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Таргетная терапия метастатического почечно-клеточного рака
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Аннотация
В настоящее время для лечения метастатического почечно-клеточного рака (мПКР) в 1-й линии терапии одобрены следующие препараты, воздействующие на различные мишени: сунитиниб, сорафениб, пазопаниб, акситиниб (ингибиторы VEGFR), бевацизумаб (антиVEGF моноклональные антитела), темсиролимус и эверолимус (ингибиторы mTOR). Согласно результатам прямых сравнительных клинических исследований сунитиниба и пазопаниба (COMPARZ и PISCES) пазопаниб обладает более предпочтительным профилем безопасности, исключая риск развития печеночных осложнений. В то же время 20–25% пациентов не отвечают на лечение препаратами 1-й линии. Тактика лечения этой группы пациентов заключается в определении последовательности назначения препаратов. Полученные клинические данные подтверждают целесообразность последовательного применения таргетных агентов у больных мПКР, объясняя это улучшением ответа на лечение без перекрестной резистентности. В настоящее время препарат эверолимус является препаратом выбора во 2-й линии таргетной терапии, так как он не только обладает достоверно высокой эффективностью, но и позволяет преодолевать резистентность к антиангиогенной терапии. В настоящее время недостаточно данных относительно активности таргетных препаратов в 3-й линии терапии мПКР.
Ключевые слова: почечно-клеточный рак, клинические исследования, общая выживаемость, эверолимус, выживаемость без прогрессирования.
Ключевые слова: почечно-клеточный рак, клинические исследования, общая выживаемость, эверолимус, выживаемость без прогрессирования.
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Seven small molecular weight targeted agents have been approved for the treatment of metastatic renal cell carcinoma (mRCC), including the humanised anti-vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab (used in combination with interferon [IFN]-a); the multi-targeted receptor tyrosine kinase inhibitors (TKIs) sunitinib, pazopanib, axitinib and sorafenib; and the mammalian target of rapamycin inhibitors (mTORIs) everolimus and temsirolimus. According to the results of comparative clinical trials of sunitinib and pazopanib (COMPARZ and PISCES), pazopanib has more preferable safety profile due to elimination of the risk of hepatic complications. However, 20–25% of patients do not respond to the first-line therapy. The treatment strategy for this group of patients is to select optimal treatment sequence. The robust clinical data confirm the advantage of consecutive usage of targeted agents in patients with mRCC, explaining the improved response with lack of cross-resistance. Currently, everolimus is an optimal choice in the second-line targeted therapy for mRCC since it has high-level evidence of its efficacy and at the same time it allows to overcome resistance to the anti-angiogenic therapy. Currently, there are no sufficient data on the effectiveness of the targeted agents in the third-line setting.
Key words: renal cell carcinoma, clinical trials, overall survival, everolimus, progression-free survival.
Полный текст
Список литературы
1. GLOBOCAN 2002. Cancer Incidence, mortality and prevalence worldwide 2002 estimates; http://www-dep.iarc.fr
2. Escudier B, Eisen T, Porta C et al. Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2012; 23 (Suppl. 7): vii65–71.
3. Escudier B et al. Ann Oncol 2012; 23 (Suppl. 7): vii65–71.
4. 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.
5. Motzer RJ, Hutson TE, Tomczak P et al. Sunitinib vs. interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007; 356: 115–24.
6. Escudier B, Bellmunt J, Negrie 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: 2144–50.
7. Rini B, Halabi S, Rosenberg J et al. Phase III trial of bevacizumab plus interferon alfa vs. interferon alfa monotherapy in patients with metastatic renal rell carcinoma: final results of CALGB 90206. J Clin Oncol 2010; 28: 2137–43.
8. Sternberg C, Davis I, 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.
9. Motzer RJ, Hutson TE, Cella D et al. Pazopanib vs. sunitinib in metastatic renal-cell carcinoma. N Engl J Med 2013; 369: 722–31.
10. Escudier B et al. J Clin Oncol 2014 (In press).
11. 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.
12. 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 (9605): 2103–11.
