medsovetМедицинский СоветMeditsinskiy sovet = Medical Council2079-701X2658-5790REMEDIUM GROUP Ltd.10.21518/2079-701X-2021-9-89-94medsovet-6251Research ArticleОНКОУРОЛОГИЯONCOUROLOGYОсталось ли место сунитинибу в современных рекомендациях по системному лечению распространенного почечно-клеточного рака?Does sunitinib still have a place in the current recommendations for the systemic treatment of advanced renal cell carcinoma?https://orcid.org/0000-0001-7754-6624ВолковаМ. И.VolkovaM. I.

Волкова Мария Игоревна, доктор медицинских наук, профессор, ведущий научный сотрудник урологического отделения

115478, Москва, Каширское шоссе, д. 24

Maria  I. Volkova, Dr. Sci. (Med.), Professor, Senior Researcher of the Department of Urology

24, Kashirskoye Shosse, Moscow, 115478

mivolkova6@gmail.comКалининС. А.KalininS. A.

Калинин Сергей Анатольевич, кандидат медицинских наук, доцент кафедры онкологии и лучевой терапии лечебного факультета

117997, Москва, ул. Островитянова, д. 1

Sergey A. Kalinin, Cand. Sci. (Med.), Associate Professor of the Department of Oncology and Radiation Therapy of the Medical Faculty

1, Ostrovityanov St., Moscow, 117997

Национальный медицинский исследовательский центр онкологии имени Н.Н. БлохинаРоссияBlokhin National Medical Research Center of OncologyRussian FederationРоссийский национальный исследовательский медицинский университет имени Н.И. ПироговаРоссияPirogov Russian National Research Medical UniversityRussian Federation202107082021098994Copyright © Волкова М.И., Калинин С.А., 20212021Волкова М.И., Калинин С.А.Volkova M.I., Kalinin S.A.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.med-sovet.pro/jour/article/view/6251

Рак почки – распространенная злокачественная опухоль. Частота встречаемости почечно-клеточного рака (ПКР) в структуре онкологических заболеваний неуклонно растет. Несмотря на миграцию стадии в сторону увеличения частоты первичного выявления локализованных форм заболевания, рак почки относится к агрессивным и непредсказуемым злокачественным новообразованиям. У трети пациентов уже на момент установки диагноза имеются отдаленные метастазы. Хирургическое вмешательство является единственным радикальным методом лечения рака почки. Однако, несмотря на успехи хирургии в лечении ПКР, по разным данным более, чем у 30% радикально оперированных пациентов в процессе наблюдения выявляется диссеминация опухолевого процесса. Лучевая терапия и  химиотерапия в  лечении метастатического ПКР (мПКР) неэффективны. Результаты применения неспецифической иммунотерапии при лечении метастатического рака почки были также неудовлетворительными. Прогресс в изучении молекулярной биологии привел к открытию новой группы противоопухолевых препаратов, относящихся к ингибиторам ангиогенеза. Использование таргетной терапии позволило в несколько раз повысить эффективность лекарственной терапии в лечении мПКР по сравнению с использованием цитокиновой иммунотерапии. Одним из  первых таких препаратов, зарегистрированных в  2007  г. для лечения мПКР, стал сунитиниб, который в  ряде клинических исследований продемонстрировал наибольшую эффективность и  приемлемую токсичность. Наряду с новыми режимами лекарственного лечения мультикиназный ингибитор сунитиниб остается препаратом предпочтения для 1-й линии терапии неоперабельного местно-распространенного и диссеминированного светлоклеточного и несветлоклеточного ПКР у больных группы благоприятного прогноза. В обзоре литературы представлен критический анализ данных, касающихся исследований сунитиниба при раке почки и изменений позиции монотерапии этим препаратом при распространенных формах заболевания.

