Abstract
Background
This article describes and compares approved targeted therapies and the newer immunotherapy agents.
Materials and methods
This article especially performs an in-depth review of currently available data for tivozanib, explaining its mechanism of action, its safety profile and its role as an efficacy drug in the management of renal cancer.
Results
Despite the fact that the treatment of advanced RCC has been dramatically modified in recent years, durable remissions are scarce and it remains a lethal disease. For first- and second-line therapy, there is now growing evidence to guide the selection of the appropriate treatment.
Conclusions
Several TKIs are standard of care at different settings. Among those approved TKIs, tivozanib has similar efficacy than others with a better safety profile. The use of prognostic factors is critical to the selection of optimal therapy.
Similar content being viewed by others
References
Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424. https://doi.org/10.3322/caac.21492(Epub 2018 Sep 12).
Ljungberg B, Campbell SC, Choi HY, et al. The epidemiology of renal cell carcinoma. Eur Urol. 2011;60(4):615–21.
Rodriguez-Vida A, Hutson TE, Bellmunt J, et al. New treatment options for metastatic renal cell carcinoma. ESMO Open. 2017;2(2):e000185.
Escudier B, Pluzanska A, Koralewski P, et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet. 2007;370:2103–11. https://doi.org/10.1016/S0140-6736(07)61904-7.
Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007;356:115–24. https://doi.org/10.1056/NEJMoa065044.
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;28:1061–8. https://doi.org/10.1200/JCO.2009.23.9764.
Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet. 2011;378:1931–9. https://doi.org/10.1016/S0140-6736(11)61613-9.
Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007;356:2271–81. https://doi.org/10.1056/NEJMoa066838 (PubMed).
Motzer RJ, Escudier B, Oudard S, et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet. 2008;372:449–56. https://doi.org/10.1016/S0140-6736(08)61039-9.
Escudier B, Porta C, Schmidinger M, et al. Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014. https://doi.org/10.1093/annonc/mdz056.
Gill DM, Agarwal N, Vaishampayan U. Evolving treatment paradigm in metastatic renal cell carcinoma. Am Soc Clin Oncol Educ Book. 2017;37:319–29. https://doi.org/10.14694/EDBK_174469.
Ellis LM, Hicklin DJ. VEGF-targeted therapy: mechanims of anti-tumor activity. Nat Rev Cancer. 2008;8(8):579–91.
Shibuya M. Vascular endothelial growth factor receptor-2: its unique signaling and specific ligand VEGF-E. Cancer Sci. 2003;94(9):751–6.
Kowanetz M, Ferrara N. Vascular endothelial growth factor signaling pathways: therapeutic perspective. Clin Cancer Res. 2006;12(7):5018–22.
Eskens FALM, de Jonge MJA, Esteves B, et al. Updated results from a phase I study of AV-951 (KRN951), a potent selective VEGFR-1,-2, and -3 tyrosine kinases inhibitor, in patients with advanced solid tumors. ASCO, San Diego, CA Abstract LB-201; 2008.
Bhargava P, Robinson MO. Development of second-generation VEGFR tyrosine kinase inhibitors: current status. Curr Oncol Rep. 2011;13(2):103–11.
Escudier B, Goe M. Axitinib for the management of metastatic renal cell carcinoma. Drugs RD. 2011;11(2):113–26.
Fotdiva, public assessment report, EMA; 2017.
Rini BI, Halabi S, Rosenberg JE, 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.
Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007;356(2):115–24.
Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Oudard S, 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(22):3584–90.
Motzer RJ, Hutson TE, Cella D, Reeves J, Hawkins R, Guo J, et al. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med. 2013;369(8):722–31.
Motzer RJ, Nosov D, Eisen T, Bondarenko I, Lesovoy V, Lipatov O, et al. Tivozanib versus sorafenib as initial targeted therapy for patients with metastatic renal cell carcinoma: results from a phase III trial. J Clin Oncol. 2013;31(30):3791–9.
Molina AM, Hutson TE, Nosov D, Lipatov O, Sternberg C, et al. Efficacy of tivozanib treatment after sorafenib in patients with advanced renal cell carcinoma: crossover of a phase 3 study. Eur J Cancer. 2018;94:87–94. https://doi.org/10.1016/j.ejca.2018.02.009.
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.
Choueiri TK, Hessel C, Halabi S, Sanford B, Michaelson MD, Hahn O, 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. 2018;94:115–25.
Motzer RJ, Tannir NM, McDermott DF, Arén Frontera O, Melichar B, Choueiri TK, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med. 2018;378:1277–90.