13. Porta C et al. Crit Rev Oncol Hematol 2012; 82: 323–37.
14. Bellmunt J. Future developments in renal cell carcinoma. Ann Oncol 2009; 20: i13–7.
15. Tabernero J, Rojo F, Calvo E et al. Dose- and schedule-dependent inhibition of the mammalian target of rapamycin pathway with everolimus: A phase I tumor pharmacodynamic study in patients with advanced solid tumors. J Clin Oncol 2008; 26 (10): 1603–10.
16. O'Donnell A, Faivre S, Burris HA et al. Phase I pharmacokinetic and pharmacodynamic study of the oral mammalian target of rapamycin inhibitor everolimus in patients with advanced solid tumors. J Clin Oncol 2008; 26 (10): 1588–95.
17. Tanaka C, O’Reilly T, Kovarik JM et al. Identifying optimal biologic doses of everolimus (RAD001) in patients with cancer based on the modeling of preclinical and clinical pharmacokinetic and pharmacodynamic data. J Clin Oncol 2008; 26 (10): 1596–602.
18. Jac J, Giessinger S, Khan M et al. A phase II trial of RAD001 in patients (Pts) with metastatic renal cell carcinoma (MRCC). 2007 ASCO Annual Meeting Proceedings.
J Clin Oncol 2007; 25: 5107.
19. Jac J, Amato RJ, Giessinger S et al. A phase II study with a daily regimen of the oral mTOR inhibitor RAD001 (everolimus) in patients with metastatic renal cell carcinoma which has progressed on tyrosine kinase inhibition therapy. 2008 ASCO Annual Meeting Proceedings. J Clin Oncol 2008; 26: 5113.
20. 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.
21. Motzer R, Kay A, Figlin R et al. Updated data from a phase III randomized trial of everolimus (RAD001) vs. PBO in metastatic renal cell carcinoma (mRCC). ASCO 2009 Genitourinary Cancers Symposium. Abstr. 278.
22. 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 (18): 4256–65.
23. Thiery-Vuillemin A, Theodore C, Jacobaschet L et al. Efficacy and safety of sequential use of everolimus (EVE) in patients (pts) with metastatic renal cell carcinoma (mRCC) previously treated with bevacizumab (BEV) with or without interferon (INF) therapy: Overall survival (OS) result from the European AVATOR retrospective study. J Clin Oncol 2013; 31 (Suppl.). Abstr. e15607.
24. http://clinicaltrials.gov/show/NCT02056587
25. Снеговой А.В., Сафина С.З., Варламов С.А. и др. Предварительные результаты оценки эффективности эверолимуса у больных метастатическим почечно-клеточным раком, прогрессирующих на терапии бевацизумабом и интерфероном (I этап многоцентрового исследования CRAD001lRU02T). Злокачественные опухоли. 2013; 2 (6): 120.
26. Snegovoy A, Manzyuk LV, Varlamov S et al. Everolimus in bevacizumab-refractory metastatic renal cell carcinoma patients. J Clin Oncol 32, 2014 (suppl; abstr e15603).
27. Rini BI, Escudier B, Tomczak P et al. Comparative effectiveness of axitinib vs. sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet 2011; 378 (9807): 1931–9.
28. Motzer RJ, Escudier B, Tomczak P et al. Axitinib vs. sorafenib as second-line 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.
29. Motzer RJ, Porta C, Vogelzang NJ et al. Dovitinib vs. 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.
2. Escudier B, Eisen T, Porta C et al. Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2012; 23 (Suppl. 7): vii65–71.
3. Escudier B et al. Ann Oncol 2012; 23 (Suppl. 7): vii65–71.
4. 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.
5. Motzer RJ, Hutson TE, Tomczak P et al. Sunitinib vs. interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007; 356: 115–24.
6. Escudier B, Bellmunt J, Negrie 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: 2144–50.
7. Rini B, Halabi S, Rosenberg J et al. Phase III trial of bevacizumab plus interferon alfa vs. interferon alfa monotherapy in patients with metastatic renal rell carcinoma: final results of CALGB 90206. J Clin Oncol 2010; 28: 2137–43.
8. Sternberg C, Davis I, 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.
9. Motzer RJ, Hutson TE, Cella D et al. Pazopanib vs. sunitinib in metastatic renal-cell carcinoma. N Engl J Med 2013; 369: 722–31.