Renal cancer is a common malignancy. The frequency of renal cell carcinoma (RCC) in the structure of oncological diseases is steadily increasing. Despite the migration of the stage towards an increase in the frequency of primary detection of localized forms of the disease, renal cancer belongs to the aggressive and unpredictable malignant neoplasms. One third of patients already have distant metastases at the time of diagnosis. Surgery is the only radical method of treatment of renal cancer. However, despite the successes of surgery in the treatment of RCC, according to various data, more than 30% of radically operated patients show dissemination of the tumor process during follow-up. Radiation therapy and chemotherapy are ineffective in treating metastatic RCC (mRCC). The results of nonspecific immunotherapy in the treatment of metastatic renal cancer were also unsatisfactory. Progress in the study of molecular biology has led to the discovery of a new group of anti-tumor drugs related to angiogenesis inhibitors. The use of targeted therapies has increased the efficacy of drug therapy in the treatment of mRCC several times over the use of cytokine immunotherapy. One of the first such drugs registered in 2007 for the treatment of mRCC was sunitinib, which in a number of clinical trials has demonstrated the greatest efficacy and acceptable toxicity. Along with new drug regimens, the multikinase inhibitor sunitinib remains the drug of choice for first-line therapy of inoperable locally advanced and disseminated clear cell and non-small cell RCC in patients with favorable prognosis. The literature review presents a critical analysis of the data related to sunitinib research in kidney cancer and changes in the position of monotherapy with this drug in advanced forms of the disease.

