Personalizing First-Line Management of Metastatic Renal Cell Carcinoma: Leveraging Current and Novel Therapeutic Options

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Kelly N. Fitzgerald Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York

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Chung-Han Lee Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York

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The treatment of metastatic renal cell carcinoma (RCC) has been revolutionized by advances in immunotherapeutic and targeted agents. Therapeutic approaches to RCC in these categories have recently evolved to include immune checkpoint inhibitors, novel vascular endothelial growth factor receptor–targeting tyrosine kinase inhibitors, and combinations of those agents. Multiple regimens within each category have been approved for use in the first-line treatment of clear cell and non–clear cell RCC. However, few of these regimens have been directly compared, leading to a new clinical challenge for physicians: how to select a first-line treatment regimen for an individual patient from among multiple approved options. In the modern era of RCC management, the initial treatment selection therefore becomes highly personalized and depends on numerous patient-specific factors, including histopathologic and clinical features of the disease, comorbid conditions, and psychosocial and economic factors. This review details current first-line treatment options for the management of metastatic RCC and proposes a framework whereby treatment selection can be optimized for individual patients.

Submitted September 23, 2021; final revision received January 11, 2022; accepted for publication January 13, 2022. Published online April 6, 2022.

Disclosures: The authors have disclosed that they have not received any financial consideration from any person or organization to support the preparation, analysis, results, or discussion of this article.

Funding: Financial support was provided by the Memorial Sloan Kettering Cancer Center Support Grant/Core Grant (NIH grant P30 CA008748).

Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Correspondence: Chung-Han Lee, MD, PhD, Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065. Email: leec4@mskcc.org

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  • 1.

    National Cancer Institute: Surveillance, Epidemiology, and End Results Program. Cancer stat facts: kidney and renal pelvis cancer. Accessed December 1, 2021. Available at: https://seer.cancer.gov/statfacts/html/kidrp.html

    • PubMed
    • Export Citation
  • 2.

    Fyfe G, Fisher RI, Rosenberg SA, et al. Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy. J Clin Oncol 1995;13:688696.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3.

    Medical Research Council Renal Cancer Collaborators. Interferon-alpha and survival in metastatic renal carcinoma: early results of a randomised controlled trial. Lancet 1999;353:1417.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4.

    Escudier B, Bellmunt J, Négrier S, et al. Phase III trial of bevacizumab plus interferon alfa-2a in patients with metastatic renal cell carcinoma (AVOREN): final analysis of overall survival. J Clin Oncol 2010;28:21442150.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5.

    Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007;356:115124.

  • 6.

    Motzer RJ, Hutson TE, Tomczak P, et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol 2009;27:35843590.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7.

    Escudier B, Eisen T, Stadler WM, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007;356:125134.

  • 8.

    Sternberg CN, Davis ID, Mardiak J, et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol 2010;28:10611068.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9.

    Motzer RJ, Escudier B, Oudard S, et al. Phase 3 trial of everolimus for metastatic renal cell carcinoma: final results and analysis of prognostic factors. Cancer 2010;116:42564265.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10.

    Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 2007;356:22712281.

  • 11.

    Motzer RJ, Mazumdar M, Bacik J, et al. Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma. J Clin Oncol 1999;17:25302540.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12.

    Heng DY, Xie W, Regan MM, et al. External validation and comparison with other models of the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model: a population-based study. Lancet Oncol 2013;14:141148.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13.

    Kwon WA, Cho IC, Yu A, et al. Validation of the MSKCC and Heng risk criteria models for predicting survival in patients with metastatic renal cell carcinoma treated with sunitinib. Ann Surg Oncol 2013;20:43974404.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14.

    Motzer RJ, Joasch E, Agarwal N, et al. NCCN Clinical Practice Guidelines in Kidney Cancer. Version 4.2022. Accessed January 4, 2022. To view the most recent version, visit NCCN.org

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15.

    Motzer RJ, Rini BI, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial. Lancet Oncol 2019;20:13701385.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16.

    Albiges L, Tannir NM, Burotto M, et al. Nivolumab plus ipilimumab versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended 4-year follow-up of the phase III CheckMate 214 trial. ESMO Open 2020;5:e001079.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17.

    Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med 2018;378:12771290.

  • 18.

