Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Towards individualized therapy for metastatic renal cell carcinoma

An Author Correction to this article was published on 25 April 2019

This article has been updated

Abstract

Over the past decade, the treatment landscape for patients with metastatic renal cell carcinoma (RCC) has evolved dramatically. The therapeutic options available have expanded and now include immune-checkpoint inhibitors, novel targeted agents and combination strategies, and thus optimal patient selection and treatment sequencing are increasingly pertinent for optimizing clinical outcomes. A better understanding of the underlying biology of the tumour and its microenvironment continues to drive the inception of new diagnostic and therapeutic approaches. Furthermore, many biomarkers robustly associated with treatment and disease-specific outcomes have been identified, and their integration into clinical decision-making for patients with advanced-stage disease will soon become a reality. Herein, we review relevant aspects of the molecular biology of metastatic RCC, with an emphasis on predictive and prognostic biomarkers, and suggest tailored algorithms to individualize and guide treatment approaches for specific subgroups of patients.

Key points

  • Metastatic renal cell carcinoma (RCC) is the most lethal form of kidney cancer, and systemic treatments include immune-checkpoint inhibitors (ICIs), VEGF receptor tyrosine kinase inhibitors (VEGFR TKIs) and mTOR inhibitors.

  • Risk models, such as those developed by the International Metastatic Renal Cell Carcinoma Database Consortium and Memorial Sloan Kettering Cancer Center, are used to stratify patients and guide initial treatment selection; the integration of genomic biomarkers (including PBRM1, BAP1 and TP53) into these models improves their performance.

  • RCC variants, characterized by the presence of specific features identified using tissue gene expression profiling, somatic mutational profiling and tumour microenvironment (TME) signatures, have different responses to VEGFR TKIs and ICIs.

  • As frontline therapies shift towards ICIs, particularly in combination strategies, biomarkers are needed to guide the choice of therapeutic agents on the basis of key features in each patient’s tumour cells and TME.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Tumorigenesis-related signalling with drug development implications in renal cell carcinoma.
Fig. 2: Treatment algorithm for frontline management of patients with metastatic renal cell carcinoma.

Similar content being viewed by others

Change history

  • 25 April 2019

    The competing interests section of the HTML and PDF versions of this manuscript originally did not include the research support received by Robert J. Motzer from Eisai. This information has been added to the competing interests section of the HTML and PDF versions of the manuscript.

References

  1. Bray, F. et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 68, 394–424 (2018).

    Article  PubMed  Google Scholar 

  2. Siegel, R. L., Miller, K. D. & Jemal, A. Cancer statistics, 2018. CA Cancer J. Clin. 68, 7–30 (2018).

    Article  PubMed  Google Scholar 

  3. Saad, A. M. et al. Trends in renal-cell carcinoma incidence and mortality in the United States in the last 2 decades: a SEER-based study. Clin. Genitourin. Cancer 17, 46–57 (2019).

    Article  PubMed  Google Scholar 

  4. Moch, H., Cubilla, A. L., Humphrey, P. A., Reuter, V. E. & Ulbright, T. M. The 2016 WHO classification of tumours of the urinary system and male genital organs-part A: renal, penile, and testicular tumours. Eur. Urol. 70, 93–105 (2016).

    Article  PubMed  Google Scholar 

  5. Kane, C. J., Mallin, K., Ritchey, J., Cooperberg, M. R. & Carroll, P. R. Renal cell cancer stage migration: analysis of the National Cancer Data Base. Cancer 113, 78–83 (2008).

    Article  PubMed  Google Scholar 

  6. Wong, M. C. S. et al. Incidence and mortality of kidney cancer: temporal patterns and global trends in 39 countries. Sci. Rep. 7, 15698 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Gelfond, J. et al. Modifiable risk factors to reduce renal cell carcinoma incidence: insight from the PLCO trial. Urol. Oncol. 36, 340.e1–340.e6 (2018).

    Article  Google Scholar 

  8. Tsivian, M., Moreira, D. M., Caso, J. R., Mouraviev, V. & Polascik, T. J. Cigarette smoking is associated with advanced renal cell carcinoma. J. Clin. Oncol. 29, 2027–2031 (2011).

    Article  PubMed  Google Scholar 

  9. Wang, F. & Xu, Y. Body mass index and risk of renal cell cancer: a dose-response meta-analysis of published cohort studies. Int. J. Cancer 135, 1673–1686 (2014).

    Article  CAS  PubMed  Google Scholar 

  10. Choi, Y. et al. Body mass index and survival in patients with renal cell carcinoma: a clinical-based cohort and meta-analysis. Int. J. Cancer 132, 625–634 (2013).

