medsovetМедицинский СоветMeditsinskiy sovet = Medical Council2079-701X2658-5790REMEDIUM GROUP Ltd.10.21518/2079-701X-2020-9-27-42medsovet-5698Research ArticleТАРГЕТНАЯ ТЕРАПИЯ ОПУХОЛЕЙTarget therapy of tumorsАбемациклиб как оригинальный представитель циклин-зависимых киназ в лечении люминального HER2-негативного диссеминированного рака молочной железыAbemaciclib as an original inhibitor of cyclin-dependent kinase for the treatment of luminal HER2-negative disseminated breast cancerhttps://orcid.org/0000-0002-1693-0523БесоваН. С.BesovaN. S.

Бесова Наталия Сергеевна, к.м.н., ведущий научный сотрудник онкологического отделения лекарственных методов лечения (химиотерапевтического) № 1 научно-исследовательского института клинической онкологии им. академика РАН и РАМН Н.Н. Трапезникова

115478, Москва, Каширское шоссе, д. 24

Natalia S. Besova, Cand. of Sci. (Med.), Lead Researcher, Cancer Drug Therapy Department (Chemotherapeutic No. 1)

24, Kashirskoye Shosse, Moscow, 115478

besovans@mail.ruНациональный медицинский исследовательский центр онкологии им. Н.Н. БлохинаРоссияN.N. Blokhin National Medical Research Center of OncologyRussian Federation202027072020092742Copyright © Бесова Н.С., 20202020Бесова Н.С.Besova N.S.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.med-sovet.pro/jour/article/view/5698

Ингибиторы циклин-зависимых киназ 4 и 6 (CDK4/6) – палбоциклиб, рибоциклиб и абемациклиб – стали новым стандартом лечения больных гормонорецепторопозитивным HER2-негативным диссеминированным или метастатическим раком молочной железы (ГР + HER2 МРМЖ) вне зависимости от линии терапии, менопаузального статуса и других индивидуальных характеристик. Кратковременное торможение CDK4/6 приводит к обратимой остановке клеточного цикла в фазе G1 с восстановлением фосфорилирования Rb-1 и полного клеточного цикла после прекращения ингибиции. Несмотря на сходный механизм действия, изложенный в статье, препараты обладают индивидуальными характеристиками. Абемациклиб, отличаясь от палбоциклиба и рибоциклиба по химической структуре, обладает более выраженной избирательностью к CDK4, меньшим миелосупрессивным действием, что позволяет принимать его непрерывно, более выраженной липофильностью, активнее взаимодействует с АТФ, вследствие чего может взаимодействовать и с другими киназами. Абемациклиб, единственный из всех ингибиторов CDK4/6, оказался эффективным при рефрактерном ГР + HER2 МРМЖ: объективный эффект (ОЭ) зарегистрирован у 19,7%, контроль заболевания – у 42,4% больных, медиана выживаемости без прогрессирования (ВБП) составила 5,95 мес., медиана общей выживаемости (ОВ) – 22,32 мес. Комбинация абемациклиба с фулвестрантом во 2-й линии лечения повышает эффективность лечения по сравнению с одной эндокринотерапией (ЭТ): медиану ВБП – с 9,3 до 16,9 мес. (р < 0,001), ОЭ – с 16 до 35% (р < 0,001) в ITT-популяции, медиану ОВ – с 37,3 до 46,7 мес. (p  = 0,01) для комбинации абемациклиба с фулвестрантом. Применение абемациклиба с нестероидными ингибиторами ароматазы (НСАИ) по сравнению с одними ингибиторами ароматазы (АИ) в 1-й линии лечения приводит к увеличению медианы ВБП с 14,76 до 28,18 мес. (p = 0,000002) и повышению ОЭ с 37 до 49,7% (р = 0,005) в ITT-популяции. Доминирующим побочным эффектом абемациклиба является диарея, регистрируемая в 82–90% случаев, не превышающая 3-й степени тяжести, частота последней не превышает 13%, диарея обратима, купируется антидиарейными препаратами. Комбинация ЭТ с абемациклибом дает возможность повысить эффективность лечения у наиболее прогностически неблагоприятного контингента больных.

Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, namely palbociclib, ribociclib and abemaciclib, have become a new standard of treatment of patients with hormone receptor-positive, HER2-negative disseminated or metastatic breast cancer (HR+ HER2- MBC), regardless of the line of therapy, menopause status and other individual characteristics. Short-term CDK4/6 inhibition leads to reversible arrest in the G1 phase of the cell cycle with restoration of Rb-1 phosphorylation and the complete cell cycle after termination of inhibition. The drugs have individual characteristics despite the similar mechanism of action described in the article. Abemaciclib, which differs from palbociclib and ribociclib in chemical structure, shows higher selectivity for CDK4, less myelosuppressive effect, which makes it possible to take it continuously, greater lipophilicity, and interacts more actively with ATP, resulting in its ability to interact with other kinases as well. Abemaciclib, the only one of all CDK4/6 inhibitors, has been proven effective in the treatment of refractory HR+ HER2-MBC: the proportion of patients with objective effect (OE) was 19.7%, that with disease control was 42.4%, median progression-free survival (PFS) was 5.95 months, median overall survival (OS) was 22.32 months. Abemaciclib combined with fulvestrant in the second-line therapy increases the effectiveness of treatment compared with endocrinotherapy (ET) alone: median PFS increased to 16.9 months from 9.3 (p < 0.001), OE to 35 from 16% (p < 0.001) in the ITT population, median OS to 46.7 from 37.3 months (p = 0.01) for abemaciclib in combination with fulvestrant. The use of abemaciclib in combination with nonsteroidal aromatase inhibitors (NSAIs) compared with aromatase inhibitors (AI) alone in the first-line therapy demonstrated increased median PFS from 14.76 to 28.18 months (p = 0.000002) and increased OE (from 37 to 49.7% (p = 0.005) in the ITT population. Diarrhea is the common adverse event of abemaciclib, which develops in 82–90% of patients. It does not exceed severity level 3, the frequency of the latter does not exceed 13%, diarrhea is reversible, and can be stopped by using antidiarrheal drugs. ET in combination with abemaciclib makes it possible to improve the effectiveness of treatment in the most prognostically unfavourable patient population.

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