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Применение комбинированных режимов терапии в лечении метастатического почечно-клеточного рака
Зуков Р.А., Черняев Д.В., Зулкайдарова А.Р. Применение комбинированных режимов терапии в лечении метастатического почечно-клеточного рака. Современная Онкология. 2022;24(2):191–198.
DOI: 10.26442/18151434.2022.2.201720
DOI: 10.26442/18151434.2022.2.201720
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Zukov RA, Chernyaev DV, Zulkaidarova AR. Combination therapy regimens in the treatment of metastatic renal cell carcinoma: A review. Journal of Modern Oncology. 2022;24(2):191–198. DOI: 10.26442/18151434.2022.2.201720
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Аннотация
Почечно-клеточный рак (ПКР) является одним из наиболее распространенных заболеваний в онкоурологии. Несмотря на улучшение методов диагностики, практически у 1/3 больных раком почки при начальном обследовании выявляют отдаленные метастазы, что обусловливает крайне высокие показатели смертности от данной онкопатологии. Долгие годы лечение запущенных форм ПКР являлось малоэффективным. Стандартные режимы химиотерапии с включением фторпиримидинов и противоопухолевых антибиотиков, цитокиновая терапия с применением интерлейкина-2 и интерферона α лишь незначительно продлевали жизнь пациентам, вызывая при этом выраженные токсико-анемические побочные явления. Попытки лечения опухоли с помощью лучевой терапии также потерпели неудачу и нашли свое применение только в симптоматической терапии отдаленных метастазов. Появление ингибиторов тирозинкиназы (ИТК) позволило получить действительно значимые результаты в лечении метастатического ПКР (мПКР). Так, знаковым событием стала регистрация ИТК – сунитиниба, а затем сорафениба, пазопаниба, акситиниба, ленватиниба, кабозантиниба и ингибиторов мишени рапамицина у млекопитающих (mTOR): эверолимуса и темсиролимуса. Последующее применение комбинаций бевацизумаба с низкими дозами интерферона α и ленватиниба с эверолимусом позволило улучшить показатели безрецидивной выживаемости и частоты объективных ответов, однако способствовало развитию нежелательных явлений (НЯ) на фоне терапии. Следующей ступенью в терапии ПКР стала регистрация Управлением по контролю пищевых продуктов и лекарств в США в апреле 2018 г. комбинации иммуноонкологических препаратов ипилимумаба и ниволумаба для лечения мПКР. В последующем зарегистрированы комбинации ингибиторов иммунных контрольных точек с таргетными препаратами, что не только позволило увеличить продолжительность жизни больных, но и снизило развитие НЯ противоопухолевой терапии. Одной из наиболее эффективных является комбинация ИТК – акситиниба или ленватиниба с ингибитором PD-1 пембролизумабом. Данная статья посвящена обзору текущих успехов в лечении пациентов с мПКР, рассмотрены результаты завершенных клинических исследований по использованию комбинированного лечения таргетными и иммуноонкологическими препаратами.
Ключевые слова: метастатический почечно-клеточный рак, ингибиторы контрольных точек, ингибиторы тирозинкиназы, комбинированные режимы, PD-1, PD-L1/2, VEGF, VEGFR, mTOR, ленватиниб, эверолимус, пембролизумаб
Ключевые слова: метастатический почечно-клеточный рак, ингибиторы контрольных точек, ингибиторы тирозинкиназы, комбинированные режимы, PD-1, PD-L1/2, VEGF, VEGFR, mTOR, ленватиниб, эверолимус, пембролизумаб
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Renal cell carcinoma (RCC) is one of the most common tumor types in urologic oncology practice. Despite the improvement of diagnostics methods, about 1/3 of patients with renal cell carcinoma have distant metastases at presentation resulting in an extremely high death rate. For many years, treatment of advanced forms of RCC was utterly ineffective. Standard chemotherapy regimens with fluoropyrimidines and antitumor antibiotics, cytokine therapy with interleukin-2, and interferon-α only slightly prolonged the life of patients while causing severe toxic side effects and anemia. Attempts to treat the tumor with radiation therapy have also failed and have been used only for symptomatic treatment of distant metastases. The introduction of tyrosine kinase inhibitors (TKIs) in the treatment of metastatic RCC (mRCC) has enabled much more significant results. Thus, a landmark event was the approval of TKIs sunitinib and then sorafenib, pazopanib, axitinib, lenvatinib, cabozantinib, and mammalian target of rapamycin (mTOR) inhibitors: everolimus and temsirolimus. Subsequent combined therapy using bevacizumab with low-dose interferon-α and lenvatinib with everolimus improved recurrence-free survival and objective response rates but contributed to increased toxicity of therapy. The next step in RCC therapy was the approval of the combination of the immuno-oncology agents ipilimumab and nivolumab for the treatment of mRCC by the U.S. Food and Drug Administration in April 2018. Later, combinations of immune checkpoint inhibitors with targeted agents were approved, which increased the life expectancy of patients and reduced the toxicity of antitumor therapy. One of the most effective regimens is the combination of a TKI axitinib or lenvatinib with the PD-1 inhibitor pembrolizumab. This article addresses the current progress in the treatment of patients with mRCC, reviewing the results of completed clinical trials on the use of combination therapy with targeted and immuno-oncology agents.