    Article  CAS  PubMed  Google Scholar 

  11. Hakimi, A. A. et al. An epidemiologic and genomic investigation into the obesity paradox in renal cell carcinoma. J. Natl Cancer Inst. 105, 1862–1870 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Albiges, L. et al. Body mass index and metastatic renal cell carcinoma: clinical and biological correlations. J. Clin. Oncol. 34, 3655–3663 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Bergerot, P. et al. Targeted therapy and immunotherapy: effect of body mass index on clinical outcomes in patients diagnosed with metastatic renal cell carcinoma. Kidney Cancer 3, 63–70 (2019).

    Article  CAS  Google Scholar 

  14. Mitchell, T. J. et al. Timing the landmark events in the evolution of clear cell renal cell cancer: TRACERx renal. Cell 173, 611–623 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Rini, B. I. et al. Validation of the 16-gene recurrence score in patients with locoregional, high-risk renal cell carcinoma from a phase 3 trial of adjuvant sunitinib. Clin. Cancer Res. 24, 4407–4415 (2018).

    Article  CAS  PubMed  Google Scholar 

  16. Ricketts, C. J. et al. The cancer genome atlas comprehensive molecular characterization of renal cell carcinoma. Cell Rep. 23, 313–326 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Lindgren, D., Sjölund, J. & Axelson, H. Tracing renal cell carcinomas back to the nephron. Trends Cancer 4, 472–484 (2018).

    Article  PubMed  Google Scholar 

  18. Sato, Y. et al. Integrated molecular analysis of clear-cell renal cell carcinoma. Nat. Genet. 45, 860–867 (2013).

    Article  CAS  PubMed  Google Scholar 

  19. Hakimi, A. A., Pham, C. G. & Hsieh, J. J. A clear picture of renal cell carcinoma. Nat. Genet. 45, 849–850 (2013).

    Article  CAS  PubMed  Google Scholar 

  20. Hakimi, A. A. et al. TCEB1-mutated renal cell carcinoma: a distinct genomic and morphological subtype. Mod. Pathol. 28, 845–853 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Zhang, J. et al. VHL substrate transcription factor ZHX2 as an oncogenic driver in clear cell renal cell carcinoma. Science 361, 290–295 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Turajlic, S. et al. Insertion-and-deletion-derived tumour-specific neoantigens and the immunogenic phenotype: a pan-cancer analysis. Lancet Oncol. 18, 1009–1021 (2017).

    Article  CAS  PubMed  Google Scholar 

  23. Zehir, A. et al. Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat. Med. 23, 703–713 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Turajlic, S. et al. Deterministic evolutionary trajectories influence primary tumor growth: TRACERx renal. Cell 173, 595–610 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Brannon, A. R. et al. Molecular stratification of clear cell renal cell carcinoma by consensus clustering reveals distinct subtypes and survival patterns. Genes Cancer 1, 152–163 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Turajlic, S. et al. Tracking cancer evolution reveals constrained routes to metastases: TRACERx renal. Cell 173, 581–594 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Gerlinger, M. et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N. Engl. J. Med. 366, 883–892 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Heng, D. Y. et al. 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, 5794–5799 (2009).

    Article  CAS  PubMed  Google Scholar 

  29. Motzer, R. J. et al. Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma. J. Clin. Oncol. 17, 2530–2540 (1999).

    Article  CAS  PubMed  Google Scholar 

  30. Motzer, R. J. et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N. Engl. J. Med. 373, 1803–1813 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Choueiri, T. K. et al. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N. Engl. J. Med. 373, 1814–1823 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Motzer, R. J. et al. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol. 16, 1473–1482 (2015).

    Article  CAS  PubMed  Google Scholar 

  33. Motzer, R. J. et al. Prognostic factors for survival in previously treated patients with metastatic renal cell carcinoma. J. Clin. Oncol. 22, 454–463 (2004).

    Article  PubMed  Google Scholar 

  34. Yip, S. M. et al. Checkpoint inhibitors in patients with metastatic renal cell carcinoma: results from the international metastatic renal cell carcinoma database consortium. Cancer 124, 3677–3683 (2018).

    Article  CAS  PubMed  Google Scholar 

  35. Kroeger, N. et al. Metastatic non-clear cell renal cell carcinoma treated with targeted therapy agents: characterization of survival outcome and application of the International mRCC Database Consortium criteria. Cancer 119, 2999–3006 (2013).

    Article  CAS  PubMed  Google Scholar 

  36. Fukushima, H., Nakanishi, Y., Kataoka, M., Tobisu, K. & Koga, F. Prognostic significance of sarcopenia in patients with metastatic renal cell carcinoma. J. Urol. 195, 26–32 (2016).

    Article  PubMed  Google Scholar 

  37. McKay, R. R. et al. Impact of bone and liver metastases on patients with renal cell carcinoma treated with targeted therapy. Eur. Urol. 65, 577–584 (2014).

