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

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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

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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

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1. 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. DOI:10.3322/caac.21492
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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.
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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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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
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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
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
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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

________________________________________________

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

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