Cancer UrologyCancer UrologyОнкоурология1726-97761996-1812Publishing House ABV Press71910.17650/1726-9776-2017-13-3-132-139REVIEWОБЗОРPossibilities of optimization of the second line targeted therapy for metastatic renal cell carcinomaВозможности оптимизации 2-й линии таргетной терапии при метастатическом почечно-клеточном ракеMarkovaA. S.МарковаА. С.
Russian Federation

24 Kashirskoe Shosse, Moscow 115478, Russia

научный сотрудник, к.м.н.

Россия, 115478 Москва, Каширское шоссе, 24

mark-ann1@yandex.ruMatveevV. B.МатвеевВ. Б.
Russian Federation

24 Kashirskoe Shosse, Moscow 115478, Russia

Член-корреспондент РАН, профессор, заведующий отделением урологии

Россия, 115478 Москва, Каширское шоссе, 24

vsevolodmatveev@mail.ruN. N. Blokhin National Medical Research Oncology Center, Ministry of Health of RussiaФГБУ 'НМИЦ онкологии им. Н.Н.Блохина'300920171331321391909201721092017https://oncourology.abvpress.ru/oncur/article/view/719

Optimization of treatment of metastatic renal cell carcinoma (mRCC) is an important problem of modern oncological urology. Targeted drugs replaced immunotherapy with cytokines and became the new standard of treatment. Their introduction resulted in increased patients» lifespan and fundamentally changed treatment of kidney cancer. Since 2005, 9 targeted drugs and 1 combination of lenvatinib and everolimus were registered and approved for treatment of mRCC. All of these drugs, except cabozantinib, are available in Russia. Currently, in mRCC treatment subsequent prescription of the drugs is used, i. e. patients receive several lines of targeted therapy. We still can»t name the most effective sequence of the 1st and 2nd lines of mRCC therapy due to a lack of clear algorithms of drug prescription. Currently, axitinib, cabozantinib,  everolimus, nivolumab, and sorafenib (in alphabetic order) and the combination of lenvatinib and everolimus are recommended for the 2nd line of mRCC therapy. However, there weren’t any direct comparative studies of their effectiveness, and therefore knowledge about differences between the targeted agents can make the selection more straightforward.

Оптимизация лечения метастатического почечно-клеточного рака (мПКР) является актуальной задачей современной онкоурологии. Внедрение таргетных препаратов, позволяющих добиться увеличения продолжительности жизни больных, в корне изменило лечение рака почки, придя на смену иммунотерапии цитокинами, и прочно вошло в стандарты лечения. Начиная с 2005 г. прошли регистрацию и одобрены для применения при мПКР 9 таргетных препаратов и 1 комбинация ленватиниба и эверолимуса, из них в России доступны все, кроме кабозантиниба. В настоящее время при лечении мПКР принято последовательное назначение препаратов, когда пациенты получают несколько линий таргетной терапии. Пока мы не можем назвать наиболее эффективную последовательность 1-й и 2-й линий лечения мПКР ввиду имеющегося дефицита четких алгоритмов назначения препаратов. В настоящее время во 2-й линии терапии мПКР рекомендованы акситиниб, кабозантиниб, ниволумаб, сорафениб и эверолимус (в алфавитном порядке), а также комбинация эверолимуса и ленватиниба. Однако прямых сравнительных исследований их эффективности не проводилось, поэтому понимание различий между таргетными агентами поможет сделать выбор более очевидным.