    Article  PubMed  Google Scholar 

  38. Chrom, P., Stec, R., Bodnar, L. & Szczylik, C. Incorporating neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio in place of neutrophil count and platelet count improves prognostic accuracy of the International Metastatic Renal Cell Carcinoma Database Consortium model. Cancer Res. Treat. 50, 103–110 (2018).

    Article  CAS  PubMed  Google Scholar 

  39. Templeton, A. J. et al. Change in neutrophil-to-lymphocyte ratio in response to targeted therapy for metastatic renal cell carcinoma as a prognosticator and biomarker of efficacy. Eur. Urol. 70, 358–364 (2016).

    Article  PubMed  Google Scholar 

  40. Lalani, A. A. et al. Change in neutrophil-to-lymphocyte ratio (NLR) in response to immune checkpoint blockade for metastatic renal cell carcinoma. J. Immunother. Cancer 6, 5 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  41. Zahoor, H. et al. Patterns, predictors and subsequent outcomes of disease progression in metastatic renal cell carcinoma patients treated with nivolumab. J. Immunother. Cancer 6, 107–107 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  42. Guida, A. et al. Identification of IMDC intermediate-risk subgroups in patients with metastatic clear-cell renal cell carcinoma (ccRCC) [abstract]. J. Clin. Oncol. 36 (Suppl. 15), e16577 (2018).

    Article  Google Scholar 

  43. Pilskog, M. et al. Predictive value of C-reactive protein in patients treated with sunitinib for metastatic clear cell renal cell carcinoma. BMC Urol. 17, 74 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Voss, M. H. et al. Genomically annotated risk model for advanced renal-cell carcinoma: a retrospective cohort study. Lancet Oncol. 19, 1688–1698 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  45. de Velasco, G. et al. Molecular subtypes improve prognostic value of International Metastatic Renal Cell Carcinoma Database Consortium prognostic model. Oncol. 22, 286–292 (2017).

    Google Scholar 

  46. Joseph, R. W. et al. Clear cell renal cell carcinoma subtypes identified by BAP1 and PBRM1 expression. J. Urol. 195, 180–187 (2016).

    Article  CAS  PubMed  Google Scholar 

  47. Hakimi, A. A. et al. Clinical and pathologic impact of select chromatin-modulating tumor suppressors in clear cell renal cell carcinoma. Eur. Urol. 63, 848–854 (2013).

    Article  PubMed  Google Scholar 

  48. Gao, W., Li, W., Xiao, T., Liu, X. S. & Kaelin, W. G. Jr. Inactivation of the PBRM1 tumor suppressor gene amplifies the HIF-response in VHL−/− clear cell renal carcinoma. Proc. Natl Acad. Sci. USA 114, 1027–1032 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Hsieh, J. J. et al. Genomic biomarkers of a randomized trial comparing first-line everolimus and sunitinib in patients with metastatic renal cell carcinoma. Eur. Urol. 71, 405–414 (2017).

    Article  CAS  PubMed  Google Scholar 

  50. McDermott, D. F. et al. Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma. Nat. Med. 24, 749–757 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Miao, D. et al. Genomic correlates of response to immune checkpoint therapies in clear cell renal cell carcinoma. Science 359, 801–806 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Carlo, M. et al. Genomic alterations and outcomes with VEGF-targeted therapy in patients with clear cell renal cell carcinoma. Kidney Cancer 1, 49–56 (2017).

    CAS  Google Scholar 

  53. The Cancer Genome Atlas Research Network. Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature 499, 43–49 (2013).

  54. Scelo, G. et al. Variation in genomic landscape of clear cell renal cell carcinoma across Europe. Nat. Commun. 5, 5135 (2014).

