safetyriskБезопасность и риск фармакотерапииSafety and Risk of Pharmacotherapy2312-78212619-1164Federal State Budgetary Institution ‘Scientific Centre for Expert Evaluation of Medicinal Products’ of the Ministry of Health of the Russian Federation (FSBI ‘SCEEMP’)10.30895/2312-7821-2023-11-2-360safetyrisk-360Research ArticleГЛАВНАЯ ТЕМА: ОТ ИССЛЕДОВАНИЙ IN VITRO К IN VIVO И КЛИНИЧЕСКИМ ИССЛЕДОВАНИЯМMAIN TOPIC: FROM IN VITRO EXPERIMENTS TO IN VIVO AND CLINICAL STUDIESТоксичность, ассоциированная с ингибиторами иммунных контрольных точек: анализ иммуноопосредованных нежелательных явлений при применении биоаналога пембролизумаба (Пемброриа)Toxicity Associated with Immune Checkpoint Inhibitors: Analysis of Immune-Related Adverse Events with a Pembrolizumab Biosimilar (Pembroria)https://orcid.org/0000-0001-5615-7806ФедянинМ. Ю.FedyaninM. Yu.

Федянин Михаил Юрьевич, д-р мед. наук, профессор

Каширское шоссе, д. 23, Москва, 115478

Mikhail Yu. Fedyanin, Dr. Sci. (Med.), Professor

23 Kashirskoe Hwy, Moscow 115478

fedianinmu@mail.ruhttps://orcid.org/0000-0002-0170-5681СнеговойА. В.SnegovoyA. V.

Снеговой Антон Владимирович, д-р мед. наук, профессор

2-й Боткинский пр., д. 3, Москва, 125284

Anton V. Snegovoy, Dr. Sci. (Med.), Professor

3 2nd Botkinskiy Dr., Moscow 125284

anvs2012@gmail.comhttps://orcid.org/0000-0002-6244-4294БредерВ. В.BrederV. V.

Бредер Валерий Владимирович, д-р мед. наук

Каширское шоссе, д. 23, Москва, 115478

Valeriy V. Breder, Dr. Sci. (Med.)

23 Kashirskoe Hwy, Moscow 115478

vbreder@yandex.ruhttps://orcid.org/0000-0002-5463-1022ЛиньковаЮ. Н.LinkovaYu. N.

Линькова Юлия Николаевна

вн. тер. г. поселок Стрельна, п. Стрельна, ул. Связи, д. 38, стр. 1, помещ. 89, Санкт-Петербург, 198515

Yulia N. Linkova

Rm 89, 38/1 Svyazi St., Strelna, St. Petersburg 198515

linkova@biocad.ruhttps://orcid.org/0000-0002-8499-2232Зинкина-ОриханА. В.Zinkina-OrikhanA. V.

Зинкина-Орихан Арина Валерьевна

вн. тер. г. поселок Стрельна, п. Стрельна, ул. Связи, д. 38, стр. 1, помещ. 89, Санкт-Петербург, 198515

Arina V. Zinkina-Orikhan

Rm 89, 38/1 Svyazi St., Strelna, St. Petersburg 198515

zinkina@biocad.ruhttps://orcid.org/0000-0002-3084-0305СеткинаС. Б.SetkinaS. B.

Сеткина Светлана Борисовна, канд. фарм. наук

вн. тер. г. поселок Стрельна, п. Стрельна, ул. Связи, д. 38, стр. 1, помещ. 89, Санкт-Петербург, 198515

Svetlana B. Setkina, Cand. Sci. (Pharm.)

Rm 89, 38/1 Svyazi St., Strelna, St. Petersburg 198515

setkinasb@biocad.ruhttps://orcid.org/0000-0001-8734-2449ФогтС. Н.FogtS. N.

Фогт Сергей Николаевич

вн. тер. г. поселок Стрельна, п. Стрельна, ул. Связи, д. 38, стр. 1, помещ. 89, Санкт-Петербург, 198515

Sergei N. Fogt

Rm 89, 38/1 Svyazi St., Strelna, St. Petersburg 198515

fogt@biocad.ruhttps://orcid.org/0000-0003-2315-7791ЧистяковВ. С.ChistiakovV. S.

Чистяков Владимир Сергеевич

вн. тер. г. поселок Стрельна, п. Стрельна, ул. Связи, д. 38, стр. 1, помещ. 89, Санкт-Петербург, 198515

Vladimir S. Chistiakov

Rm 89, 38/1 Svyazi St., Strelna, St. Petersburg 198515

chistiakov@biocad.ruhttps://orcid.org/0000-0001-6250-5774КравцоваН. А.KravtsovaN. A.