сунитинибраспространенный почечно-клеточный ракгруппа хорошего прогнозапервая линия терапииsunitinibadvanced renal cell cancergood prognosis groupfirst-line therapyReferencesМатвеев В.Б., Волкова М.И., Ольшанская А.С. Изменение позиций иммунотерапии при распространенном раке почки: ниволумаб в комбинации с ипилимумабом в 1 линии лечения. Онкоурология. 2019;15(1):125–130. https://doi.org/10.17650/1726-9776-2019-15-1-125-130.Matveev V.B., Volkova M.I., Olshanskaya A.S. Changing paradigm of immunooncology in advanced kidney cancer: nivolumab and ipilimumab combination in the first line therapy. Onkourologiya = Cancer Urology. 2019;15(1): 125–130. (In Russ.) https://doi.org/10.17650/1726-9776-2019-15-1-125-130.Heng D.Y., Xie W., Regan M.M., Warren M.A., Golshayan A.R., 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(34): 5794−5799. https://doi.org/10.1200/JCO.2008.21.4809.Heng D.Y., Xie W., Regan M.M., Warren M.A., Golshayan A.R., 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(34): 5794−5799. https://doi.org/10.1200/JCO.2008.21.4809.Chow L.Q., Eckhardt S.G. Sunitinib: from rational design to clinical efficacy. J Clin Oncol. 2007;25(7):884–896. https://doi.org/10.1200/JCO.2006.06.3602.Chow L.Q., Eckhardt S.G. Sunitinib: from rational design to clinical efficacy. J Clin Oncol. 2007;25(7):884–896. https://doi.org/10.1200/JCO.2006.06.3602.Houk B.E., Bello C.L., Poland B., Rosen L.S., Demetri G.D., Motzer R.J. Relationship between exposure to sunitinib and efficacy and tolerability endpoints in patients with cancer: results of a pharmacokinetic/pharmacodynamic meta-analysis. Cancer Chemother Pharmacol. 2010;66(2): 357–371. https://doi.org/10.1007/s00280-009-1170-y.Houk B.E., Bello C.L., Poland B., Rosen L.S., Demetri G.D., Motzer R.J. Relationship between exposure to sunitinib and efficacy and tolerability endpoints in patients with cancer: results of a pharmacokinetic/pharmacodynamic meta-analysis. Cancer Chemother Pharmacol. 2010;66(2): 357–371. https://doi.org/10.1007/s00280-009-1170-y.Motzer R.J., Michaelson M.D., Redman B.G., Hudes G.R., Wilding G., Figlin R.A. et al. Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol. 2006;24(1):16–24. https://doi.org/10.1200/jco.2005.02.2574.Motzer R.J., Michaelson M.D., Redman B.G., Hudes G.R., Wilding G., Figlin R.A. et al. Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol. 2006;24(1):16–24. https://doi.org/10.1200/jco.2005.02.2574.Motzer R.J., Rini B.I., Bukowski R.M., Curti B.D., George D.J., Hudes G.R. et al. Sunitinib in patients with metastatic renal cell carcinoma. JAMA. 2006;295(21):2516–2524. https://doi.org/10.1001/jama.295.21.2516.Motzer R.J., Rini B.I., Bukowski R.M., Curti B.D., George D.J., Hudes G.R. et al. Sunitinib in patients with metastatic renal cell carcinoma. JAMA. 2006;295(21):2516–2524. https://doi.org/10.1001/jama.295.21.2516.Motzer R.J., Hutson T.E., Tomczak P., Michaelson M.D., Bukowski R.M., Rixe O. et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. New Engl J Med. 2007;356:115–124. https://doi.org/10.1056/NEJMoa065044.Motzer R.J., Hutson T.E., Tomczak P., Michaelson M.D., Bukowski R.M., Rixe O. et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. New Engl J Med. 2007;356:115–124. https://doi.org/10.1056/NEJMoa065044.Motzer R.J., Hutson T.E., Tomczak P., Michaelson M.D., Bukowski R.M., 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):3584–3590. https://doi.org/10.1200/JCO.2008.20.1293.Motzer R.J., Hutson T.E., Tomczak P., Michaelson M.D., Bukowski R.M., 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):3584–3590. https://doi.org/10.1200/JCO.2008.20.1293.Motzer R.J., Escudier B., Bukowski R.M., Rini B.I., Hutson T.E., Barrios C.H. et al. Prognostic factors for survival in 1059 patients treated with sunitinib for metastatic renal cell carcinoma. Br J Cancer. 