metastatic renal cell carcinomatargeted therapysecond lineaxitinibnivolumabeverolimuslenvatinibprogression-free survivalметастатический почечно-клеточный рактаргетная терапия2-я линияакситинибниволумабэверолимусленватинибвыживаемость без прогрессирования1. Ljungberg B., Campbell S. C., Choi H. Y. et al. The epidemiology of renal cell carcinoma. Eur Urol 2011;60(4):615–21. DOI: 10.1016/j.eururo2011.06.049. PMID: 21741761.Ljungberg B., Campbell S. C., Choi H. Y. et al. The epidemiology of renal cell carcinoma. Eur Urol 2011;60(4):615–21. DOI: 10.1016/j.eururo2011.06.049. PMID: 21741761.2. Злокачественные новообразования в России в 2015 году (заболеваемость и смертность). Под ред. А. Д. Каприна, В. В. Старинского, Г. В. Петровой. М.: МНИОИ им. П. А. Герцена – филиал ФГБУ «НМИРЦ» Минздрава России, 2017. 250 с. [Malignant tumors in Russia in 2015 (morbidity and fatality). Eds.: А. D. Kaprin, V. V. Starinskiy, G. V. Petrova. Moscow: MNIOI im. P. A. Gertsena – filial FGBU “NMIRTS” Minzdrava Rossii, 2017. 250 p. (In Russ.)].Злокачественные новообразования в России в 2015 году (заболеваемость и смертность). Под ред. А. Д. Каприна, В. В. Старинского, Г. В. Петровой. М.: МНИОИ им. П. А. Герцена – филиал ФГБУ «НМИРЦ» Минздрава России, 2017. 250 с. [Malignant tumors in Russia in 2015 (morbidity and fatality). Eds.: А. D. Kaprin, V. V. Starinskiy, G. V. Petrova. Moscow: MNIOI im. P. A. Gertsena – filial FGBU “NMIRTS” Minzdrava Rossii, 2017. 250 p. (In Russ.)].3. Состояние онкологической помощи населению России в 2016 году. Под ред. А. Д. Каприна, В. В. Старинского, Г. В. Петровой. М.: МНИОИ им. П. А. Герцена – филиал ФГБУ «НМИРЦ» Минздрава России, 2016. 236 с. [State of oncological care in Russia in 2016. Eds.: A. D. Kaprin, V. V. Starinskiy, G. V. Petrova. Moscow: MNIOI im. P. A. Gertsena – filial FGBU “NMIRTS” Minzdrava Rossii, 2016. 236 p. (In Russ.)].Состояние онкологической помощи населению России в 2016 году. Под ред. А. Д. Каприна, В. В. Старинского, Г. В. Петровой. М.: МНИОИ им. П. А. Герцена – филиал ФГБУ «НМИРЦ» Минздрава России, 2016. 236 с. [State of oncological care in Russia in 2016. Eds.: A. D. Kaprin, V. V. Starinskiy, G. V. Petrova. Moscow: MNIOI im. P. A. Gertsena – filial FGBU “NMIRTS” Minzdrava Rossii, 2016. 236 p. (In Russ.)].4. Larriba J. L., Espinosa E., Carbonero I. G. et al. Sequential therapy in metastatic renal cell carcinoma: pre-clinical and clinical rationale for selecting a second- or subsequent-line therapy with a different mechanism of action. Cancer Metastasis Rev 2012;31(suppl 1):11–7. DOI: 10.1007/s10555-012-9354-z. PMID: 22674353.Larriba J. L., Espinosa E., Carbonero I. G. et al. Sequential therapy in metastatic renal cell carcinoma: pre-clinical and clinical rationale for selecting a second- or subsequent-line therapy with a different mechanism of action. Cancer Metastasis Rev 2012;31(suppl 1):11–7. DOI: 10.1007/s10555-012-9354-z. PMID: 22674353.5. Oudard S., Elaidi R. T. Sequential therapy with targeted agents in patients with advanced renal cell carcinoma: optimizing patient benefit. Cancer Treat Rev 2012;38(8):981–7. DOI:10.1016/jctrv.2011.12.009. PMID: 22289686.Oudard S., Elaidi R. T. Sequential therapy with targeted agents in patients with advanced renal cell carcinoma: optimizing patient benefit. Cancer Treat Rev 2012;38(8):981–7. DOI:10.1016/jctrv.2011.12.009. PMID: 22289686.6. Procopio G., Verzoni E., Iacovelli R. et al. Targeted therapies used sequentially in metastatic renal cell cancer: overall results from a large experience. Expert Rev Anticancer Ther 2011;11(11):1631–40. DOI: 10.1586/era.11.154. PMID: 22050012.Procopio G., Verzoni E., Iacovelli R. et al. Targeted therapies used sequentially in metastatic renal cell cancer: overall results from a large experience. Expert Rev Anticancer Ther 2011;11(11):1631–40. DOI: 10.1586/era.11.154. PMID: 22050012.7. Stenner F., Chastonay R., Liewen H. et al. A pooled analysis of sequential therapies with sorafenib and sunitinib in metastatic renal cell carcinoma. Oncology 2012;82(6):333–40. DOI: 10.1159/000338001. PMID: 22677881.Stenner F., Chastonay R., Liewen H. et al. A pooled analysis of sequential therapies with sorafenib and sunitinib in metastatic renal cell carcinoma. Oncology 2012;82(6):333–40. DOI: 10.1159/000338001. PMID: 22677881.8. Guidelines on Renal Cell Carcinoma. European Association of Urology (EAU), 2017. 