Keywords: metastatic renal cell carcinoma, immune checkpoint inhibitors, tyrosine kinase inhibitors, combination regimens, PD-1, PD-L1/2, VEGF, VEGFR, mTOR, lenvatinib, everolimus, pembrolizumab
Полный текст
Список литературы
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2. Каприн А.Д., Старинский В.В., Петрова Г.В. Злокачественные новообразования в России в 2018 году (заболеваемость и смертность). М.: МНИОИ им. П.А. Герцена − филиал ФГБУ «НМИЦ радиологии» Минздрава России, 2019 [Kaprin AD, Starinskii VV, Petrova GV. Zlokachestvennye novoobrazovaniia v Rossii v 2018 godu (zabolevaemost' i smertnost'). Moscow: MNIOI im. PA Gertsena − filial FGBU “NMITs radiologii” Minzdrava Rossii, 2019 (in Russian)].
3. Abe H, Kami T. Recent advances in the treatment of metastatic renal cell carcinoma. Int J Urol. 2013;20(10):944-55. DOI:10.1111/iju.12187
4. Méjean A, Ravaud A, Thezenas S, et al. Sunitinib alone or after nephrectomy in metastatic renal-cell carcinoma. N Engl J Med. 2018;379:417-27.
5. Buti S, Brighenti M, Bongiovanni C, et al. Role of chemotherapy with gemcitabine plus 5-fluorouracil and chemoimmunotherapy in metastatic renal cell cancer (mRCC). J Immunother. 1997;30(7):780-6. DOI:10.1097/CJI.0b013e31814fb2ec
6. Носов Д.А., Ворошилова Е.А., Саяпина М.С. Современное представление об алгоритме лекарственного лечения и оптимальной последовательности использования таргетных препаратов. Онкоурология. 2014;(3):12‑21 [Nosov DA, Voroshilova EA, Sayapina MS. Current idea of an algorithm for drug treatment and optimal succession of using targeted drugs. Cancer Urology. 2014;10(3):12-21 (in Russian)].
7. Folkman J, Merler E, Abernathy C, Williams G. Isolation of a tumor factor responsible for angiogenesis. J Exp Med. 1971;133(2):275-88. DOI:10.1084/jem.133.2.275
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9. Motzer RJ, Hutson TE, Tomczak P, 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):3584-590. DOI:10.1200/JCO.2008.20.1293
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20. Beaumont JL, Salsman JM, Diaz J, et al. Quality adjusted time without symptoms or toxicity analysis of pazopanib versus sunitinib in patients with renal cell carcinoma. Cancer. 2016;122(7):1108-15.
21. Sonpavde G, Hutson TE, Rini BI. Axitinib for renal cell carcinoma. Expert Opin Investig Drugs. 2008;17:741-8.
22. 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.
23. Motzer RJ, Escudier B, Powles T, et al. Long-term follow-up of overall survival for cabozantinib versus everolimus in advanced renal cell carcinoma. Br J Cancer. 2018;118(9):1176-8.
24. 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. DOI:10.1016/S0140-6736(07)61904-7
25. Rini BI, Halabi S, Rosenberg JE, at al. Phase III trial 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. DOI:10.1200/JCO.2009.26.5561; PMID: 20368558
26. Coulie P, Van den Eynde BJ, van der Bruggen P, Boon T. Tumor antigens recognized by T-lymphocytes: at the core of cancer immunotherapy. Nat Rev Cancer. 2014;14:135-46.