2013;108:2470–2477. https://doi.org/10.1038/bjc.2013.236.Motzer R.J., Escudier B., Bukowski R.M., Rini B.I., Hutson T.E., Barrios C.H. et al. Prognostic factors for survival in 1059 patients treated with sunitinib for metastatic renal cell carcinoma. Br J Cancer. 2013;108:2470–2477. https://doi.org/10.1038/bjc.2013.236.Ravaud A., Sire M. Arterial hypertension and clinical benefit of sunitinib, sorafenib and bevacizumab in first and second-line treatment of metastatic renal cell cancer. Ann Oncol. 2009;20(5):966–967; author reply 967. https://doi.org/10.1093/annonc/mdp201.Ravaud A., Sire M. Arterial hypertension and clinical benefit of sunitinib, sorafenib and bevacizumab in first and second-line treatment of metastatic renal cell cancer. Ann Oncol. 2009;20(5):966–967; author reply 967. https://doi.org/10.1093/annonc/mdp201.Buda-Nowak A., Kucharz J., Dumnicka P., Kuzniewski M., Herman R.M., Zygulska A.L., Kusnierz-Cabala B. Sunitinib-induced hypothyroidism predicts progression-free survival in metastatic renal cell carcinoma patients. Med Oncol. 2017;34(4):68. https://doi.org/10.1007/s12032-017-0928-z.Buda-Nowak A., Kucharz J., Dumnicka P., Kuzniewski M., Herman R.M., Zygulska A.L., Kusnierz-Cabala B. Sunitinib-induced hypothyroidism predicts progression-free survival in metastatic renal cell carcinoma patients. Med Oncol. 2017;34(4):68. https://doi.org/10.1007/s12032-017-0928-z.Heng D., Xie W., Regan M., Waren M., Golshayan R., 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, multicentre study. J Clin Oncol. 2009;27(34):5794– 5799. https://doi.org/10.1200/JCO.2008.21.4809.Heng D., Xie W., Regan M., Waren M., Golshayan R., 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, multicentre study. J Clin Oncol. 2009;27(34):5794– 5799. https://doi.org/10.1200/JCO.2008.21.4809.Porta C., Levy A., Hawkins R., Castellano D., Bellmunt J., Nathan P. et al. Impact of adverse events, treatment modifications, and dose intensity on survival among patients with advanced renal cell carcinoma treated with first-line sunitinib: a medical chart review across ten centers in five European countries. Cancer Med. 2014;3(6):1517–1526. https://doi.org/10.1002/cam4.302.Porta C., Levy A., Hawkins R., Castellano D., Bellmunt J., Nathan P. et al. Impact of adverse events, treatment modifications, and dose intensity on survival among patients with advanced renal cell carcinoma treated with first-line sunitinib: a medical chart review across ten centers in five European countries. Cancer Med. 2014;3(6):1517–1526. https://doi.org/10.1002/cam4.302.Motzer R., Hutson T., Olsen M., Hudes G., Burke J., Edenfield W. et al. Randomized phase II trial of sunitinib on an intermittent versus continuous dosing schedule as first-line therapy for advanced renal cell carcinoma. J Clin Oncol. 2012;30(12):1371–1377. https://doi.org/10.1200/JCO.2011.36.4133.Motzer R., Hutson T., Olsen M., Hudes G., Burke J., Edenfield W. et al. Randomized phase II trial of sunitinib on an intermittent versus continuous dosing schedule as first-line therapy for advanced renal cell carcinoma. J Clin Oncol. 2012;30(12):1371–1377. https://doi.org/10.1200/JCO.2011.36.4133.Lee J., Kim M., Park I., Ahn J.-H., Lee D., Ryoo H. et al. Randomized phase II trial of sunitinib four weeks on and two weeks off versus two weeks on and one week off in metastatic clear-cell type renal cell carcinoma: RESTORE trial. Ann Oncol. 2015;26(11):2300–2305. https://doi.org/10.1093/annonc/mdv357.Lee J., Kim M., Park I., Ahn J.-H., Lee D., Ryoo H. et al. Randomized phase II trial of sunitinib four weeks on and two weeks off versus two weeks on and one week off in metastatic clear-cell type renal cell carcinoma: RESTORE trial. Ann Oncol. 