Journal of Modern OncologyJournal of Modern OncologyСовременная онкология1815-14341815-1442LLC Obyedinennaya Redaktsiya27024ArticlesСтатьиResearch ArticleAfatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung (LUX-Lung 8): an open-label randomised controlled phase 3 trialРезультаты открытого рандомизированного контролируемого исследования III фазы LUX-Lung 8: сравнение эффективности афатиниба и эрлотиниба в терапии второй линии больных распространенным плоскоклеточным раком легкогоSoriaJean-CharlesJean-Charles.Soria@gustaveroussy.frFelipEnriquetaCoboManuelLuShunSyrigosKonstantinosLeeKi HyeongGökerErdemGeorgouliasVassilisLiWeiIslaDoloresGucluSalih ZMorabitoAlessandroMinYoung JArdizzoniAndreaGadgeelShirish MWangBushiChandVikram KGossGlenwood DGustave Roussy Cancer Campus and University Paris-SudMedical Oncology Department, Vall d’ Hebron University Hospital, Vall d’ Hebron Institute of Oncology, Barcelona, SpainHospital Carlos Haya, Malaga, SpainShanghai Chest Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaAthens School of Medicine, Athens, GreeceChungbuk National University College of Medicine, Cheongju, South KoreaEge University Faculty of Medicine, Izmir, TurkeyDepartment of Medical Oncology, University Hospital of Heraklion, Heraklion, Crete, GreeceFirst Hospital Affiliated to Jilin University, Jilin, ChinaHospital Lozano Blesa, Zaragoza, SpainIzmir Chest Diseases Research Hospital, Izmir, TurkeyIstituto Nazionale Tumori “Fondazione G Pascale”-IRCCS, Naples, ItalyDepartment of Medicine, Ulsan University Hospital, Ulsan, South KoreaUniversity Hospital, Bologna, ItalyKarmanos Cancer Institute/Wayne State University, Detroit, MI, USABoehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, USADivision of Medical Oncology, University of Ottawa, Ottawa, ON, Canada15092015173VOL 17, NO3 (2015)ТОМ 17, №3 (2015)425209042020Copyright ©; 2015, Consilium MedicumCopyright ©; 2015, ООО "Консилиум Медикум"2015Consilium MedicumООО "Консилиум Медикум"https://creativecommons.org/licenses/by-nc/4.0https://modernonco.orscience.ru/1815-1434/article/view/27024

Background. There is a major unmet need for effective treatments in patients with squamous cell carcinoma of the lung. LUX-Lung 8 compared afatinib (an irreversible ErbB family blocker) with erlotinib (a reversible EGFR tyrosine kinase inhibitor), as second-line treatment for patients with advanced squamous cell carcinoma of the lung. Methods. We did this open-label, phase 3 randomised controlled trial at 183 cancer centres in 23 countries worldwide. We enrolled adults with stage IIIB or IV squamous cell carcinoma of the lung who had progressed after at least four cycles of platinum-based-chemotherapy. Participants were randomly assigned (1:1) to receive afatinib (40 mg per day) or erlotinib (150 mg per day) until disease progression. The randomisation was done centrally with an interactive voice or web-based response system and stratified by ethnic origin (eastern Asian vs non-eastern Asian). Clinicians and patients were not masked to treatment allocation. The primary endpoint was progression-free survival assessed by independent central review (intention-to-treat population). The key secondary endpoint was overall survival. This trial is registered with ClinicalTrials.gov, NCT01523587. Findings. 795 eligible patients were randomly assigned (398 to afatinib, 397 to erlotinib). Median follow-up at the time of the primary analysis of progression-free survival was 6.7 months (IQR 3.1-10.2), at which point enrolment was not complete. Progression free-survival at the primary analysis was significantly longer with afatinib than with erlotinib [median 2.4 months (95% CI 1.9-2.9) vs 1.9 months (1.9-2.2); hazard ratio (HR) 0.82 (95% CI 0.68-1.00), p=0.0427]. At the time of the primary analysis of overall survival [median follow-up 18.4 months (IQR 13.8-22.4)], overall survival was significantly greater in the afatinib group than in the erloinib group [median 7.9 months (95% CI 7.2-8.7] vs 6.8 months (5.9-7.8); HR 0.81 (95% CI 0.69-0.95), p=0.0077], as were progression-free survival [median 2.6 months (95% CI 2.0-2.9) vs 1.9 months (1.9-2.1); HR 0.81 (95% CI 0.69-0.96), p=0.0103] and disease control [201 (51%) of 398 patients vs 157 (40%) of 397; p=0.0020]. The proportion of patients with an objective response did not differ significantly between groups [22 (6%) vs 11 (3%); p=0.0551]. Tumour shrinkage occurred in 103 (26%) of 398 patients versus 90 (23%) of 397 patients. Adverse event profiles were similar in each group: 224 (57%) of 392 patients in the afatinib group versus 227 (57%) of 395 in the erlotinib group had grade 3 or higher adverse events. We recorded higher incidences of treatment-related grade 3 diarrhoea with afatinib [39 (10%) vs 9 (2%)], of grade 3 stomatitis with afatinib [16 (4%) vs none], and of grade 3 rash or acne with erlotinib [23 (6%) vs 41 (10%)]. Interpretation. The significant improvements in progression-free survival and overall survival with afatinib compared with erlotinib, along with a manageable safety profile and the convenience of oral administration suggest that afatinib could be an additional option for the treatment of patients with squamous cell carcinoma of the lung.