27. Champiat S, Dercle L, Ammari S, et al. Hyperprogressive disease is a new pattern of progression in cancer patients treated by anti-PD-1/PD-L1. Clin Cancer Res. 2017;23(8):1920-8.
28. Deleuze A, Deleuze A, Saout J, et al. Immunotherapy in Renal Cell Carcinoma: The Future Is Now. Int J Mol Sci. 2020;21(7):25-32. DOI:10.3390/ijms21072532
29. Kammerer-Jacquet SF, Deleuze A, Saout J, et al. Targeting the PD-1/PD-L1 Pathway in Renal Cell Carcinoma. Int J Mol Sci. 2019;20(7):1692. DOI:10.3390/ijms20071692
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32. Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 2019;380:1103-15. DOI:10.1056/NEJMoa1816047
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40. Flaherty KT, Manola JB, Pins M, et al. BEST: A randomized Phase II study of vascular endothelial growth factor, RAF kinase, and mammalian target of rapamycin combination targeted therapy with bevacizumab, sorafenib, and temsirolimus in advanced renal cell carcinoma – A Trial of the ECOG-ACRIN Cancer Research Group (E2804). J Clin Oncol. 2015;33(21):2384-91. DOI:10.1200/JCO.2015.60.9727
41. Bukowski RM, Kabbinavar FF, Figlin RA, et al. Randomized phase II study of erlotinib combined with bevacizumab compared with bevacizumab alone in metastatic renal cell cancer. J Clin Oncol. 2007;25:4536-41.
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43. Ravaud A, Barrios S, Anak O, et al. Randomized phase II study of first-line everolimus (EVE)+ bevacizumab (BEV) versus interferon alfa-2a (IFN)+ BEV in patients (pts) with metastatic renal cell carcinoma (mRCC): RECORD-2. Ann Oncol. 2012;23:ix258.
44. Rini BI, Bellmunt J, Clancy J, et al. Randomized phase III trial of temsirolimus and bevacizumab versus interferon alfa and bevacizumab in metastatic renal cell carcinoma: INTORACT trial. J Clin Oncol. 2014;32(8):752-9. DOI:10.1200/JCO.2013.50.5305
45. Negrier, Gravis G, Pérol D, et al. Temsirolimus and bevacizumab, or sunitinib, or interferon alfa and bevacizumab for patients with advanced renal cell carcinoma (TORAVA): a randomised phase 2 trial. Lancet Oncol. 2011;12(7):673-80.
46. Motzer RJ, Hutson TE, 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
47. Tohyama O, Matsui J, Kodama K, et al. Antitumor activity of lenvatinib (e7080): an angiogenesis inhibitor that targets multiple receptor tyrosine kinases in preclinical human thyroid cancer models. J Thyroid Res. 2014;(638747):1-13.
48. Yamamoto Y, Matsui J, Matsushima T, et al. Lenvatinib, an angiogenesis inhibitor targeting VEGFR/FGFR, shows broad antitumor activity in human tumor xenograft models associated with microvessel density and pericyte coverage. Vasc Cell. 2014;6(1):1-13.
49. Ho TH, Liu XD, Huang Y, et al. The impact of FGFR1 and FRS2α expression on sorafenib treatment in metastatic renal cell carcinoma. BMC cancer. 2015;15(1):1‑7.
50. Touat M, Ileana E, Postel-Vinay S, et al. Targeting FGFR signaling in cancer. Clin Cancer Res. 2015;21(12):2684-94.
51. Shin SJ, Jeon YK, Cho YM, et al. The association between PD-L1 expression and the clinical outcomes to vascular endothelial growth factor-targeted therapy in patients with metastatic clear cell renal cell carcinoma. Oncologist. 2015;20(11):1253-60. DOI:10.1634/theoncologist.2015-0151
52. Motzer RJ, Powles T, Atkins MB, et al. Final overall survival and molecular analysis in IMmotion151, a phase 3 trial comparing atezolizumab plus bevacizumab vs sunitinib in patients with previously untreated metastatic renal cell carcinoma. JAMA Oncol. 2022;8(2):275-80. DOI:10.1001/jamaoncol.2021.5981
53. Powles T, Plimarck ER, Stus V, et al. Pembrolizumab (pembro) plus axitinib (axi) versus sunitinib as first-line therapy for locally advanced or metastatic renal cell carcinoma (mRCC): phase III KEYNOTE-426 study. J Clin Oncol. 2019;37(Suppl. 7S):abstr.543.