    Article  CAS  PubMed  Google Scholar 

  55. Turajlic, S., Larkin, J. & Swanton, C. SnapShot: renal cell carcinoma. Cell 163, 1556–1556.e1 (2015).

    Article  CAS  PubMed  Google Scholar 

  56. Bononi, A. et al. Germline BAP1 mutations induce a Warburg effect. Cell Death Differ. 24, 1694–1704 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Wang, T. et al. An empirical approach leveraging tumorgrafts to dissect the tumor microenvironment in renal cell carcinoma identifies missing link to prognostic inflammatory factors. Cancer Discov. 8, 1142–1155 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Espana-Agusti, J., Warren, A., Chew, S. K., Adams, D. J. & Matakidou, A. Loss of PBRM1 rescues VHL dependent replication stress to promote renal carcinogenesis. Nat. Commun. 8, 2026 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Pena-Llopis, S. et al. BAP1 loss defines a new class of renal cell carcinoma. Nat. Genet. 44, 751–759 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Chiang, Y. C. et al. SETD2 haploinsufficiency for microtubule methylation is an early driver of genomic instability in renal cell carcinoma. Cancer Res. 78, 3135–3146 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Pfister, S. X. et al. Inhibiting WEE1 selectively kills histone H3K36me3-deficient cancers by dNTP starvation. Cancer Cell 28, 557–568 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Pili, R. et al. Combination of the histone deacetylase inhibitor vorinostat with bevacizumab in patients with clear-cell renal cell carcinoma: a multicentre, single-arm phase I/II clinical trial. Br. J. Cancer 116, 874–883 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Pili, R. et al. Immunomodulation by entinostat in renal cell carcinoma patients receiving high dose interleukin 2: a multicenter, single-arm, phase 1/2 trial (NCI-CTEP#7870). Clin. Cancer Res. 23, 7199–7208 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. McDermott, D. F. et al. A Phase (Ph) 1 dose finding study of X4P-001 (an oral CXCR4 inhibitor) and axitinib in patients with advanced renal cell carcinoma (RCC) [abstract 896P]. Ann. Oncol. 28 (Suppl. 5), mdx371.050 (2017).

    Google Scholar 

  65. Atkins, M. et al. A phase 1 dose-finding study of X4P-001 (an oral CXCR4 inhibitor) and axitinib in patients with advanced renal cell carcinoma (RCC) [abstract B201]. Mol. Cancer Ther. 17 (Suppl. 1), B201 (2018).

    Google Scholar 

  66. Courtney, K. D. et al. Phase I dose-escalation trial of PT2385, a first-in-class hypoxia-inducible factor-2alpha antagonist in patients with previously treated advanced clear cell renal cell carcinoma. J. Clin. Oncol. 36, 867–874 (2018).

    Article  CAS  PubMed  Google Scholar 

  67. Rausch, S. et al. mTOR and mTOR phosphorylation status in primary and metastatic renal cell carcinoma tissue: differential expression and clinical relevance. J. Cancer Res. Clin. Oncol. 145, 153–163 (2018).

    Article  PubMed  CAS  Google Scholar 

  68. Voss, M. H. et al. Tumor genetic analyses of patients with metastatic renal cell carcinoma and extended benefit from mTOR inhibitor therapy. Clin. Cancer Res. 20, 1955–1964 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Kwiatkowski, D. J. et al. Mutations in TSC1, TSC2, and MTOR are associated with response to rapalogs in patients with metastatic renal cell carcinoma. Clin. Cancer Res. 22, 2445–2452 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Voss, M. H. et al. PTEN expression, not mutation status in TSC1, TSC2, or mTOR, correlates with the outcome on everolimus in patients with renal cell carcinoma treated on the randomized RECORD-3 trial. Clin. Cancer Res. 25, 506–514 (2019).

    Article  PubMed  Google Scholar 

  71. Casuscelli, J. et al. Characterization and impact of TERT promoter region mutations on clinical outcome in renal cell carcinoma. Eur. Urol. Focus https://doi.org/10.1016/j.euf.2017.09.008 (2017).

    Article  Google Scholar 

  72. Chen, Y. B. et al. Molecular analysis of aggressive renal cell carcinoma with unclassified histology reveals distinct subsets. Nat. Commun. 7, 13131 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Choueiri, T. K. et al. Biomarker-based phase II trial of savolitinib in patients with advanced papillary renal cell cancer. J. Clin. Oncol. 35, 2993–3001 (2017).

    Article  CAS  PubMed  Google Scholar 

  74. Choueiri, T. K. et al. Phase II and biomarker study of the dual MET/VEGFR2 inhibitor foretinib in patients with papillary renal cell carcinoma. J. Clin. Oncol. 31, 181–186 (2013).

    Article  CAS  PubMed  Google Scholar 

  75. The Cancer Genome Atlas Research Network. Comprehensive molecular characterization of papillary renal-cell carcinoma. N. Engl. J. Med. 374, 135–145 (2015).

    Article  CAS  Google Scholar 

  76. Casuscelli, J. et al. Genomic landscape and evolution of metastatic chromophobe renal cell carcinoma. JCI Insight 2, 92688 (2017).

    Article  PubMed  Google Scholar 

  77. Srinivasan, R. et al. 5 Mechanism based targeted therapy for hereditary leiomyomatosis and renal cell cancer (HLRCC) and sporadic papillary renal cell carcinoma: interim results from a phase 2 study of bevacizumab and erlotinib. Eur. J. Cancer 50, 8 (2014).

    Article  Google Scholar 

  78. Voss, M. H. et al. Phase II trial and correlative genomic analysis of everolimus plus bevacizumab in advanced non-clear cell renal cell carcinoma. J. Clin. Oncol. 34, 3846–3853 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Shuch, B. et al. Defining early-onset kidney cancer: implications for germline and somatic mutation testing and clinical management. J. Clin. Oncol. 32, 431–437 (2014).