Напечатано с разрешения Elsevier. Опубликовано в Lancet Oncol 2015; 16 (8): 897-907 Обоснование. Возможности лечения плоскоклеточного рака легкого на сегодняшний день ограниченны, поэтому назрела потребность в поиске новых эффективных методов лечения этого заболевания. В исследовании LUX-Lung 8 проводилось сравнение афатиниба (необратимого ингибитора рецепторов семейства ErbB) и эрлотиниба (обратимого ингибитора тирозинкиназы рецептора эпидермального фактора роста - EGFR) в терапии 2-й линии распространенного плоскоклеточного рака легкого. Методы. Представленное открытое рандомизированное контролируемое исследование III фазы было проведено в 183 онкологических центрах в 23 странах мира. Включали взрослых пациентов с III и IV стадией плоскоклеточного рака легкого, у которых регистрировалось прогрессирование заболевания после по крайней мере 4 циклов платиносодержащей химиотерапии. Включенные пациенты были рандомизированы в 2 группы (1:1): 1-я группа получала афатиниб (40 мг в день), 2-я - эрлотиниб (150 мг в день) до момента прогрессирования заболевания. Рандомизация осуществлялась централизованно с использованием интерактивных систем голосового ответа или интерактивных систем веб-ответа, и проводилась стратификация по этническому происхождению (из Восточной Азии и других регионов Азии). Результаты распределения не маскировались для клиницистов и пациентов. Первичной конечной точкой в исследовании была выживаемость без прогрессирования (ВБП), которая оценивалась при независимой центральной проверке. Ключевая вторичная конечная точка - общая выживаемость (ОВ). Данное исследование зарегистрировано на портале CinicalTrials.gov, NCT01523587. Результаты. Были оценены результаты лечения 795 включенных пациентов (398 в группе афатиниба, 397 в группе эрлотиниба). Медиана периода наблюдения к моменту первичной оценки ВБП составила 6,7 мес (3,1-10,2), к этому моменту набор пациентов не был закончен. Первичный анализ ВБП показал, что лечение афатинибом привело к достоверному увеличению ВБП по сравнению с эрлотинибом [медиана ВБП 2,4 мес (95% доверительный интервал - ДИ 1,9-2,9) vs 1,9 мес (1,9-2,2), отношение рисков - HR 0,82 (95% ДИ 0,68-1,00); p=0,0427]. К моменту первичного анализа ОВ [медиана периода наблюдения составила 18,4 мес (13,8-22,4)] ОВ в группе афатиниба достоверно увеличилась по сравнению с группой эрлотиниба [медиана ОВ 7,9 мес (95% ДИ 7,2-8,7) vs 6,8 мес (95% ДИ 5,9-7,8); HR 0,81 (95% ДИ 0,69-0,95)]; p=0,0077. Аналогичные результаты были получены и в отношении ВБП [медиана ВБП 2,6 мес (95% ДИ 2,0-2,9) и 1,9 мес (1,9-2,1); HR 0,81 (95% ДИ 0,69-0,96), p=0,0103]; а также в отношении доли пациентов с контролем заболевания [201 (51%) из 398 vs 157 (40%) из 397; p=0,0020]. Не было выявлено достоверных различий доли пациентов с объективным ответом между группами [22 (6%) vs 11 (3%); p=0,0551]. Объем опухоли уменьшился у 103 (26%) из 398 пациентов, получавших афатиниб, и у 90 (23%) из 397 пациентов, получавших эрлотиниб. По спектру побочных эффектов не было выявлено различий между группами: у 224 (57%) из 392 пациентов группы афатиниба и у 227 (57%) из 395 пациентов группы эрлотиниба наблюдались нежелательные явления 3-й степени тяжести и более. В группе афатиниба чаще встречались связанные с приемом препарата диарея 3-й степени тяжести - 39 (10%) vs 9 (2%), стоматит 3-й степени тяжести - 16 (4%) vs 0, в группе эрлотиниба чаще встречалась сыпь или акне 3-й степени тяжести - 23 (6%) vs 41 (10%). Выводы. Достоверное увеличение ВБП и ОВ при приеме афатиниба по сравнению с эрлотинибом наряду с управляемым профилем безопасности и удобным пероральным способом приема позволяет считать применение афатиниба дополнительной возможностью в терапии 2-й линии трудно поддающейся лечению популяции больных распространенным плоскоклеточным раком легкого.

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