10. Escudier B et al. J Clin Oncol 2014 (In press).
11. 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.
12. 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 (9605): 2103–11.
13. Porta C et al. Crit Rev Oncol Hematol 2012; 82: 323–37.
14. Bellmunt J. Future developments in renal cell carcinoma. Ann Oncol 2009; 20: i13–7.
15. Tabernero J, Rojo F, Calvo E et al. Dose- and schedule-dependent inhibition of the mammalian target of rapamycin pathway with everolimus: A phase I tumor pharmacodynamic study in patients with advanced solid tumors. J Clin Oncol 2008; 26 (10): 1603–10.
16. O'Donnell A, Faivre S, Burris HA et al. Phase I pharmacokinetic and pharmacodynamic study of the oral mammalian target of rapamycin inhibitor everolimus in patients with advanced solid tumors. J Clin Oncol 2008; 26 (10): 1588–95.
17. Tanaka C, O’Reilly T, Kovarik JM et al. Identifying optimal biologic doses of everolimus (RAD001) in patients with cancer based on the modeling of preclinical and clinical pharmacokinetic and pharmacodynamic data. J Clin Oncol 2008; 26 (10): 1596–602.
18. Jac J, Giessinger S, Khan M et al. A phase II trial of RAD001 in patients (Pts) with metastatic renal cell carcinoma (MRCC). 2007 ASCO Annual Meeting Proceedings.
J Clin Oncol 2007; 25: 5107.
19. Jac J, Amato RJ, Giessinger S et al. A phase II study with a daily regimen of the oral mTOR inhibitor RAD001 (everolimus) in patients with metastatic renal cell carcinoma which has progressed on tyrosine kinase inhibition therapy. 2008 ASCO Annual Meeting Proceedings. J Clin Oncol 2008; 26: 5113.
20. 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.
21. Motzer R, Kay A, Figlin R et al. Updated data from a phase III randomized trial of everolimus (RAD001) vs. PBO in metastatic renal cell carcinoma (mRCC). ASCO 2009 Genitourinary Cancers Symposium. Abstr. 278.
22. 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 (18): 4256–65.
23. Thiery-Vuillemin A, Theodore C, Jacobaschet L et al. Efficacy and safety of sequential use of everolimus (EVE) in patients (pts) with metastatic renal cell carcinoma (mRCC) previously treated with bevacizumab (BEV) with or without interferon (INF) therapy: Overall survival (OS) result from the European AVATOR retrospective study. J Clin Oncol 2013; 31 (Suppl.). Abstr. e15607.
24. http://clinicaltrials.gov/show/NCT02056587
25. Снеговой А.В., Сафина С.З., Варламов С.А. и др. Предварительные результаты оценки эффективности эверолимуса у больных метастатическим почечно-клеточным раком, прогрессирующих на терапии бевацизумабом и интерфероном (I этап многоцентрового исследования CRAD001lRU02T). Злокачественные опухоли. 2013; 2 (6): 120.
26. Snegovoy A, Manzyuk LV, Varlamov S et al. Everolimus in bevacizumab-refractory metastatic renal cell carcinoma patients. J Clin Oncol 32, 2014 (suppl; abstr e15603).
27. Rini BI, Escudier B, Tomczak P et al. Comparative effectiveness of axitinib vs. sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet 2011; 378 (9807): 1931–9.
28. Motzer RJ, Escudier B, Tomczak P et al. Axitinib vs. sorafenib as second-line 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.
29. Motzer RJ, Porta C, Vogelzang NJ et al. Dovitinib vs. 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.
Авторы
Камилло Порта1, И.В.Тимофеев2
1 НИИ онкологии и реабилитации им. Сан Маттео Университетского госпиталя г. Пайвы, Италия;
2 Общество онкологов-химиотерапевтов России (RUSSCO), Бюро по изучению рака почки, Москва, Россия
1 НИИ онкологии и реабилитации им. Сан Маттео Университетского госпиталя г. Пайвы, Италия;
2 Общество онкологов-химиотерапевтов России (RUSSCO), Бюро по изучению рака почки, Москва, Россия
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Camillo Porta, Ilya Tsimafeyeu
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