    Article  PubMed  Google Scholar 

  80. Nguyen, K. A. et al. Advances in the diagnosis of hereditary kidney cancer: initial results of a multigene panel test. Cancer 123, 4363–4371 (2017).

    Article  CAS  PubMed  Google Scholar 

  81. Carlo, M. I. et al. Prevalence of germline mutations in cancer susceptibility genes in patients with advanced renal cell carcinoma. JAMA Oncol. 4, 1228–1235 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  82. The National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Kidney Cancer 2, 5 (2019).

  83. Zhu, J. et al. Biomarkers of immunotherapy in urothelial and renal cell carcinoma: PD-L1, tumor mutational burden, and beyond. J. Immunother. Cancer 6, 4 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  84. Callea, M. et al. Differential expression of PD-L1 between primary and metastatic sites in clear-cell renal cell carcinoma. Cancer Immunol. Res. 3, 1158–1164 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Iacovelli, R. et al. Prognostic role of PD-L1 expression in renal cell carcinoma. A systematic review and meta-analysis. Target Oncol. 11, 143–148 (2016).

    Article  PubMed  Google Scholar 

  86. Thompson, R. H., Dong, H. & Kwon, E. D. Implications of B7-H1 expression in clear cell carcinoma of the kidney for prognostication and therapy. Clin. Cancer Res. 13, 709s–715s (2007).

    Article  CAS  PubMed  Google Scholar 

  87. Thompson, R. H. et al. Costimulatory B7-H1 in renal cell carcinoma patients: indicator of tumor aggressiveness and potential therapeutic target. Proc. Natl Acad. Sci. USA 101, 17174–17179 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Choueiri, T. K. et al. Correlation of PD-L1 tumor expression and treatment outcomes in patients with renal cell carcinoma receiving sunitinib or pazopanib: results from COMPARZ, a randomized controlled trial. Clin. Cancer Res. 21, 1071–1077 (2015).

    Article  CAS  PubMed  Google Scholar 

  89. Motzer, R. J. et al. Nivolumab for metastatic renal cell carcinoma: results of a randomized phase II trial. J. Clin. Oncol. 33, 1430–1437 (2015).

    Article  CAS  PubMed  Google Scholar 

  90. Motzer, R. J. et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N. Engl. J. Med. 378, 1277–1290 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Motzer, R. J. et al. IMmotion151: a randomized phase III study of atezolizumab plus bevacizumab versus sunitinib in untreated metastatic renal cell carcinoma (mRCC) [abstract]. J. Clin. Oncol. 36, 578 (2018).

    Article  Google Scholar 

  92. Motzer, R. J. et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N. Engl. J. Med. 380, 1103–1115 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Rini, B. I. et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N. Engl. J. Med. 380, 1116–1127 (2019).

    Article  CAS  PubMed  Google Scholar 

  94. Senbabaoglu, Y. et al. Tumor immune microenvironment characterization in clear cell renal cell carcinoma identifies prognostic and immunotherapeutically relevant messenger RNA signatures. Genome Biol. 17, 231 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  95. Ock, C. Y. et al. Pan-cancer immunogenomic perspective on the tumor microenvironment based on PD-L1 and CD8 T-cell infiltration. Clin. Cancer Res. 22, 2261–2270 (2016).

    Article  CAS  PubMed  Google Scholar 

  96. Chevrier, S. et al. An immune atlas of clear cell renal cell carcinoma. Cell 169, 736–749 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Voss, M. H. et al. Correlation of degree of tumor immune infiltration and insertion-and-deletion (indel) burden with outcome on programmed death 1 (PD1) therapy in advanced renal cell cancer (RCC) [abstract]. J. Clin. Oncol. 36, 4518 (2018).

    Article  Google Scholar 

  98. Giraldo, N. A. et al. Orchestration and prognostic significance of immune checkpoints in the microenvironment of primary and metastatic renal cell cancer. Clin. Cancer Res. 21, 3031–3040 (2015).

    Article  CAS  PubMed  Google Scholar 

  99. Remark, R. et al. Characteristics and clinical impacts of the immune environments in colorectal and renal cell carcinoma lung metastases: influence of tumor origin. Clin. Cancer Res. 19, 4079–4091 (2013).

    Article  CAS  PubMed  Google Scholar 

  100. Zizzari, I. G. et al. TK inhibitor pazopanib primes DCs by downregulation of the beta-catenin pathway. Cancer Immunol. Res. 6, 711–722 (2018).

