    Google Scholar 

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Karachaliou, G.S., Kaye, D.R., George, D.J., Zhang, T. (2022). The Search for the Optimal Immunotherapy Sequencing in the Perioperative Setting of RCC. In: Necchi, A., Spiess, P.E. (eds) Neoadjuvant Immunotherapy Treatment of Localized Genitourinary Cancers. Springer, Cham. https://doi.org/10.1007/978-3-030-80546-3_16

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