Tannir NM, Frontera OA, Hammers HJ. 30-Month follow-up of the phase 3 CheckMate 214 trial of first-line nivolumab plus ipilimumab or sunitinib in patients with advanced renal cell carcinoma. ASCO-GU, editor. ASCO GU; 2019.
McDermott D, Rini B, Motzer R. Treatment-free survival following discontinuation of first-line nivolumab plus ipilimumab or sunitinib in patients with advanced renal cell carcinoma: CheckMate 214 analysis. ESMO, editor. ESMO; 2018.
Rini B, Plimack ER, Stus V, Gafanov R. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019;380:1–12.
Motzer R, Powles T, Atkins M. IMmotion151: a randomized phase III study of atezolizumab plus bevacizumab versus sunitinib in untreated metastatic renal cell carcinoma. J Clin Oncol. 2018;36(Suppl 6S):Abstract578.
Motzer R, Penkov K, Haanen J. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019;380:1–13.
Barthelemy P, Escudier B, Ravaud A, Negrier S, Needle MN, et al. TiNivo—tivozanib combined with nivolumab: safety and efficacy in patients with metastatic renal cell carcinoma (mRCC). Ann Oncol. 2018;29(suppl_8):mdy283.087.
Motzer RJ, Bacik J, Murphy BA, et al. Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. J Clin Oncol. 2002;20:289–96.
Motzer RJ, Escudier B, Bukowski R, Rini BI, Hutson TE, Barrios CH, et al. Prognostic factors for survival in 1059 patients treated with sunitinib for metastatic renal cell carcinoma. Br J Cancer. 2013;108:2470–7.
Heng DY, Xie W, Regan MM, Warren MA, Golshayan AR, Sahi C, 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. 2009;27:5794–9.
Tamada S, Iguchi T, Yasuda S, Kato M, Yamasaki T, Nakatani T. The difference in the survival rate of patients with metastatic renal cell carcinoma in the intermediate-risk group of the Memorial Sloan Kettering Cancer Center criteria. Oncotarget. 2018;9:27752–9.
Sella A, Michaelson MD, Matczak E, Simantov R, Lin X, Figlin RA. Heterogeneity of patients with intermediate-prognosis metastatic renal cell carcinoma treated with sunitinib. Clin Genitourin Cancer. 2017;15:291–9(e1).
Iacovelli R, De Giorgi U, Galli L, Zucali P, Nole F, Sabbatini R, et al. Is it possible to improve prognostic classification in patients affected by metastatic renal cell carcinoma with an intermediate or poor prognosis? Clin Genitourin Cancer. 2018. https://doi.org/10.1016/j.clgc.2018.04.007(Epub ahead of print).
Rini BI, Hutson TE, Figlin RA, Lechuga MJ, Valota O, Serfass L, et al. Sunitinib in patients with metastatic renal cell carcinoma: clinical outcome according to international metastatic renal cell carcinoma database consortium risk group. Clin Genitourin Cancer. 2018;16:298–304.
Procopio G, Bamias A, Schmidinger M, Hawkins R, Rodríguez Sánchez A, Vázquez Estévez S, et al. Real-world efectiveness of pazopanib in patients with intermediate prognostic risk advanced renal cell carcinoma (PRINCIPAL Study). Ann Oncol. 2018;29(suppl_8):vii303–viii331.
Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373:1814–23. https://doi.org/10.1056/NEJMoa1510016([PMC free article] [PubMed] [CrossRef]).
Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2016;17:917–27. https://doi.org/10.1016/S1470-2045(16)30107-3.
Motzer RJ, Hutson TE, Glen H, et al. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol. 2015;16:1473–82. https://doi.org/10.1016/S1470-2045(15)00290-9.
Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373:1803–13. https://doi.org/10.1056/NEJMoa1510665([PMC free article] [PubMed] [CrossRef]).
National Comprehensive Cancer Network. https://www.nccn.org/professionals/physician_gls/PDF/kidney.pdf. Accessed Jan 2017.
Motzer RJ, Porta C, Vogelzang NJ, et al. Dovitinib versus sorafenib for third-line targeted treatment of patients with metastatic renal cell carcinoma: an open-label, randomised phase 3 trial. Lancet Oncol. 2014;15(3):286–96. https://doi.org/10.1016/S1470-2045(14)70030-0([PMC free article] [PubMed] [CrossRef]).
Calvo E, Escudier B, Motzer RJ, et al. Everolimus in metastatic renal cell carcinoma: subgroup analysis of patients with 1 or 2 previous vascular endothelial growth factor receptor-tyrosine kinase inhibitor therapies enrolled in the phase III RECORD-1 study. Eur J Cancer. 2012;48(3):333–9. https://doi.org/10.1016/j.ejca.2011.11.027.