    CAS  Google Scholar 

  101. Choueiri, T. K. et al. Immunomodulatory activity of nivolumab in metastatic renal cell carcinoma. Clin. Cancer Res. 22, 5461–5471 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Hakimi, A. A. et al. Transcriptomic profiling of the tumor microenvironment reveals distinct subgroups of clear cell renal cell cancer - data from a randomized phase III trial. Cancer Discov. https://doi.org/10.1158/2159-8290.CD-18-0957 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Motzer, R. J. et al. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N. Engl. J. Med. 369, 722–731 (2013).

    Article  CAS  PubMed  Google Scholar 

  104. Rini, B. I. et al. Molecular correlates differentiate response to atezolizumab (atezo) + bevacizumab (bev) versus sunitinib (sun): results from a phase III study (IMmotion151) in untreated metastatic renal cell carcinoma (mRCC) [abstract LBA31]. Ann. Oncol. 29 (Suppl. 8), mdy424.037 (2018).

    Google Scholar 

  105. Pal, S. K. et al. Evolution of circulating tumor DNA profile from first-line to subsequent therapy in metastatic renal cell carcinoma. Eur. Urol. 72, 557–564 (2017).

    Article  CAS  PubMed  Google Scholar 

  106. Dizman, N. et al. Exceptional response to nivolumab rechallenge in metastatic renal cell carcinoma with parallel changes in genomic profile. Eur. Urol. 73, 308–310 (2018).

    Article  PubMed  Google Scholar 

  107. Feng, G. et al. Quantification of plasma cell-free DNA in predicting therapeutic efficacy of sorafenib on metastatic clear cell renal cell carcinoma. Dis. Markers 34, 105–111 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Maia, M. C. et al. Association of circulating tumor DNA (ctDNA) detection in metastatic renal cell carcinoma (mRCC) with tumor burden. Kidney Cancer 1, 65–70 (2017).

    Google Scholar 

  109. Ikeda, S., Schwaederle, M., Mohindra, M., Fontes Jardim, D. L. & Kurzrock, R. MET alterations detected in blood-derived circulating tumor DNA correlate with bone metastases and poor prognosis. J. Hematol. Oncol. 11, 76 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  110. Hahn, A. W. et al. Correlation of genomic alterations assessed by next-generation sequencing (NGS) of tumor tissue DNA and circulating tumor DNA (ctDNA) in metastatic renal cell carcinoma (mRCC): potential clinical implications. Oncotarget 8, 33614–33620 (2017).

    PubMed  PubMed Central  Google Scholar 

  111. Yamamoto, Y. et al. Increased level and fragmentation of plasma circulating cell-free DNA are diagnostic and prognostic markers for renal cell carcinoma. Oncotarget 9, 20467–20475 (2018).

    PubMed  PubMed Central  Google Scholar 

  112. Broncy, L. et al. Single-cell genetic analysis validates cytopathological identification of circulating cancer cells in patients with clear cell renal cell carcinoma. Oncotarget 9, 20058–20074 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  113. Zurita, A. J. et al. A cytokine and angiogenic factor (CAF) analysis in plasma for selection of sorafenib therapy in patients with metastatic renal cell carcinoma. Ann. Oncol. 23, 46–52 (2012).

    Article  CAS  PubMed  Google Scholar 

  114. Gigante, M. et al. Prognostic value of serum CA9 in patients with metastatic clear cell renal cell carcinoma under targeted therapy. Anticancer Res. 32, 5447–5451 (2012).

    CAS  PubMed  Google Scholar 

  115. Tran, H. T. et al. Prognostic or predictive plasma cytokines and angiogenic factors for patients treated with pazopanib for metastatic renal-cell cancer: a retrospective analysis of phase 2 and phase 3 trials. Lancet Oncol. 13, 827–837 (2012).

    Article  CAS  PubMed  Google Scholar 

  116. Deprimo, S. E. et al. Circulating protein biomarkers of pharmacodynamic activity of sunitinib in patients with metastatic renal cell carcinoma: modulation of VEGF and VEGF-related proteins. J. Transl Med. 5, 32 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  117. Voss, M. H. et al. Circulating biomarkers and outcome from a randomised phase II trial of sunitinib versus everolimus for patients with metastatic renal cell carcinoma. Br. J. Cancer 114, 642–649 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Flanigan, R. C. et al. Nephrectomy followed by interferon Alfa-2b compared with interferon Alfa-2b alone for metastatic renal-cell cancer. N. Engl. J. Med. 345, 1655–1659 (2001).

    Article  CAS  PubMed  Google Scholar 

  119. Mickisch, G. H. J., 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 358, 966–970 (2001).

    Article  CAS  PubMed  Google Scholar 

  120. Mejean, A. et al. Sunitinib alone or after nephrectomy in metastatic renal-cell carcinoma. N. Engl. J. Med. 379, 417–427 (2018).