66 p.Guidelines on Renal Cell Carcinoma. European Association of Urology (EAU), 2017. 66 p.9. NCCN Clinical Practice Guidelines in Oncology(NCCN Guidelines®) Kidney Cancer. Version 2.2017, 2016. Available at: https://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf.NCCN Clinical Practice Guidelines in Oncology(NCCN Guidelines®) Kidney Cancer. Version 2.2017, 2016. Available at: https://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf.10. Motzer R. J., Escudier B., Oudard S. et al. Phase 3 trial of everolimus for metastatic renal cell carcinoma. Cancer 2010;116(18):4256–65. DOI: 10.1002/cncr.25219. PMID: 20549832.Motzer R. J., Escudier B., Oudard S. et al. Phase 3 trial of everolimus for metastatic renal cell carcinoma. Cancer 2010;116(18):4256–65. DOI: 10.1002/cncr.25219. PMID: 20549832.11. Rini B. I., Escudier B., Tomczak P. et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomized phase 3 trial. Lancet 2011;378(9807):1931–9. DOI: 10.1016/S0140–6736(11)61613–9. PMID: 22056247.Rini B. I., Escudier B., Tomczak P. et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomized phase 3 trial. Lancet 2011;378(9807):1931–9. DOI: 10.1016/S0140–6736(11)61613–9. PMID: 22056247.12. Motzer R. J., Escudier B., McDermott D. F. et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med 2015;373(19):1803–13. DOI: 10.1056/NEJMoa1510665. PMID: 26406148.Motzer R. J., Escudier B., McDermott D. F. et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med 2015;373(19):1803–13. DOI: 10.1056/NEJMoa1510665. PMID: 26406148.13. Motzer R. J., Hutson T. E., Glen H. et al. Lenvatinib, everolimus, and the combination in patients with metastatic renal-cell carcinoma: a randomized, phase II, open-label, multicenter trial. Lancet Oncol 2015;16(15):1473–82. DOI: 10.1016/S1470–2045(15)00290– 9. PMID: 26482279.Motzer R. J., Hutson T. E., Glen H. et al. Lenvatinib, everolimus, and the combination in patients with metastatic renal-cell carcinoma: a randomized, phase II, open-label, multicenter trial. Lancet Oncol 2015;16(15):1473–82. DOI: 10.1016/S1470–2045(15)00290– 9. PMID: 26482279.14. Escudier B., Tannir N., McDermott D. et al. CheckMate 214: efficacy and safety of Nivolumab + Ipilimumab vs Sunitinib for treatment-naïve advanced or metastatic renal cell carcinoma, including IMDC risk and PD-L1 expression subgroups. ESMO, 2017. Abstr. LBA5.Escudier B., Tannir N., McDermott D. et al. CheckMate 214: efficacy and safety of Nivolumab + Ipilimumab vs Sunitinib for treatment-naïve advanced or metastatic renal cell carcinoma, including IMDC risk and PD-L1 expression subgroups. ESMO, 2017. Abstr. LBA5.15. Choueiri T.K., Halabi S., Sanford B.L. et al. Cabozantinib versus Sunitinib as initial targeted therapy for patients with meta static renal cell carcinoma of poor or intermediate risk: the Alliance A031203 CABOSUN Trial. J Clin Oncol 2017;35(6):591–7. DOI: 10.1200/JCO.2016.70.7398. PMID: 28199818.Choueiri T.K., Halabi S., Sanford B.L. et al. Cabozantinib versus Sunitinib as initial targeted therapy for patients with meta static renal cell carcinoma of poor or intermediate risk: the Alliance A031203 CABOSUN Trial. J Clin Oncol 2017;35(6):591–7. DOI: 10.1200/JCO.2016.70.7398. PMID: 28199818.16. Calvo E., Escudier B., Motzer R. J. 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. DOI: 10.1016/j.ejca.2011.11.027. PMID: 22209391.Calvo E., Escudier B., Motzer R. J. 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. DOI: 10.1016/j.ejca.2011.11.027. PMID: 22209391.17. Hutson T. E., Escudier B., Esteban E. et al. Randomized phase III trial of temsirolimus versus sorafenib as second-line therapy after sunitinib in patients with metastatic renal cell carcinoma. J Clin Oncol 2014;32(8);760–7. DOI: 10.1200/JCO.2013.50.3961. PMID: 24297950.Hutson T. E., Escudier B., Esteban E. et al. Randomized phase III trial of temsirolimus versus sorafenib as second-line therapy after sunitinib in patients with metastatic renal cell carcinoma. J Clin Oncol 2014;32(8);760–7. DOI: 10.1200/JCO.2013.50.3961. PMID: 24297950.18. Rini B. I., de La Motte Rouge T., Harzstark A. L. et al. Five-year survival in patients with cytokine-refractory metastatic renal cell carcinoma treated with axitinib. Clin Genitourin Cancer 2013;11(2):107–14. DOI: 10.1016/j.clgc.2012.12.004. PMID: 23391371.Rini B. I., de La Motte Rouge T., Harzstark A. L. et al. Five-year survival in patients with cytokine-refractory metastatic renal cell carcinoma treated with axitinib. Clin Genitourin Cancer 2013;11(2):107–14. DOI: 10.1016/j.clgc.2012.12.004. PMID: 23391371.19. Motzer R. J., Escudier B., Tomczak P. et al. Axitinib versus sorafenib as secondline treatment for advanced renal cell carcinoma: overall survival analysis and updated results from a randomised phase 3 trial. Lancet Oncol 2013;14(6):552–62. DOI: 10.1016/S1470– 2045(13)70093–7. PMID: 23598172.Motzer R. J., Escudier B., Tomczak P. et al. Axitinib versus sorafenib as secondline treatment for advanced renal cell carcinoma: overall survival analysis and updated results from a randomised phase 3 trial. Lancet Oncol 2013;14(6):552–62. DOI: 10.1016/S1470– 2045(13)70093–7. PMID: 23598172.20. Rini B. I., Quinn D. I., Baum M. Hypertension among patients with renal cell carcinoma receiving axitinib or sorafenib: analysis from the randomized phase III AXIS trial. Targ Oncol 2015;10(1):45–53. DOI: 10.1007/s11523-014-0307-z. PMID: 24595903.Rini B. I., Quinn D. I., Baum M. Hypertension among patients with renal cell carcinoma receiving axitinib or sorafenib: analysis from the randomized phase III AXIS trial. Targ Oncol 2015;10(1):45–53. DOI: 10.1007/s11523-014-0307-z. PMID: 24595903.21. Matias M., Le Teuff G., Albiges L. et al. Real world prospective experience of axitinib in metastatic renal cell carcinoma in a large comprehensive cancer centre. Eur J Cancer 2017;79:185–92. DOI: 10.1016/j.ejca.2017.04.015. PMID: 28511146.Matias M., Le Teuff G., Albiges L. et al. Real world prospective experience of axitinib in metastatic renal cell carcinoma in a large comprehensive cancer centre. Eur J Cancer 2017;79:185–92. DOI: 10.1016/j.ejca.2017.04.015. PMID: 28511146.22. Villaruz L. C., Socinski M. A. The clinical viewpoint: definitions, limitations of recist, practical considerations of measurement. Clin Cancer Res 2013;19(10):2629–36. DOI: 10.1158/1078–0432.CCR-12–2935. PMID: 23669423.Villaruz L. C., Socinski M. A. The clinical viewpoint: definitions, limitations of recist, practical considerations of measurement. Clin Cancer Res 2013;19(10):2629–36. DOI: 10.1158/1078–0432.CCR-12–2935. PMID: 23669423.23. George S., Motzer R. J., Hammers H. J. 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. DOI: 10.1001/jamaoncol.2016.0775. PMID: 27243803.George S., Motzer R. J., Hammers H. J. 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. DOI: 10.1001/jamaoncol.2016.0775. PMID: 27243803.24. Escudier B., Eisen T., Stadler W. M. et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007;356(2):125–34. DOI: 10.1056/NEJMoa060655. PMID: 17215530.Escudier B., Eisen T., Stadler W. M. et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007;356(2):125–34. DOI: 10.1056/NEJMoa060655. PMID: 17215530.25. Lang J. M., Harrison M. R. Pazopanib for the treatment of patients with advanced renal cell carcinoma. Clin Med Insights Oncol 2010;4:95–105. DOI: 10.4137/CMO.S4088. PMID: 20981133.Lang J. M., Harrison M. R. Pazopanib for the treatment of patients with advanced renal cell carcinoma. Clin Med Insights Oncol 2010;4:95–105. DOI: 10.4137/CMO.S4088. PMID: 20981133.