Bedke J, Gauler T, Grünwald V, et al. Systemic therapy in metastatic renal cell carcinoma. World J Urol. 2017;35(2):179–88.
Rini BI, Pal SK, Escudier B, Atkins MB, Hitson TE, et al. TIVO-3: a phase III, randomized, controlled, multicenter, open-label study to compare tivozanib to sorafenib in subjects with refractory advanced renal cell carcinoma (RCC). J Clin Oncol. 2019;37(7_suppl):541–541. https://doi.org/10.1200/JCO.2019.37.7_suppl.541.
Porta C, Verzoni E, Escudier B, et al. TIVO-3: subgroup analysis of progression-free survival of tivozanib compared to sorafenib in subjects with refractory advanced renal cell carcinoma (RCC). J Clin Oncol. 2019;37(15_suppl):4572–4572. https://doi.org/10.1200/JCO.2019.37.15_suppl.4572.
Miyazaki A, Miyake H, Harada KI, Inoue TA, Fujisawa M. Prognostic outcome in patients treated with tyrosine kinase inhibitors as first-line molecular-targeted therapy for metastatic renal cell carcinoma: experience in real-world clinical practice in Japan. Mol Clin Oncol. 2015;3(3):601–6.
Beuselinck B, Verbiest A, Couchy G, Job S, de Reynies S, et al. Tumor molecular characteristics in patients (pts) with international metastatic renal cell carcinoma database consortium (IMDC) good (G) and intermediate/poor (I/P) risk. Ann Oncol. 2018;29(suppl_8):mdy283.078.
Giraldo N, Becht E, Pages F, Skliris G, Verkarre V, et al. Orchestration and prognostic significance of immune checkpoints in the microenvironment of primary and metastatic renal cell cancer. Clin Cancer Res. 2015;21(13):3031–40.
Acknowledgements
The recommendations described herein are a result of expert panel meetings, funded by Eusapharma. Eusapharma was not involved in neither the interpretation of the discussions and recommendations, nor in the preparation of the manuscript, but provided honoraria for medical writing support.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
Dr. Martín Lázaro has been consultant for BMS, MSD, Takeda, Roche, Pfizer, Ipsen, Astra-Zeneca, Boehringer, Pierre-Fabre, Bayer. Has been speaker for Roche, Ipsen, Lilly, Astellas, Janssen, Novartis, Boehringer, Vifor. Has received grant or travel support from MSD, Ipsen, Roche, Janssen, Pfizer, Astellas, Pierre-Fabre. Dr. Anido Herranz reports non-financial support and other from Pfizer, personal fees, non-financial support and other from Novartis, non-financial support and other from Bayer, personal fees, non-financial support and other from Ipsen, other from EUSA, non-financial support and other from Sanofi, non-financial support and other from Advanced Accelerator Applications, grants and non-financial support from Pierre Fabre, personal fees and non-financial support from BMS, non-financial support from Roche, personal fees and non-financial support from Astellas, personal fees from Janssen, personal fees from Kyowa Kirin, personal fees from Lilly, outside the submitted work. Dr. Vázquez Estévez reports non-financial support and other from Pfizer, personal fees, non-financial support and other from Novartis, non-financial support and other from Bayer, personal fees, non-financial support and other from Ipsen, other from EUSA, non-financial support and other from Sanofi, grants and non-financial support from Pierre Fabre, personal fees and non-financial support from BMS, non-financial support from Roche, personal fees and non-financial support from Astellas, personal fees from Janssen. Dr. Fernández has had consultant or advisore role for Astellas Pharma, Roche, Pfizer, Bristol-Myers-Squibb, Sanofi, EUSA Pharma and Sanofi; has received honorari as speaker for Pierre-Fabre, Novartis, Bristol-Myers-Squibb, Ipsen, Roche, Astellas Pharma, Bayer and Janssen; has received travel/accommodations fees from Bristol-Myers-Squibb, Ipsen, Astellas. Rest of the authors have no relevant conflicts of interests.
Research involving human participants and/or animals
The manuscript does not contain clinical studies or patient data.
Informed consent
Not applicable.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Vázquez Estévez, S., Anido, U., Lázaro, M. et al. A new scenario in metastatic renal cell carcinoma: a SOG-GU consensus. Clin Transl Oncol 22, 1565–1579 (2020). https://doi.org/10.1007/s12094-020-02300-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12094-020-02300-2