    Article  CAS  PubMed  Google Scholar 

  121. Culp, S. H. et al. Can we better select patients with metastatic renal cell carcinoma for cytoreductive nephrectomy? Cancer 116, 3378–3388 (2010).

    Article  PubMed  Google Scholar 

  122. Heng, D. Y. C. 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. 66, 704–710 (2014).

    Article  PubMed  Google Scholar 

  123. Park, I. et al. Active surveillance for metastatic or recurrent renal cell carcinoma. J. Cancer Res. Clin. Oncol. 140, 1421–1428 (2014).

    Article  CAS  PubMed  Google Scholar 

  124. Rini, B. I. et al. Active surveillance in metastatic renal-cell carcinoma: a prospective, phase 2 trial. Lancet Oncol. 17, 1317–1324 (2016).

    Article  PubMed  Google Scholar 

  125. Jonasch, E. et al. Phase II study of two weeks on, one week off sunitinib scheduling in patients with metastatic renal cell carcinoma. J. Clin. Oncol. 36, 1588–1593 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Tannir, N. M. et al. Thirty-month follow-up of the phase III CheckMate 214 trial of first-line nivolumab + ipilimumab (N+I) or sunitinib (S) in patients (pts) with advanced renal cell carcinoma (aRCC) [abstract]. J. Clin. Oncol. 37, 547 (2019).

    Article  Google Scholar 

  127. Arbour, K. C. et al. Impact of baseline steroids on efficacy of programmed cell death-1 and programmed death-ligand 1 blockade in patients with non–small-cell lung cancer. J. Clin. Oncol. 36, 2872–2878 (2018).

    Article  CAS  PubMed  Google Scholar 

  128. Choueiri, T. K. 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. 35, 591–597 (2017).

    Article  CAS  PubMed  Google Scholar 

  129. Escudier, B. et al. Cabozantinib, a new standard of care for patients with advanced renal cell carcinoma and bone metastases? Subgroup analysis of the METEOR trial. J. Clin. Oncol. 36, 765–772 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Choueiri, T. K. 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 94, 115–125 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Hudes, G. et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N. Engl. J. Med. 356, 2271–2281 (2007).

    Article  CAS  PubMed  Google Scholar 

  132. Amin, A. 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 6, 109 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  133. Chowdhury, S. et al. A phase I/II study to assess the safety and efficacy of pazopanib (PAZ) and pembrolizumab (PEM) in patients (pts) with advanced renal cell carcinoma (aRCC). J. Clin. Oncol. 35, 4506–4506 (2017).

    Article  Google Scholar 

  134. Terme, M. et al. VEGFA-VEGFR pathway blockade inhibits tumor-induced regulatory T cell proliferation in colorectal cancer. Cancer Res. 73, 539–549 (2013).

    Article  CAS  PubMed  Google Scholar 

  135. Bouzin, C., Brouet, A., De Vriese, J., DeWever, J. & Feron, O. Effects of vascular endothelial growth factor on the lymphocyte-endothelium interactions: identification of caveolin-1 and nitric oxide as control points of endothelial cell anergy. J. Immunol. 178, 1505–1511 (2007).

    Article  CAS  PubMed  Google Scholar 

  136. Gavalas, N. G. et al. VEGF directly suppresses activation of T cells from ascites secondary to ovarian cancer via VEGF receptor type 2. Br. J. Cancer 107, 1869–1875 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. McDermott, D. F. et al. Pembrolizumab monotherapy as first-line therapy in advanced clear cell renal cell carcinoma (accRCC): results from cohort A of KEYNOTE-427 [abstract]. J. Clin. Oncol. 36, 4500 (2018).

    Article  Google Scholar 

  138. Leone, R. D. & Emens, L. A. Targeting adenosine for cancer immunotherapy. J. Immunother. Cancer 6, 57 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  139. Yu, Y. I. et al. Ecto-5′-nucleotidase expression is associated with the progression of renal cell carcinoma. Oncol. Lett. 9, 2485–2494 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Hotson, A. et al.Clinical activity of adenosine 2A receptor (A2AR) inhibitor CPI-444 is associated with tumor expression of adenosine pathway genes and tumor immune modulation [abstract O4]. J. Immunother. Cancer 5 (Suppl. 2), 86 (2017).

  141. Fong, L. et al. Safety and clinical activity of adenosine A2a receptor (A2aR) antagonist, CPI-444, in anti-PD1/PDL1 treatment-refractory renal cell (RCC) and non-small cell lung cancer (NSCLC) patients [abstract]. J. Clin. Oncol. 35, 3004 (2017).

    Article  Google Scholar 

  142. Hotson, A. et al. Adenosine signature genes associate with tumor regression in renal cell carcinoma (RCC) patients treated with the adenosine A2A receptor (A2AR) antagonist, CPI-444 [abstract P54]. J. Immunother. Cancer 6 (Suppl. 1), 114 (2018).