Кравцова Надежда Алексеевна

вн. тер. г. поселок Стрельна, п. Стрельна, ул. Связи, д. 38, стр. 1, помещ. 89, Санкт-Петербург, 198515

Nadezhda A. Kravtsova

Rm 89, 38/1 Svyazi St., Strelna, St. Petersburg 198515

kravtsovana@biocad.ruФедеральное государственное бюджетное учреждение «Национальный медицинский исследовательский центр онкологии имени Н.Н. Блохина» Министерства здравоохранения Российской ФедерацииРоссияNational Medical Research Center of Oncology named after N.N. BlokhinRussian FederationМосковский научно-исследовательский онкологический институт им. П.А. Герцена — филиал федерального государственного бюджетного учреждения «Национальный медицинский исследовательский радиологический центр» Министерства здравоохранения Российской ФедерацииРоссияМ.P. Hertsen Moscow Oncology Research Institute, Branch of the National Medical Research Radiological Centre of the Ministry of Health of the Russian FederationRussian FederationАкционерное общество «БИОКАД»РоссияBIOCAD JSCRussian Federation202328042023112215230Copyright © Федянин М.Ю., Снеговой А.В., Бредер В.В., Линькова Ю.Н., Зинкина-Орихан А.В., Сеткина С.Б., Фогт С.Н., Чистяков В.С., Кравцова Н.А., 20232023Федянин М.Ю., Снеговой А.В., Бредер В.В., Линькова Ю.Н., Зинкина-Орихан А.В., Сеткина С.Б., Фогт С.Н., Чистяков В.С., Кравцова Н.А.Fedyanin M.Y., Snegovoy A.V., Breder V.V., Linkova Y.N., Zinkina-Orikhan A.V., Setkina S.B., Fogt S.N., Chistiakov V.S., Kravtsova N.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.risksafety.ru/jour/article/view/360

В последние годы значительно увеличилось количество пациентов со злокачественными новообразованиями, получающих терапию ингибиторами иммунных контрольных точек (иИКТ), включая препарат пембролизумаб, блокирующий белок запрограммированной клеточной гибели-1 (PD-1). Одним из важных аспектов при проведении клинических исследований с применением иИКТ является оценка риска развития иммуноопосредованных нежелательных явлений (иНЯ).

Цель работы

Цель работы: оценка безопасности биоаналога пембролизумаба (BCD-201, Пемброриа) в сравнении с референтным препаратом на основании результатов клинического исследования I фазы и имеющихся данных медицинской литературы.

Материалы и методы

Материалы и методы: проведено двойное слепое рандомизированное контролируемое клиническое исследование I фазы BCD-201-1 с участием пациентов с распространенными формами меланомы и немелкоклеточного рака легкого (n=131), которым проводилась терапия препаратом BCD-201 (Пемброриа) либо референтным препаратом Китруда® внутривенно в дозе 200 мг каждые 3 недели до достижения 24 недель терапии или прогрессии заболевания, или до развития признаков неприемлемой токсичности. Пациенты были рандомизированы в соотношении 1:1 в одну из двух групп (биоаналога или референтного препарата пембролизумаба). На момент написания статьи результаты исследования остаются заслепленными, данные по группам терапии представлены в маскированном виде.

Результаты

Результаты: в исследовании доказана эквивалентность показателей фармакокинетики и сопоставимость профилей безопасности биоаналога пембролизумаба и референтного препарата. Оба препарата характеризовались хорошей переносимостью; частота иНЯ любой степени тяжести была сопоставима между группами терапии (21,2% в группе 1 и 21,5% в группе 2). Большинство иНЯ были легкой и умеренной степени тяжести, за исключением случая диареи и иммуноопосредованного энтероколита 3-й степени тяжести у одного субъекта исследования. Статистически значимые отличия по медиане времени до развития иНЯ между группами терапии отсутствовали (р=0,22, двусторонний критерий Уилкоксона).

Выводы

Выводы: в рамках проанализированного периода двойного слепого исследования BCD-201-1 продемонстрированы схожие характеристики безопасности препаратов Пемброриа и Китруда®, согласующиеся с опубликованными данными по референтному препарату. Информация о соответствии профилей безопасности биоаналога пембролизумаба и референтного препарата при длительном применении будет получена в продолжающихся клинических исследованиях.

In recent years, there has been a significant increase in the number of patients with malignancies treated with immune checkpoint inhibitors (ICIs), including the anti-programmed cell death protein 1 (anti–PD-1) agent pembrolizumab. One of the important aspects of conducting clinical trials with ICIs is the assessment of the risk of developing immune-related adverse events (irAEs).

The aim of the study was to evaluate the safety of a pembrolizumab biosimilar (BCD-201, Pembroria) compared with a reference medicinal product using the results of a phase I clinical trial and the available medical literature.

Materials and methods

Materials and methods. A phase I double-blind, randomised, controlled clinical trial (BCD-201-1) has been conducted in patients with advanced melanoma and non-small-cell lung cancer (n=131). Patients were randomly allocated in a 1:1 ratio to receive either BCD-201 (Pembroria) or the reference medicinal product (Keytruda®), administered intravenously at a dose of 200 mg every 3 weeks for up to 24 weeks or until disease progression or unacceptable toxicity is observed. Since the trial results remain blinded at the time of this writing, treatment group data are masked.

Results

Results. The study demonstrated the equivalence of pharmacokinetics and comparable safety profiles of pembrolizumab biosimilar and reference medicinal products. Both medicinal products were well tolerated; the frequency of all-grade irAEs was comparable between treatment groups (21.2% in Group 1 vs 21.5% in Group 2). Most irAEs were mild to moderate, with the exception of a case of Grade 3 diarrhoea and immune-mediated enterocolitis in one study subject; there were no statistically significant differences in the median time to development of irAEs between treatment groups (Р=0.22, two-sided Wilcoxon test).

Conclusions

Conclusions. The analysed period of the BCD-201-1 trial demonstrated comparable safety characteristics of Pembroria and Keytruda®, which is consistent with the published safety data on the latter. Information on the similarity of long-term safety profiles of the pembrolizumab biosimilar and the reference medicinal product will be obtained from ongoing clinical trials.

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