    Regan MM, Jegede OA, Mantia CM, et al. Treatment-free survival after immune checkpoint inhibitor therapy versus targeted therapy for advanced renal cell carcinoma: 42-month results of the CheckMate 214 trial. Clin Cancer Res 2021;27:66876695.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19.

    Rassy E, Flippot R, Albiges L. Tyrosine kinase inhibitors and immunotherapy combinations in renal cell carcinoma. Ther Adv Med Oncol 2020;12:1758835920907504.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20.

    Escudier B, Eisen T, Stadler WM, et al. Sorafenib for treatment of renal cell carcinoma: final efficacy and safety results of the phase III treatment approaches in renal cancer global evaluation trial. J Clin Oncol 2009;27:33123318.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21.

    Rini BI, Pal SK, Escudier BJ, et al. Tivozanib versus sorafenib in patients with advanced renal cell carcinoma (TIVO-3): a phase 3, multicentre, randomised, controlled, open-label study. Lancet Oncol 2020;21:95104.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22.

    Gordon MS, Hussey M, Nagle RB, et al. Phase II study of erlotinib in patients with locally advanced or metastatic papillary histology renal cell cancer: SWOG S0317. J Clin Oncol 2009;27:57885793.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23.

    Choueiri TK, Halabi S, Sanford BL, et al. Cabozantinib versus sunitinib as initial targeted therapy for patients with metastatic renal cell carcinoma of poor or intermediate risk: the Alliance A031203 CABOSUN trial. J Clin Oncol 2017;35:591597.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24.

    Armstrong AJ, Halabi S, Eisen T, et al. Everolimus versus sunitinib for patients with metastatic non-clear cell renal cell carcinoma (ASPEN): a multicentre, open-label, randomised phase 2 trial. Lancet Oncol 2016;17:378388.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25.

    Martínez Chanzá N, Xie W, Asim Bilen M, et al. Cabozantinib in advanced non-clear-cell renal cell carcinoma: a multicentre, retrospective, cohort study. Lancet Oncol 2019;20:581590.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26.

    Kerbel RS, Yu J, Tran J, et al. Possible mechanisms of acquired resistance to anti-angiogenic drugs: implications for the use of combination therapy approaches. Cancer Metastasis Rev 2001;20:7986.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27.

    Leibovich BC, Lohse CM, Crispen PL, et al. Histological subtype is an independent predictor of outcome for patients with renal cell carcinoma. J Urol 2010;183:13091316.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28.

    Jonasch E, Donskov F, Iliopoulos O, et al. Belzutifan for renal cell carcinoma in von Hippel-Lindau disease. N Engl J Med 2021;385:20362046.

  • 29.

    Motzer R, Alekseev B, Rha SY, et al. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med 2021;384:12891300.

  • 30.

    Choueiri TK, Powles T, Burotto M, et al. Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 2021;384:829841.

  • 31.

    Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 2019;380:11161127.

  • 32.

    Harrison MR, Costello BA, Bhavsar NA, et al. Active surveillance of metastatic renal cell carcinoma: results from a prospective observational study (MaRCC). Cancer 2021;127:22042212.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33.

    Flanigan RC, Salmon SE, Blumenstein BA, et al. Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer. N Engl J Med 2001;345:16551659.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34.

    Mickisch GH, Garin A, van Poppel H, et al. Radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: a randomised trial. Lancet 2001;358:966970.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 35.

    Méjean A, Ravaud A, Thezenas S, et al. Sunitinib alone or after nephrectomy in metastatic renal-cell carcinoma. N Engl J Med 2018;379:417427.

  • 36.

    Motzer RJ, Russo P. Cytoreductive nephrectomy — patient selection is key. N Engl J Med 2018;379:481482.

  • 37.

    Escudier B, Powles T, Motzer RJ, 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 2018;36:765772.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 38.

    Hirsch L, Martinez Chanza N, Farah S, et al. Activity and safety of cabozantinib (cabo) in brain metastases (BM) from metastatic renal cell carcinoma (mRCC): an international multicenter study [abstract]. J Clin Oncol 2021;39(Suppl):Abstract 310.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 39.

    Peverelli G, Raimondi A, Ratta R, et al. Cabozantinib in renal cell carcinoma with brain metastases: safety and efficacy in a real-world population. Clin Genitourin Cancer 2019;17:291298.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 40.

    Chevreau C, Ravaud A, Escudier B, et al. A phase II trial of sunitinib in patients with renal cell cancer and untreated brain metastases. Clin Genitourin Cancer 2014;12:5054.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 41.

    Emamekhoo H, et al. Safety and efficacy outcomes with nivolumab plus ipilimumab in patients with advanced renal cell carcinoma and brain metastases: results from the CheckMate 920 trial [abstract]. J Clin Oncol 2021;39(Suppl):Abstract 4515.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 42.

    Schepisi G, Conteduca V, Casadei C, et al. Potential application of chimeric antigen receptor (CAR)-T cell therapy in renal cell tumors. Front Oncol 2020;10:565857.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 43.

    Cheng H, Force T. Molecular mechanisms of cardiovascular toxicity of targeted cancer therapeutics. Circ Res 2010;106:2134.

  • 44.

    Secombe KR, Van Sebille YZA, Mayo BJ, et al. Diarrhea induced by small molecule tyrosine kinase inhibitors compared with chemotherapy: potential role of the microbiome. Integr Cancer Ther 2020;19:1534735420928493.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 45.

    Dy GK, Adjei AA. Understanding, recognizing, and managing toxicities of targeted anticancer therapies. CA Cancer J Clin 2013;63:249279.

  • 46.

    Basolo A, Matrone A, Elisei R, et al. Effects of tyrosine kinase inhibitors on thyroid function and thyroid hormone metabolism [published online January 18, 2021]. Semin Cancer Biol, doi: 10.1016/j.semcancer.2020. 12.008

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 47.

    Shah RR, Morganroth J, Shah DR. Hepatotoxicity of tyrosine kinase inhibitors: clinical and regulatory perspectives. Drug Saf 2013;36:491503.

  • 48.

    Pottier C, Fresnais M, Gilon M, et al. Tyrosine kinase inhibitors in cancer: breakthrough and challenges of targeted therapy. Cancers (Basel) 2020;12:731.

  • 49.

    Dienstmann R, Rodon J, Serra V, et al. Picking the point of inhibition: a comparative review of PI3K/AKT/mTOR pathway inhibitors. Mol Cancer Ther 2014;13:10211031.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 50.

    Du Four S, Maenhout SK, Niclou SP, et al. Combined VEGFR and CTLA-4 blockade increases the antigen-presenting function of intratumoral DCs and reduces the suppressive capacity of intratumoral MDSCs. Am J Cancer Res 2016;6:25142531.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 51.

    Du Four S, Maenhout SK, De Pierre K, et al. Axitinib increases the infiltration of immune cells and reduces the suppressive capacity of monocytic MDSCs in an intracranial mouse melanoma model. OncoImmunology 2015;4:e998107.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 52.

    Ziogas AC, Gavalas NG, Tsiatas M, et al. VEGF directly suppresses activation of T cells from ovarian cancer patients and healthy individuals via VEGF receptor type 2. Int J Cancer 2012;130:857864.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 53.

    Kaur S, Chang T, Singh SP, et al. CD47 signaling regulates the immunosuppressive activity of VEGF in T cells. J Immunol 2014;193:39143924.

  • 54.

    Wada J, Suzuki H, Fuchino R, et al. The contribution of vascular endothelial growth factor to the induction of regulatory T-cells in malignant effusions. Anticancer Res 2009;29:881888.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 55.

    Dikov MM, Ohm JE, Ray N, et al. Differential roles of vascular endothelial growth factor receptors 1 and 2 in dendritic cell differentiation. J Immunol 2005;174:215222.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 56.

    Bronte V, Kasic T, Gri G, et al. Boosting antitumor responses of T lymphocytes infiltrating human prostate cancers. J Exp Med 2005;201:12571268.

  • 57.

    Saxton RA, Sabatini DM. mTOR signaling in growth, metabolism, and disease. Cell 2017;168:960976.

  • 58.

    Powles T, Plimack ER, Soulières D, et al. Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): extended follow-up from a randomised, open-label, phase 3 trial. Lancet Oncol 2020;21:15631573.

    • PubMed
    • Search Google Scholar
    • Export Citation

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