    Google Scholar 

  143. Bensch, F. et al. 89Zr-atezolizumab imaging as a non-invasive approach to assess clinical response to PD-L1 blockade in cancer. Nat. Med. 24, 1852–1858 (2018).

    Article  CAS  PubMed  Google Scholar 

  144. Meric-Bernstam, F. G. et al. A phase 1/2 study of CB-839, a first-in-class glutaminase inhibitor, combined with nivolumab in patients with advanced melanoma (MEL), renal cell carcinoma (RCC), or non-small cell lung cancer (NSCLC) [abstract O16]. J. Immunother. Cancer 5 (Suppl. 2), 86 (2017).

    Google Scholar 

  145. Lucarelli, G. et al. Activation of the kynurenine pathway predicts poor outcome in patients with clear cell renal cell carcinoma. Urol. Oncol. 35, 461.e15–461.e27 (2017).

    Article  CAS  Google Scholar 

  146. Diab, A. et al. NKTR-214 (CD122-biased agonist) plus nivolumab in patients with advanced solid tumors: preliminary phase 1/2 results of PIVOT [abstract]. J. Clin. Oncol. 36, 3006 (2018).

    Article  Google Scholar 

  147. Tannir, N. M. et al. Pegilodecakin with nivolumab (nivo) or pembrolizumab (pembro) in patients (pts) with metastatic renal cell carcinoma (RCC) [abstract]. J. Clin. Oncol. 36, 4509 (2018).

    Article  Google Scholar 

  148. Tannir, N. M. 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) [abstract]. J. Clin. Oncol. 36, 603 (2018).

    Article  Google Scholar 

  149. Tannir, N. M. et al. CANTATA: a randomized phase 2 study of CB-839 in combination with cabozantinib versus placebo with cabozantinib in patients with advanced/metastatic renal cell carcinoma [abstract]. J. Clin. Oncol. 36 (Suppl. 15), TPS4601 (2018).

    Article  Google Scholar 

  150. Courtney, K. D. et al. Isotope tracing of human clear cell renal cell carcinomas demonstrates suppressed glucose oxidation in vivo. Cell Metab. 28, 793–800 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Sulkowski, P. L. et al. Krebs-cycle-deficient hereditary cancer syndromes are defined by defects in homologous-recombination DNA repair. Nat. Genet. 50, 1086–1092 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Lamers, C. H., Klaver, Y., Gratama, J. W., Sleijfer, S. & Debets, R. Treatment of metastatic renal cell carcinoma (mRCC) with CAIX CAR-engineered T cells-a completed study overview. Biochem. Soc. Trans. 44, 951–959 (2016).

    Article  CAS  PubMed  Google Scholar 

  153. Cherkasova, E. et al. Detection of an immunogenic HERV-E envelope with selective expression in clear cell kidney cancer. Cancer Res. 76, 2177–2185 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Ruf, M. et al. pVHL/HIF-regulated CD70 expression is associated with infiltration of CD27+lymphocytes and increased serum levels of soluble CD27 in clear cell renal cell carcinoma. Clin. Cancer Res. 21, 889–898 (2015).

    Article  CAS  PubMed  Google Scholar 

  155. Pal, S. K. et al. A phase 1 trial of SGN-CD70A in patients with CD70-positive, metastatic renal cell carcinoma. Cancer 125, 1124–1132 (2019).

    Article  CAS  PubMed  Google Scholar 

Download references

Reviewer information

Nature Reviews Clinical Oncology thanks R. Figlin, E. Jonasch and W. Stadler for their contribution to the peer review of this work.

Author information

Authors and Affiliations

Authors

Contributions

All authors contributed to each stage of preparation of this manuscript for publication.

Corresponding author

Correspondence to Martin H. Voss.

Ethics declarations

Competing interests

R.R.K. declares no competing interests. R.J.M. has received research support from Bristol-Myers Squibb, Eisai, Genentech, Novartis and Pfizer and honoraria for advisory and consulting roles from Genentech, Incyte, Merck, Novartis and Pfizer. M.H.V. has received research support from Bristol-Myers Squibb, Genentech, Novartis and Roche, travel and accommodation support from Eisai, Novartis and Takeda and has been a paid consultant for Alexion, Bayer, Calithera, Corvus, Eisai, Exelixis, GlaxoSmithKline, Natera, Novartis and Pfizer.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Related links

US NIH ClinicalTrials.gov database: https://www.clinicaltrials.gov

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kotecha, R.R., Motzer, R.J. & Voss, M.H. Towards individualized therapy for metastatic renal cell carcinoma. Nat Rev Clin Oncol 16, 621–633 (2019). https://doi.org/10.1038/s41571-019-0209-1

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41571-019-0209-1

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing