Current and Emerging Therapeutic Targets for Metastatic Renal Cell Carcinoma
- 313 Downloads
Purpose of review
The treatment of advanced renal cell carcinoma has evolved dramatically over recent years. In this review, we will summarize current and emerging therapies based on molecular targets and provide insight into treatment strategy for metastatic renal cell carcinoma.
We have witnessed a paradigm shift in the therapeutic landscape as treatment was formerly reliant on cytokine-based agents which have now been replaced with therapies targeting angiogenesis, mammalian target of rapamycin pathways, and immune responses. These dramatic changes are primarily due to our improved understanding of the underlying mutations and molecular mechanisms leading to tumorigenesis and progression.
We now have targeted agents in the form of small-molecule tyrosine kinase inhibitors, monoclonal antibodies, and mTOR inhibitors. Moreover, immunotherapy-targeting checkpoints of T-lymphocyte activity has provided increased overall survival and a new class of agents with potential to radically change the treatment options. With these agents and their combination, durable responses are increasingly seen even though treatment resistance remains a huge challenge. New treatment strategies are rapidly developing and the therapeutic landscape is expected for further evolution.
KeywordsRenal cell carcinoma Targeted therapy Immunotherapy
renal cell carcinoma
tyrosine kinase inhibitor
metastatic renal cell carcinoma
vascular endothelial growth factor
platelet-derived growth factor
mammalian target of rapamycin
National Comprehensive Cancer Network
median progression free survival
mesenchymal epithelial transition
objective response rate
fibroblast growth factor receptor
non-small cell lung cancer
health-related quality of life
activin receptor-like kinase 1
KZ and SW contributed to the data collection, data analysis, and writing of the manuscript.
This report required no funding.
Compliance with Ethical Standards
Conflict of Interest
Kevin Zarrabi declares that he has no conflict of interest.
Shenhong Wu has served as a speaker for Exelixis, Novartis, and Pfizer.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Ethics Approval and Consent to Participate
Consent for Publication
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 13.NCCN Clinical Practice Guidelines in Oncology. [Webpage] 2016 2016]; Available from: https://www.nccn.org/professionals/physician_gls/f_guidelines.asp.
- 16.Sternberg CN, Hawkins RE, Wagstaff J, Salman P, Mardiak J, Barrios CH, et al. A randomised, double-blind phase III study of pazopanib in patients with advanced and/or metastatic renal cell carcinoma: final overall survival results and safety update. Eur J Cancer. 2013;49(6):1287–96.CrossRefPubMedGoogle Scholar
- 19.Escudier B, Porta C, Bono P, Powles T, Eisen T, Sternberg CN, et al. Randomized, controlled, double-blind, cross-over trial assessing treatment preference for pazopanib versus sunitinib in patients with metastatic renal cell carcinoma: PISCES study. J Clin Oncol. 2014;32(14):1412–8.CrossRefPubMedGoogle Scholar
- 24.Rini BI, Halabi S, Rosenberg JE, Stadler WM, Vaena DA, Archer L, et al. Phase III trial of bevacizumab plus interferon alfa versus interferon alfa monotherapy in patients with metastatic renal cell carcinoma: final results of CALGB 90206. J Clin Oncol. 2010;28(13):2137–43.CrossRefPubMedPubMedCentralGoogle Scholar
- 28.Choueiri TK, Halabi S, Sanford BL, Hahn O, Michaelson MD, Walsh MK, 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(6):591–7.CrossRefPubMedGoogle Scholar
- 30.U.S National Library of Medicine, C.g. Study of efficacy and safety of sunitinib given on an individualized schedule, NCT01499121. 2017. Available from: https://clinicaltrials.gov/ct2/show/NCT01499121.
- 31.U.S National Library of Medicine, C.g., Sunitinib scheduling in metastatic renal cell carcinoma (mRCC), NCT02060370. 2017. M.D. Anderson Cancer center.Google Scholar
- 37.• Choueiri TK, et al. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2016;17(7):917–27. The METEOR trial is a landmark study which led to the approval of cabozantinib for clinical use in patients with mRCC. METEOR served as a proof-or-principle that MET and AXL are drug targets with clinical benefit. Due to the success of METEOR, multiple agents which target MET and AXL are in development. CrossRefPubMedGoogle Scholar
- 41.Brivanib Metastatic Renal Cell Carcinoma, NCT01253668. 2017. Available from: https://www.clinicaltrials.gov/show/NCT01253668.
- 43.Bendell JC, Gordon MS, Hurwitz HI, Jones SF, Mendelson DS, Blobe GC, et al. Safety, pharmacokinetics, pharmacodynamics, and antitumor activity of dalantercept, an activin receptor-like kinase-1 ligand trap, in patients with advanced cancer. Clin Cancer Res. 2014;20(2):480–9.CrossRefPubMedGoogle Scholar
- 44.ClinicalTrials.gov. A randomized phase 2 trial of axitinib and TRC105 versus axitinib alone in patients with advanced or metastatic renal cell carcinoma. 2017. U.S. National Library of medicine.