2015;26(11):2300–2305. https://doi.org/10.1093/annonc/mdv357.Atkinson B., Kalra S., Wang X., Bathala T., Cjun P., Tannir N., Jonasch E. Clinical outcomes for patients with metastatic renal cell carcinoma treated with alternative sunitinib schedules. J Urol. 2014;191(3):611–618. https://doi.org/10.1016/j.juro.2013.08.090.Atkinson B., Kalra S., Wang X., Bathala T., Cjun P., Tannir N., Jonasch E. Clinical outcomes for patients with metastatic renal cell carcinoma treated with alternative sunitinib schedules. J Urol. 2014;191(3):611–618. https://doi.org/10.1016/j.juro.2013.08.090.Bjarnason G., Khalil B., Hudson J., Williams R., Milot L., Atri M. et al. Outcomes in patients with metastatic renal cell cancer treated with individualized sunitinib therapy: correlation with dynamic microbubble ultrasound data and review of the literature. Urol Oncol. 2014;32(4):480–487. https://doi.org/10.1016/j.urolonc.2013.10.004.Bjarnason G., Khalil B., Hudson J., Williams R., Milot L., Atri M. et al. Outcomes in patients with metastatic renal cell cancer treated with individualized sunitinib therapy: correlation with dynamic microbubble ultrasound data and review of the literature. Urol Oncol. 2014;32(4):480–487. https://doi.org/10.1016/j.urolonc.2013.10.004.Lee J., Kim M., Park I., Ahn J.-H., Lee D., Ryoo H. et al. Randomized phase II trial of sunitinib four weeks on and two weeks off versus two weeks on and one week off in metastatic clear-cell type renal cell carcinoma: RESTORE trial. Ann Oncol. 2015;26(11):2300–2305. https://doi.org/10.1093/annonc/mdv357.Lee J., Kim M., Park I., Ahn J.-H., Lee D., Ryoo H. et al. Randomized phase II trial of sunitinib four weeks on and two weeks off versus two weeks on and one week off in metastatic clear-cell type renal cell carcinoma: RESTORE trial. Ann Oncol. 2015;26(11):2300–2305. https://doi.org/10.1093/annonc/mdv357.Bracarda S., Negrier S., Casper J., Porta C., Schmidinger M., Larkin J. et al. How clinical practice is changing the rules: the sunitinib 2/1 schedule in metastatic renal cell carcinoma. Expert Rev Anticancer Ther. 2017;17(3):227–233. https://doi.org/10.1080/14737140.2017.1276830.Bracarda S., Negrier S., Casper J., Porta C., Schmidinger M., Larkin J. et al. How clinical practice is changing the rules: the sunitinib 2/1 schedule in metastatic renal cell carcinoma. Expert Rev Anticancer Ther. 2017;17(3):227–233. https://doi.org/10.1080/14737140.2017.1276830.Gore M., Szczylik C., Porta C., Bacarda S., Bjarnason G., Oudard S. et al. Safety and efficacy of sunitinib for metastatic renal-cell carcinoma: an expanded-access trial. Lancet Oncol. 2009;10(8):757–763. https://doi.org/10.1016/S1470-2045(09)70162-7.Gore M., Szczylik C., Porta C., Bacarda S., Bjarnason G., Oudard S. et al. Safety and efficacy of sunitinib for metastatic renal-cell carcinoma: an expanded-access trial. Lancet Oncol. 2009;10(8):757–763. https://doi.org/10.1016/S1470-2045(09)70162-7.Gore M., Szczylik C., Porta C., Bracarda S., Bjarnason G., Oudard S. et al. Final results from the large sunitinib global expanded-access trial in metastatic renal cell carcinoma. Br J Cancer. 2015;113(1):12–19. https://doi.org/10.1038/bjc.2015.196.Gore M., Szczylik C., Porta C., Bracarda S., Bjarnason G., Oudard S. et al. Final results from the large sunitinib global expanded-access trial in metastatic renal cell carcinoma. Br J Cancer. 2015;113(1):12–19. https://doi.org/10.1038/bjc.2015.196.Sternberg C.N., Calabrò F., Bracarda S., Carteni G., Lo Re G., Ruggeri E. et al. Safety and efficacy of sunitinib in patients from Italy with metastatic renal cell carcinoma: final results from an expanded-access trial. Oncology. 2015;88(5):273–280. https://doi.org/10.1159/000369256.Sternberg C.N., Calabrò F., Bracarda S., Carteni G., Lo Re G., Ruggeri E. et al. Safety and efficacy of sunitinib in patients from Italy with metastatic renal cell carcinoma: final results from an expanded-access trial. Oncology. 2015;88(5):273–280. https://doi.org/10.1159/000369256.Moran M., Nickens D., Adcock K., Bennets M., Desscan A., Charnley N., Fife K. Sunitinib for Metastatic Renal Cell Carcinoma: A Systematic Review and Meta-Analysis of Real-World and Clinical Trials Data. Targ Oncol. 