54. Lee CH, Shah AY, Rasco D, et al. Lenvatinib plus pembrolizumab in patients with either treatment-naive or previously treated metastatic renal cell carcinoma (Study 111/KEYNOTE-146): a phase 1b/2 study. Lancet Oncol. 2021;22(7):946-58. DOI:10.1016/S1470-2045(21)00241-2
55. McDonald R. CLEAR study readout shows survival enhancement with lenvatinib plus pembrolizumab versus sunitinib in frontline RCC. Conference ASCO Genitourinary Cancers Symposium. February 14, 2021.
56. Choueiri TK, Powles T, Burotto M, et al. Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2021;384:829-41. DOI:10.1056/NEJMoa2026982
57. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med. 2018;378(14):1277‑90. DOI:10.1056/NEJMoa1712126
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29. Kammerer-Jacquet SF, Deleuze A, Saout J, et al. Targeting the PD-1/PD-L1 Pathway in Renal Cell Carcinoma. Int J Mol Sci. 2019;20(7):1692. DOI:10.3390/ijms20071692
30. Davies M, Duffield EA. Safety of checkpoint inhibitors for cancer treatment: strategies for patient monitoring and management of immune-mediated adverse events. Immunotargets Ther. 2017;6:51-71.
31. Wang Y, Zhou S, Yang F, et al. Treatment-related adverse events of PD-1 and PD-L1 inhibitors in clinical trials: a systematic review and meta-analysis. JAMA Oncol. 2019;5(7):1008-19. DOI:10.1001/jamaoncol.2019.0393
32. Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 2019;380:1103-15. DOI:10.1056/NEJMoa1816047
33. Linsley PS, Wallace PM, Johnson J, et al. Immunosuppression in vivo by a soluble form of the CTLA-4 T cell activation molecule. Science. 1992;257(5071):792-5. DOI:10.1126/science.1496399
34. Wolchok JD, Saenger Y. The mechanism of anti-CTLA-4 activity and the negative regulation of T-cell activation. Oncologist. 2008;13(4):2-9.
DOI:10.1634/theoncologist.13-S4-2
35. Motzer RJ, Jeon YK, Cho YM, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373(19):1803-13. DOI:10.1056/NEJMoa1510665
36. Greulich H, Chen TH, Feng W, et al. Oncogenic transformation by inhibitor-sensitive and-resistant EGFR mutants. PLoS Med. 2005;2:e313.
37. 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(6):1061-8.
38. Liu XD, Hang A, Zhou L, et al. Resistance to antiangiogenic therapy is associated with an immunosuppressive tumor microenvironment in metastatic renal cell carcinoma. Cancer Immunol Res. 2015;3(9):1017-29.
39. Shin SJ, Jeon YK, Cho YM, et al. The association between PD-L1 expression and the clinical outcomes to vascular endothelial growth factor-targeted therapy in patients with metastatic clear cell renal cell carcinoma. Oncologist. 2015;20(11):1253-60.
40. Flaherty KT, Manola JB, Pins M, et al. BEST: A randomized Phase II study of vascular endothelial growth factor, RAF kinase, and mammalian target of rapamycin combination targeted therapy with bevacizumab, sorafenib, and temsirolimus in advanced renal cell carcinoma – A Trial of the ECOG-ACRIN Cancer Research Group (E2804). J Clin Oncol. 2015;33(21):2384-91. DOI:10.1200/JCO.2015.60.9727
41. Bukowski RM, Kabbinavar FF, Figlin RA, et al. Randomized phase II study of erlotinib combined with bevacizumab compared with bevacizumab alone in metastatic renal cell cancer. J Clin Oncol. 2007;25:4536-41.
42. Hainsworth JD, Spigel DR, Burris HA, et al. Phase II trial of bevacizumab and everolimus in patients with advanced renal cell carcinoma. J Clin Oncol. 2010;28(13):2131-6.
43. Ravaud A, Barrios S, Anak O, et al. Randomized phase II study of first-line everolimus (EVE)+ bevacizumab (BEV) versus interferon alfa-2a (IFN)+ BEV in patients (pts) with metastatic renal cell carcinoma (mRCC): RECORD-2. Ann Oncol. 2012;23:ix258.
44. Rini BI, Bellmunt J, Clancy J, et al. Randomized phase III trial of temsirolimus and bevacizumab versus interferon alfa and bevacizumab in metastatic renal cell carcinoma: INTORACT trial. J Clin Oncol. 2014;32(8):752-9. DOI:10.1200/JCO.2013.50.5305
45. Negrier, Gravis G, Pérol D, et al. Temsirolimus and bevacizumab, or sunitinib, or interferon alfa and bevacizumab for patients with advanced renal cell carcinoma (TORAVA): a randomised phase 2 trial. Lancet Oncol. 2011;12(7):673-80.
46. Motzer RJ, Hutson TE, 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
47. Tohyama O, Matsui J, Kodama K, et al. Antitumor activity of lenvatinib (e7080): an angiogenesis inhibitor that targets multiple receptor tyrosine kinases in preclinical human thyroid cancer models. J Thyroid Res. 2014;(638747):1-13.
48. Yamamoto Y, Matsui J, Matsushima T, et al. Lenvatinib, an angiogenesis inhibitor targeting VEGFR/FGFR, shows broad antitumor activity in human tumor xenograft models associated with microvessel density and pericyte coverage. Vasc Cell. 2014;6(1):1-13.
49. Ho TH, Liu XD, Huang Y, et al. The impact of FGFR1 and FRS2α expression on sorafenib treatment in metastatic renal cell carcinoma. BMC cancer. 2015;15(1):1‑7.
50. Touat M, Ileana E, Postel-Vinay S, et al. Targeting FGFR signaling in cancer. Clin Cancer Res. 2015;21(12):2684-94.
51. Shin SJ, Jeon YK, Cho YM, et al. The association between PD-L1 expression and the clinical outcomes to vascular endothelial growth factor-targeted therapy in patients with metastatic clear cell renal cell carcinoma. Oncologist. 2015;20(11):1253-60. DOI:10.1634/theoncologist.2015-0151
52. Motzer RJ, Powles T, Atkins MB, et al. Final overall survival and molecular analysis in IMmotion151, a phase 3 trial comparing atezolizumab plus bevacizumab vs sunitinib in patients with previously untreated metastatic renal cell carcinoma. JAMA Oncol. 2022;8(2):275-80. DOI:10.1001/jamaoncol.2021.5981
53. Powles T, Plimarck ER, Stus V, et al. Pembrolizumab (pembro) plus axitinib (axi) versus sunitinib as first-line therapy for locally advanced or metastatic renal cell carcinoma (mRCC): phase III KEYNOTE-426 study. J Clin Oncol. 2019;37(Suppl. 7S):abstr.543.
54. Lee CH, Shah AY, Rasco D, et al. Lenvatinib plus pembrolizumab in patients with either treatment-naive or previously treated metastatic renal cell carcinoma (Study 111/KEYNOTE-146): a phase 1b/2 study. Lancet Oncol. 2021;22(7):946-58. DOI:10.1016/S1470-2045(21)00241-2
55. McDonald R. CLEAR study readout shows survival enhancement with lenvatinib plus pembrolizumab versus sunitinib in frontline RCC. Conference ASCO Genitourinary Cancers Symposium. February 14, 2021.
56. Choueiri TK, Powles T, Burotto M, et al. Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2021;384:829-41. DOI:10.1056/NEJMoa2026982
57. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med. 2018;378(14):1277‑90. DOI:10.1056/NEJMoa1712126
Авторы
Р.А. Зуков*1,2, Д.В. Черняев1,2, А.Р. Зулкайдарова1
1 ФГБОУ ВО «Красноярский государственный медицинский университет им. проф. В.Ф. Войно-Ясенецкого» Минздрава России, Красноярск, Россия;
2 КГБУЗ «Красноярский краевой онкологический диспансер им. А.И. Крыжановского», Красноярск, Россия
*zukov_rus@mail.ru
1 ФГБОУ ВО «Красноярский государственный медицинский университет им. проф. В.Ф. Войно-Ясенецкого» Минздрава России, Красноярск, Россия;
2 КГБУЗ «Красноярский краевой онкологический диспансер им. А.И. Крыжановского», Красноярск, Россия
*zukov_rus@mail.ru
________________________________________________
Ruslan A. Zukov*1,2, Denis V. Chernyaev1,2, Alexandra R. Zulkaidarova1
1 Voino-Yasenetsky Krasnoyarsk State Medical University, Krasnoyarsk, Russia;
2 Kryzhanovsky Krasnoyarsk Regional Oncological Dispensary, Krasnoyarsk, Russia
*zukov_rus@mail.ru
Цель портала OmniDoctor – предоставление профессиональной информации врачам, провизорам и фармацевтам.