- 49.Plitas G, Wu K, Carlson J, Cimaglia N, Morrow M, Rudensky AY, Wolchok JD. Phase I/II study of mogamulizumab, an anti-CCR4 antibody targeting regulatory T cells in advanced cancer patients. J Clin Oncol. 2016;34(suppl 15):TPS3098Google Scholar
- 50.Study of pre-operative combination therapy with mogamulizumab and nivolumab against solid cancer patients. 2017. Available from: https://clinicaltrials.gov/ct2/show/NCT02946671.
- 57.Knox JJ, Barrios CH, Kim TM, Cosgriff T, Srimuninnimit V, Pittman K, et al. Final overall survival analysis for the phase II RECORD-3 study of first-line everolimus followed by sunitinib versus first-line sunitinib followed by everolimus in metastatic RCC. Ann Oncol. 2017;28(6):1339–45.CrossRefPubMedPubMedCentralGoogle Scholar
- 61.Choueiri TK, Figueroa DJ, Fay AP, Signoretti S, Liu Y, Gagnon R, 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. 2015;21(5):1071–7.CrossRefPubMedGoogle Scholar
- 62.Brahmer JR, Drake CG, Wollner I, Powderly JD, Picus J, Sharfman WH, et al. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol. 2010;28(19):3167–75.CrossRefPubMedPubMedCentralGoogle Scholar
- 63.•• Motzer RJ, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373(19):1803–13. The CheckMate 025 trial was the first randomized phase III trial examining immunotherapy in mRCC patients and has revolutionized the treatment landscape of this disease process. Nivolumab is the most promising of the novel treatment agents and the therapeutic potential continues to be examined in ongoing trials. CrossRefPubMedPubMedCentralGoogle Scholar
- 65.McDermott DF, Sosman JA, Sznol M, Massard C, Gordon MS, Hamid O, et al. Atezolizumab, an anti-programmed death-ligand 1 antibody, in metastatic renal cell carcinoma: long-term safety, clinical activity, and immune correlates from a phase Ia study. J Clin Oncol. 2016;34(8):833–42.CrossRefPubMedGoogle Scholar
- 68.Hammers HJ, Plimack ER, Infante JR, Ernstoff MS, Rini BI, McDermott DF, et al. Phase I study of nivolumab in combination with ipilimumab in metastatic renal cell carcinoma (mRCC). 2014 ASCO Annual Meeting. J Clin Oncol. 2014;32:5s (suppl; abstr 4504).Google Scholar
- 69.• Escudier B, Tannir NM, McDermott DF, Frontera OA, Melichar B, Plimack ER, et al. LBA5 CheckMate 214: Efficacy and safety of nivolumab + ipilimumab (N+I) v sunitinib (S) for treatment-naïve advanced or metastatic renal cell carcinoma (mRCC), including IMDC risk and PD-L1 expression subgroups. In: ESMO. 2017. Spain: Annals of Oncology. The nivolumab plus ipilimumab combination therapy in the first-line setting has the potential to alter treatment recommendations for previously untreated patients with mRCC. The prospect of combination immunotherapy is novel to the field of mRCC. Google Scholar
- 73.Rini BI, Stenzl A, Zdrojowy R, Kogan M, Shkolnik M, Oudard S, et al. IMA901, a multipeptide cancer vaccine, plus sunitinib versus sunitinib alone, as first-line therapy for advanced or metastatic renal cell carcinoma (IMPRINT): a multicentre, open-label, randomised, controlled, phase 3 trial. Lancet Oncol. 2016;17(11):1599–611.CrossRefPubMedGoogle Scholar
- 74.Amin A, Dudek AZ, Logan TF, Lance RS, Holzbeierlein JM, Knox JJ, et al. Survival with AGS-003, an autologous dendritic cell-based immunotherapy, in combination with sunitinib in unfavorable risk patients with advanced renal cell carcinoma (RCC): phase 2 study results. J Immunother Cancer. 2015;3:14.CrossRefPubMedPubMedCentralGoogle Scholar
- 82.Choueiri TK, Larkin JMG, Oya M, et al. First-line avelumab + axitinib therapy in patients (pts) with advanced renal cell carcinoma (aRCC): results from a phase Ib trial. J Clin Oncol. 2017;35(suppl; abstr 4504)Google Scholar
- 83.McDermott DF, Atkins MB, Motzer RJ, Rini BI, Escudier BJ, Fong L, et al. A phase II study of atezolizumab (atezo) with or without bevacizumab (bev) versus sunitinib (sun) in untreated metastatic renal cell carcinoma (mRCC) patients (pts). In: 2017 Genitourinary Cancers Symposium. 2017.Google Scholar
- 85.George S, Motzer RJ, Hammers HJ, Redman BG, Kuzel TM, Tykodi SS, et al. Safety and efficacy of Nivolumab in patients with metastatic renal cell carcinoma treated beyond progression: a subgroup analysis of a randomized clinical trial. JAMA Oncol. 2016;2(9):1179–86.CrossRefPubMedPubMedCentralGoogle Scholar
- 89.Bernard J, Escudier TP, Motzer RJ, Olencki T, Aren OR, Oudard S. Efficacy of cabozantinib (C) vs everolimus (E) in patients (pts) with advanced renal cell carcinoma (RCC) and bone metastases (mets) from the phase III METEOR study. In: ASCO Annual Meeting 2016. 2017. Journal of Cilnical Oncology: Chicago.Google Scholar