Top

International Journal of Clinical Oncology

Published in:

18-12-2023 | Kidney Cancer | Invited Review Article

Current status and future perspective of immunotherapy for renal cell carcinoma

Authors: Leandro Blas, Keisuke Monji, Jun Mutaguchi, Satoshi Kobayashi, Shunsuke Goto, Takashi Matsumoto, Masaki Shiota, Junichi Inokuchi, Masatoshi Eto

Published in: International Journal of Clinical Oncology | Issue 8/2024

Abstract

In the last decade, the standard treatment for advanced renal cell carcinoma (RCC) has evolved, mainly driven by the development and approval of immune checkpoint inhibitors (ICIs). Currently, ICI monotherapy and ICI-based combinations with tyrosine kinase inhibitors and targeted therapies against mammalian target of rapamycin or vascular endothelial growth factor have become new standard treatments for first-line and subsequent-line therapies. ICIs play an important role as an adjuvant postoperative therapy, and this field is the subject of active research. Furthermore, ongoing randomized controlled trials are investigating the clinical value of more intense treatments by combining multiple effective treatments for RCC. Additionally, novel biomarkers for prognosis have been investigated. This study reviews the current evidence on immunotherapy as a treatment for RCC patients, randomized controlled trials, and ongoing studies including RCC patients and recent findings, and discusses future perspectives.

Siegel RL, Miller KD, Wagle NS et al (2023) Cancer statistics, 2023. CA Cancer J Clin 73(1):17–48. https://doi.org/10.3322/caac.21763CrossRefPubMed

Sung H, Ferlay J, Siegel RL et al (2021) Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. https://doi.org/10.3322/caac.21492CrossRefPubMed

Lam JS, Leppert JT, Belldegrun AS et al (2005) Novel approaches in the therapy of metastatic renal cell carcinoma. World J Urol 23(3):202–212. https://doi.org/10.1007/s00345-004-0466-0CrossRefPubMed

Capitanio U, Bensalah K, Bex A et al (2019) Epidemiology of renal cell carcinoma. Eur Urol 75(1):74–84. https://doi.org/10.1016/j.eururo.2018.08.036CrossRefPubMed

Motzer RJ, Hutson TE, Tomczak P et al (2007) Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J 356(2):115–124. https://doi.org/10.1056/NEJMoa065044CrossRef

Blas L, Roberti J, Petroni J et al (2019) Renal medullary carcinoma: a report of the current literature. Curr Urol Rep. https://doi.org/10.1007/s11934-019-0865-9CrossRefPubMed

Motzer RJ, Jonasch E, Agarwal N et al (2022) Kidney Cancer, Version 3.2022, NCCN clinical practice guidelines in oncology. JNCCN J Natl Compr Cancer Netw. 20(1):71–90. https://doi.org/10.6004/jnccn.2022.0001CrossRef

Griffiths RW, Elkord E, Gilham DE et al (2007) Frequency of regulatory T cells in renal cell carcinoma patients and investigation of correlation with survival. Cancer Immunol Immunother 56(11):1743–1753CrossRefPubMedPubMedCentral

Chemnitz JM, Riley JL, Frauwirth KA et al (2004) CTLA-4 and PD-1 receptors inhibit T cell activation by distinct mechanisms. Blood 104(11):2657–2657. https://doi.org/10.1182/blood.v104.11.2657.2657CrossRef

10.

Motzer RJ, Tannir NM, McDermott DF et al (2018) Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med 378(14):1277–1290. https://doi.org/10.1056/nejmoa1712126CrossRefPubMedPubMedCentral

11.

Heng DYC, Xie W, Regan MM et al (2009) 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 27(34):5794–5799. https://doi.org/10.1200/JCO.2008.21.4809CrossRefPubMed

12.

Heng DYC, Xie W, Regan MM et al (2013) External validation and comparison with other models of the international metastatic renal-cell carcinoma database consortium prognostic model: a population-based study. Lancet Oncol 14(2):141–148. https://doi.org/10.1016/S1470-2045(12)70559-4CrossRefPubMedPubMedCentral

13.

Albiges L, Tannir NM, Burotto M et al (2020) Nivolumab plus ipilimumab versus sunitinib for first-line treatment of advanced renal cell carcinoma: E##xtended 4-year follow-up of the phase III CheckMate 214 trial. ESMO Open 5(6):1–10. https://doi.org/10.1136/esmoopen-2020-001079CrossRef

14.

Choueiri TK, Powles T, Burotto M et al (2021) Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 384(9):829–841. https://doi.org/10.1056/nejmoa2026982CrossRefPubMedPubMedCentral

15.

Motzer RJ, Powles T, Burotto M et al (2022) Nivolumab plus cabozantinib versus sunitinib in first-line treatment for advanced renal cell carcinoma (CheckMate 9ER): long-term follow-up results from an open-label, randomized, phase 3 trial. Lancet Oncol 23(7):888–898. https://doi.org/10.1016/S1470-2045(22)00290-XCrossRefPubMedPubMedCentral

16.

Rini BI, Plimack ER, Stus V et al (2019) Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 380(12):1116–1127. https://doi.org/10.1056/nejmoa1816714CrossRefPubMed

17.

Plimack ER, Powles T, Stus V et al (2023) Pembrolizumab plus axitinib versus sunitinib as first-line treatment of advanced renal cell carcinoma: 43-month follow-up of phase 3 KEYNOTE-426 study. Eur Urol. https://doi.org/10.1016/j.eururo.2023.06.006CrossRefPubMedPubMedCentral

18.

Motzer R, Alekseev B, Rha SY et al (2021) Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med 384(14):1289–1300. https://doi.org/10.1056/nejmoa2035716CrossRefPubMed

19.

Choueiri TK, Eto M, Motzer R et al (2023) Lenvatinib plus pembrolizumab versus sunitinib as first-line treatment of patients with advanced renal cell carcinoma (CLEAR): extended follow-up from the phase 3, randomised, open-label study. Lancet Oncol 24(3):228–238. https://doi.org/10.1016/S1470-2045(23)00049-9CrossRefPubMed

20.

Ljungberg B, Albiges L, Abu-Ghanem Y et al (2022) European Association of Urology Guidelines on renal cell carcinoma: the 2022 update. Eur Urol 82(4):399–410. https://doi.org/10.1016/j.eururo.2022.03.006CrossRefPubMed

21.

Motzer RJ, Penkov K, Haanen J et al (2019) Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 380(12):1103–1115. https://doi.org/10.1056/nejmoa1816047CrossRefPubMedPubMedCentral

22.

Haanen JBAG, Larkin J, Choueiri TK et al (2023) Extended follow-up from JAVELIN renal 101: subgroup analysis of avelumab plus axitinib versus sunitinib by the International Metastatic Renal Cell Carcinoma Database Consortium risk group in patients with advanced renal cell carcinoma. ESMO Open 8(3):101210. https://doi.org/10.1016/j.esmoop.2023.101210CrossRefPubMedPubMedCentral

23.

Rini BI, Powles T, Atkins MB et al (2019) 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 393(10189):2404–2415. https://doi.org/10.1016/S0140-6736(19)30723-8CrossRefPubMed

24.

Motzer RJ, Powles T, Atkins MB et al (2022) Final overall survival and molecular analysis in IMmotion151, a phase 3 trial comparing atezolizumab plus bevacizumab vs sunitinib in patients with previously untreated metastatic renal cell carcinoma. JAMA Oncol 8(2):275–280. https://doi.org/10.1001/jamaoncol.2021.5981CrossRefPubMed

25.

Choueiri TK, Powles T, Albiges L et al (2023) Cabozantinib plus nivolumab and ipilimumab in renal-cell carcinoma. N Engl J Med 388(19):1767–1778. https://doi.org/10.1056/NEJMoa2212851CrossRefPubMedPubMedCentral

26.

Quhal F, Mori K, Bruchbacher A et al (2021) First-line immunotherapy-based combinations for metastatic renal cell carcinoma: a systematic review and network meta-analysis. Eur Urol Oncol 4(5):755–765. https://doi.org/10.1016/j.euo.2021.03.001CrossRefPubMed

27.

Nocera L, Karakiewicz PI, Wenzel M et al (2022) Clinical outcomes and adverse events after first-line treatment in metastatic renal cell carcinoma: a systematic review and network meta-analysis. J Urol 207(1):16–24. https://doi.org/10.1097/JU.0000000000002252CrossRefPubMed

28.

Blas L, Shiota M, Tsukahara S et al (2023) Adverse events of cabozantinib plus nivolumab versus ipilimumab plus nivolumab. Clin Genitourin Cancer. https://doi.org/10.1016/j.clgc.2023.09.003. (Epub ahead of print)CrossRefPubMed

29.

Hammers HJ, Plimack ER, Infante JR et al (2017) Safety and efficacy of nivolumab in combination with ipilimumab in metastatic renal cell carcinoma: the checkmate 016 study. J Clin Oncol 35(34):3851–3858. https://doi.org/10.1200/JCO.2016.72.1985CrossRefPubMedPubMedCentral

30.

Grimm MO, Schmidinger M, Duran Martinez I et al (2019) Tailored immunotherapy approach with nivolumab in advanced renal cell carcinoma (TITAN-RCC). Ann Oncol 30(October):v892. https://doi.org/10.1093/annonc/mdz394.051CrossRef

31.

Yang Y, Mori SV, Li M et al (2022) Salvage nivolumab and ipilimumab after prior anti-PD-1/PD-L1 therapy in metastatic renal cell carcinoma: a meta-analysis. Cancer Med 11(7):1669–1677. https://doi.org/10.1002/cam4.4587CrossRefPubMedPubMedCentral

32.

Motzer RJ, Escudier B, McDermott DF et al (2015) Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med 373(19):1803–1813. https://doi.org/10.1056/nejmoa1510665CrossRefPubMedPubMedCentral

33.

Motzer RJ, Escudier B, George S et al (2020) Nivolumab versus everolimus in patients with advanced renal cell carcinoma: updated results with long-term follow-up of the randomized, open-label, phase 3 CheckMate 025 trial. Cancer 126(18):4156–4167. https://doi.org/10.1002/cncr.33033CrossRefPubMed

34.

Pal SK, Albiges L, Tomczak P et al (2023) Atezolizumab plus cabozantinib versus cabozantinib monotherapy for patients with renal cell carcinoma after progression with previous immune checkpoint inhibitor treatment (CONTACT-03): a multicentre, randomised, open-label, phase 3 trial. Lancet 402:185–195. https://doi.org/10.1016/s0140-6736(23)00922-4CrossRefPubMedPubMedCentral

35.

Ornstein MC, Wood LS, Hobbs BP et al (2019) 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 7(1):1–5. https://doi.org/10.1186/s40425-019-0615-zCrossRef

36.

Lee CH, Shah AY, Rasco D et al (2021) Lenvatinib plus pembrolizumab in patients with either treatment-naive or previously treated metastatic renal cell carcinoma (Study 111/KEYNOTE-146): a phase 1b/2 study. Lancet Oncol 22(7):946–958. https://doi.org/10.1016/S1470-2045(21)00241-2CrossRefPubMedPubMedCentral

37.

Choueiri TK, McDermott DF, Merchan J et al (2023) Belzutifan plus cabozantinib for patients with advanced clear cell renal cell carcinoma previously treated with immunotherapy: an open-label, single-arm, phase 2 study. Lancet Oncol 24(5):553–562. https://doi.org/10.1016/S1470-2045(23)00097-9CrossRefPubMed

38.

Eisen T, Frangou E, Oza B et al (2020) Adjuvant sorafenib for renal cell carcinoma at intermediate or high risk of relapse: results from the SORCE randomized phase III intergroup trial. J Clin Oncol 38(34):4064–4075. https://doi.org/10.1200/JCO.20.01800CrossRefPubMedPubMedCentral

39.

Gross-Goupil M, Kwon TG, Eto M et al (2018) Axitinib versus placebo as an adjuvant treatment of renal cell carcinoma: results from the phase III, randomized ATLAS trial. Ann Oncol 29(12):2371–2378. https://doi.org/10.1093/annonc/mdy454CrossRefPubMedPubMedCentral

40.

Motzer RJ, Haas NB, Donskov F et al (2017) Randomized phase III trial of adjuvant pazopanib versus placebo after nephrectomy in patients with localized or locally advanced renal cell carcinoma. J Clin Oncol 35(35):3916–3923. https://doi.org/10.1200/JCO.2017.73.5324CrossRefPubMedPubMedCentral

41.

Haas NB, Manola J, Dutcher JP et al (2017) Adjuvant treatment for high-risk clear cell renal cancer: updated results of a high-risk subset of the ASSURE randomized trial. JAMA Oncol 3(9):1249–1252. https://doi.org/10.1001/jamaoncol.2017.0076CrossRefPubMedPubMedCentral

42.

Haas NB, Manola J, Uzzo RG et al (2016) Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): a double-blind, placebo-controlled, randomised, phase 3 trial. Lancet 387(10032):2008–2016. https://doi.org/10.1016/S0140-6736(16)00559-6CrossRefPubMedPubMedCentral

43.

Ravaud A, Motzer RJ, Pandha HS et al (2016) Adjuvant sunitinib in high-risk renal-cell carcinoma after nephrectomy. N Engl J Med 375(23):2246–2254. https://doi.org/10.1056/nejmoa1611406CrossRefPubMed

44.

Ryan CW, Tangen CM, Heath EI et al (2023) Adjuvant everolimus after surgery for renal cell carcinoma (EVEREST): a double-blind, placebo-controlled, randomised, phase 3 trial. Lancet (Lond, Engl) 6736(23):1–9. https://doi.org/10.1016/S0140-6736(23)00913-3CrossRef

45.

Choueiri TK, Tomczak P, Park SH et al (2021) Adjuvant pembrolizumab after nephrectomy in renal-cell carcinoma. N Engl J Med 385(8):683–694. https://doi.org/10.1056/nejmoa2106391CrossRefPubMed

46.

Allaf M, Kim SE, Harshman LC et al (2022) LBA67 phase III randomized study comparing perioperative nivolumab (nivo) versus observation in patients (Pts) with renal cell carcinoma (RCC) undergoing nephrectomy (PROSPER, ECOG-ACRIN EA8143), a National Clinical Trials Network trial. Ann Oncol 33:S1432–S1433. https://doi.org/10.1016/j.annonc.2022.08.072CrossRef

47.

Motzer RJ, Russo P, Grünwald V et al (2023) Adjuvant nivolumab plus ipilimumab versus placebo for localised renal cell carcinoma after nephrectomy (CheckMate 914): a double-blind, randomised, phase 3 trial. Lancet 401(10379):821–832. https://doi.org/10.1016/S0140-6736(22)02574-0CrossRefPubMedPubMedCentral

48.

Pal SK, Uzzo R, Karam JA et al (2022) Adjuvant atezolizumab versus placebo for patients with renal cell carcinoma at increased risk of recurrence following resection (IMmotion010): a multicentre, randomised, double-blind, phase 3 trial. Lancet 400(10358):1103–1116. https://doi.org/10.1016/S0140-6736(22)01658-0CrossRefPubMed

49.

Powles T, Tomczak P, Park SH et al (2022) Pembrolizumab versus placebo as post-nephrectomy adjuvant therapy for clear cell renal cell carcinoma (KEYNOTE-564): 30-month follow-up analysis of a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 23(9):1133–1144. https://doi.org/10.1016/S1470-2045(22)00487-9CrossRefPubMed

50.

Bedke J, Albiges L, Capitanio U et al (2023) The 2022 updated European Association of Urology Guidelines on the use of adjuvant immune checkpoint inhibitor therapy for renal cell carcinoma. Eur Urol 83(1):10–14. https://doi.org/10.1016/j.eururo.2022.10.010CrossRefPubMed

51.

Vogelzang NJ, Olsen MR, McFarlane JJ et al (2020) Safety and efficacy of nivolumab in patients with advanced non-clear cell renal cell carcinoma: results from the phase IIIb/IV CheckMate 374 study. Clin Genitourin Cancer 18(6):461-468.e3. https://doi.org/10.1016/j.clgc.2020.05.006CrossRefPubMed

52.

Tykodi SS, Gordan LN, Alter RS et al (2022) Safety and efficacy of nivolumab plus ipilimumab in patients with advanced non-clear cell renal cell carcinoma: results from the phase 3b/4 CheckMate 920 trial. J Immunother Cancer 10(2):e003844. https://doi.org/10.1136/jitc-2021-003844CrossRefPubMedPubMedCentral

53.

Albiges L, Gurney H, Atduev V et al (2023) Pembrolizumab plus lenvatinib as first-line therapy for advanced non-clear-cell renal cell carcinoma (KEYNOTE-B61): a single-arm, multicentre, phase 2 trial. Lancet Oncol 24(8):881–891. https://doi.org/10.1016/S1470-2045(23)00276-0CrossRefPubMed

54.

Lee CH, Voss MH, Carlo MI et al (2022) Phase II trial of cabozantinib plus nivolumab in patients with non-clear-cell renal cell carcinoma and genomic correlates. J Clin Oncol 40(21):2333–2341. https://doi.org/10.1200/JCO.21.01944CrossRefPubMedPubMedCentral

55.

McGregor BA, McKay RR, Braun DA et al (2020) 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 38(1):63–70. https://doi.org/10.1200/JCO.19.01882CrossRefPubMed

56.

Motzer RJ, Robbins PB, Powles T et al (2020) Avelumab plus axitinib versus sunitinib in advanced renal cell carcinoma: biomarker analysis of the phase 3 JAVELIN renal 101 trial. Nat Med 26(11):1733–1741. https://doi.org/10.1038/s41591-020-1044-8CrossRefPubMedPubMedCentral

57.

McDermott DF, Huseni MA, Atkins MB et al (2018) Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma. Nat Med 24(6):749–757. https://doi.org/10.1038/s41591-018-0053-3CrossRefPubMedPubMedCentral

58.

Lalani AKA, Xie W, Martini DJ et al (2018) Change in neutrophil-to-lymphocyte ratio (NLR) in response to immune checkpoint blockade for metastatic renal cell carcinoma. J Immunother Cancer 6(1):1–9. https://doi.org/10.1186/s40425-018-0315-0CrossRef

59.

Basu A, Phone A, Bice T et al (2021) Change in neutrophil to lymphocyte ratio (NLR) as a predictor of treatment failure in renal cell carcinoma patients: analysis of the IROC (Investigating RCC Outcomes) cohort. J Clin Oncol 39(6):344–354. https://doi.org/10.1200/JCO.2021.39.6_suppl.344CrossRef

60.

Miao D, Margolis CA, Gao W et al (2018) Genomic correlates of response to immune checkpoint therapies in clear cell renal cell carcinoma. Science 806(February):801–806CrossRef

61.

Ficial M, Jegede O, Sant’Angelo M, et al (2020) Evaluation of predictive biomarkers for nivolumab in patients with metastatic clear cell renal cell carcinoma (mccRCC) from the CheckMate-025 trial. J Clin Oncol 38(15):502

62.

Sakuishi K, Ngiow SF, Sullivan JM et al (2013) TIM3+FOXP3+ regulatory T cells are tissue-specific promoters of T cell dysfunction in cancer. Oncoimmunology. https://doi.org/10.4161/onci.23849CrossRefPubMedPubMedCentral

Title: Current status and future perspective of immunotherapy for renal cell carcinoma
Authors: Leandro Blas
Keisuke Monji
Jun Mutaguchi
Satoshi Kobayashi
Shunsuke Goto
Takashi Matsumoto
Masaki Shiota
Junichi Inokuchi
Masatoshi Eto
Publication date: 18-12-2023
Publisher: Springer Nature Singapore
Keywords: Kidney Cancer
Kidney Cancer
Kidney Cancer
Sunitinib
Checkpoint Inhibitors
Cabozantinib
Lenvatinib
Biomarkers
Axitinib
Published in: International Journal of Clinical Oncology / Issue 8/2024
Print ISSN: 1341-9625
Electronic ISSN: 1437-7772
DOI: https://doi.org/10.1007/s10147-023-02446-3

EASD 2024

Springer Medicine

Current status and future perspective of immunotherapy for renal cell carcinoma

Abstract

EASD 2024

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 8/2024

Primary prophylaxis with G-CSF for patients with non-round cell soft tissue sarcomas: a systematic review for the Clinical Practice Guidelines for the Use of G-CSF 2022 of the Japan Society of Clinical Oncology

Prognostic impact of the combination of p16INK4a, p21 and Immunoscore in rectal cancer

Phase 2 trial of crizotinib in Japanese patients with advanced NSCLC harboring a MET gene alteration: a Co-MET study

Zinc supplementation for dysgeusia in patients with unresectable pancreatic cancer

PMDA regulatory update on approval and revision of the precautions for use of anticancer drugs; approval of pembrolizumab for gastric and biliary tract cancer and encorafenib and binimetinib for thyroid cancer in Japan

New predictors of microvascular invasion for small hepatocellular carcinoma ≤ 3 cm