2019;14(4):405–416. https://doi.org/10.1007/s11523-019-00653-5.Moran M., Nickens D., Adcock K., Bennets M., Desscan A., Charnley N., Fife K. Sunitinib for Metastatic Renal Cell Carcinoma: A Systematic Review and Meta-Analysis of Real-World and Clinical Trials Data. Targ Oncol. 2019;14(4):405–416. https://doi.org/10.1007/s11523-019-00653-5.Motzer R., Hutson T., 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):722–731. https://doi.org/10.1056/NEJMoa1303989.Motzer R., Hutson T., 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):722–731. https://doi.org/10.1056/NEJMoa1303989.Escudier B., Porta C., Bono P., Powles T., Eisen T., Sternberg C. 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):1412–1418. https://doi.org/10.1200/JCO.2013.50.8267.Escudier B., Porta C., Bono P., Powles T., Eisen T., Sternberg C. 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):1412–1418. https://doi.org/10.1200/JCO.2013.50.8267.Choueiri T., Hessel C., Halabi S., Sanford B., Michaelson M., 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;103:287. https://doi.org/10.1016/j.ejca.2018.09.022.Choueiri T., Hessel C., Halabi S., Sanford B., Michaelson M., 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;103:287. https://doi.org/10.1016/j.ejca.2018.09.022.Albiges L., Tannir N.M., Burotto M., McDermott D., Plimack E.R., Barthélémy P. 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(6):e001079. https://doi.org/10.1136/esmoopen-2020-001079.Albiges L., Tannir N.M., Burotto M., McDermott D., Plimack E.R., Barthélémy P. 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(6):e001079. https://doi.org/10.1136/esmoopen-2020-001079.Rini B.I., Plimack E.R., Stus V., Gafanov R., Hawkins R., Nosov D. et al. Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 2019;380(12):1116–1127. https://doi.org/10.1056/NEJMoa1816714.Rini B.I., Plimack E.R., Stus V., Gafanov R., Hawkins R., Nosov D. et al. Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 2019;380(12):1116–1127. https://doi.org/10.1056/NEJMoa1816714.Choueiri T., Motzer R., Rini B., Haanen J., Campbell M., Venugopal B. et al. Updated efficacy results from the JAVELIn Renal 101 trial: first-line avelumab plus axitinib versus sunitinib in patients with advanced renal cell carcinoma. Ann Oncol. 2020:31(8):1030-1039. https://doi.org/10.1016/j.annonc.2020.04.010.Choueiri T., Motzer R., Rini B., Haanen J., Campbell M., Venugopal B. et al. Updated efficacy results from the JAVELIn Renal 101 trial: first-line avelumab plus axitinib versus sunitinib in patients with advanced renal cell carcinoma. Ann Oncol. 2020:31(8):1030-1039. https://doi.org/10.1016/j.annonc.2020.04.010.Choueiri T.K., Powles T., Burotto M., Escudier B., Bourlon M.T., Zurawski B. et al. Nivolumab plus Cabozantinib versus Sunitinib for Advanced RenalCell Carcinoma. N Engl J Med. 2020;384(9):829–841. https://doi.org/10.1056/NEJMoa2026982.Choueiri T.K., Powles T., Burotto M., Escudier B., Bourlon M.T., Zurawski B. et al. Nivolumab plus Cabozantinib versus Sunitinib for Advanced RenalCell Carcinoma. N Engl J Med. 2020;384(9):829–841. https://doi.org/10.1056/NEJMoa2026982.Motzer R., Alekseev B., Rha S.-Y., Porta C., Eto M., Powles T. et al. Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma. N Engl J Med. 2021;384(14):1289–1300. https://doi.org/10.1056/NEJMoa2035716.Motzer R., Alekseev B., Rha S.-Y., Porta C., Eto M., Powles T. et al. Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma. N Engl J Med. 2021;384(14):1289–1300. https://doi.org/10.1056/NEJMoa2035716.Ljungberg B., Albiges L., Abu-Ghanem Y., Bensalah K., Dabestani S., Fernandes-Pello S. et al. European Association of Urology Guidelines on Renal Cell Carcinoma: The 2019 Update. Eur Urol. 2019;75(5):799–810. https://doi.org/10.1016/j.eururo.2019.02.011.Ljungberg B., Albiges L., Abu-Ghanem Y., Bensalah K., Dabestani S., Fernandes-Pello S. et al. European Association of Urology Guidelines on Renal Cell Carcinoma: The 2019 Update. Eur Urol. 2019;75(5):799–810. https://doi.org/10.1016/j.eururo.2019.02.011.Campbell M., Bilen M., Shah A., Lemke E., Jonasch E., Venkatesan A. et al. Cabozantinib for the treatment of patients with metastatic non-clear cell renal cell carcinoma: A retrospective analysis. Eur J Cancer. 2018;104:188– 194. https://doi.org/10.1016/j.ejca.2018.08.014.Campbell M., Bilen M., Shah A., Lemke E., Jonasch E., Venkatesan A. et al. Cabozantinib for the treatment of patients with metastatic non-clear cell renal cell carcinoma: A retrospective analysis. Eur J Cancer. 2018;104:188– 194. https://doi.org/10.1016/j.ejca.2018.08.014.McKay R., Bossé D., Xie W., Wankowicz S., Flaifel A., Brandao R. et al. The Clinical Activity of PD-1/PD-L1 Inhibitors in Metastatic Non-Clear Cell Renal Cell Carcinoma. Cancer Immunol Res. 2018;6(7):758–765. https://doi.org/10.1158/2326-6066.CIR-17-0475.McKay R., Bossé D., Xie W., Wankowicz S., Flaifel A., Brandao R. et al. The Clinical Activity of PD-1/PD-L1 Inhibitors in Metastatic Non-Clear Cell Renal Cell Carcinoma. Cancer Immunol Res. 2018;6(7):758–765. https://doi.org/10.1158/2326-6066.CIR-17-0475.Tannir N., Jonasch E., Albiges L., Altimakas E., Ng C., Matin S. et al. Everolimus versus sunitinib prospective evaluation in metastatic non-clear cell renal cell carcinoma (ESPN): a randomized multicentre phase 2 trial. Eur Urol. 2016;69(5):866–874. https://doi.org/10.1016/j.eururo.2015.10.049.Tannir N., Jonasch E., Albiges L., Altimakas E., Ng C., Matin S. et al. Everolimus versus sunitinib prospective evaluation in metastatic non-clear cell renal cell carcinoma (ESPN): a randomized multicentre phase 2 trial. Eur Urol. 2016;69(5):866–874. https://doi.org/10.1016/j.eururo.2015.10.049.Armstrong A., Halabi S., Eisen T., Broderick S., Stadler W., Jones R. et al. Everolimus versus sunitinib for patients with metastatic non-clear cell renal cell carcinoma (ASPEN): a multicentre, open-label, randomized phase 2 trial. Lancet Oncol. 2016;17(3):378–388. https://doi.org/10.1016/S1470-2045(15)00515-X.Armstrong A., Halabi S., Eisen T., Broderick S., Stadler W., Jones R. et al. Everolimus versus sunitinib for patients with metastatic non-clear cell renal cell carcinoma (ASPEN): a multicentre, open-label, randomized phase 2 trial. Lancet Oncol. 2016;17(3):378–388. https://doi.org/10.1016/S1470-2045(15)00515-X.Ravaud A., Oudard S., De Fromont M., Chevreau C., Gravis G., Zanetta S. et al. First-line treatment with sunitinib for type 1 and type 2 locally advanced or metastatic papillary renal cell carcinoma: a phase II study (SUPAP) by the French Genitourinary Group (GETUG). Ann Oncol. 2015;26(6):1123–1128. https://doi.org/10.1093/annonc/mdv149.Ravaud A., Oudard S., De Fromont M., Chevreau C., Gravis G., Zanetta S. et al. First-line treatment with sunitinib for type 1 and type 2 locally advanced or metastatic papillary renal cell carcinoma: a phase II study (SUPAP) by the French Genitourinary Group (GETUG). Ann Oncol. 2015;26(6):1123–1128. https://doi.org/10.1093/annonc/mdv149.Haas N., Manola J., Uzzo R., Flaherty K., Wood C., Kane C. et al. 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. 2016;387(10032):2008–2016. https://doi.org/10.1016/S0140-6736(16)00559-6.Haas N., Manola J., Uzzo R., Flaherty K., Wood C., Kane C. et al. 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. 2016;387(10032):2008–2016. https://doi.org/10.1016/S0140-6736(16)00559-6.Ravaud A., Motzer R., Pandha H., George D., Pantuck A., Patel A. et al. Adjuvant sunitinib in high-risk renal-cell carcinoma after nephrectomy. N Engl J Med. 2016;375(23):2246–2254. https://doi.org/10.1056/NEJMoa1611406.Ravaud A., Motzer R., Pandha H., George D., Pantuck A., Patel A. et al. Adjuvant sunitinib in high-risk renal-cell carcinoma after nephrectomy. N Engl J Med. 2016;375(23):2246–2254. https://doi.org/10.1056/NEJMoa1611406.

The authors declare that there are no conflicts of interest present.