Everolimus in patients with metastatic renal cell carcinoma previously treated with bevacizumab: a prospective multicenter study CRAD001LRU02T⃰

Everolimus is an orally administered inhibitor of the mammalian target of rapamycin (mTOR) recommended for patients with metastatic renal cell carcinoma (mRCC) who progressed on previous vascular endothelial growth factor (VEGF) receptor-tyrosine kinase inhibitor therapy. Efficacy of everolimus in patients who progressed on anti-VEGF monoclonal antibody bevacizumab is unknown. We did a multicenter prospective trial of everolimus in patients with mRCC whose disease had progressed on bevacizumab ± interferon alpha (IFN). Patients with clear-cell mRCC which had progressed on bevacizumab ± IFN received everolimus 10 mg once daily. The primary end point was the proportion of patients remaining progression-free for 56 days, and a two-stage Simon design was used, with 80 % power and an alpha risk of 5 %. This study is registered with ClinicalTrials.gov, number NCT02056587. From December 2011 to October 2013, a total of 37 patients (28 M, 9 F) were enrolled. Median age was 60.5 years (range 41-66), 11 % had Eastern Cooperative Oncology Group Performance Status (ECOG PS) > 2, and Memorial Sloan-Kettering Cancer Center (MSKCC) favorable/intermediate risk was 38/62 %. Five (14 %) patients had a confirmed partial response and 26 (70 %) patients had a stable disease. Median progression-free survival was 11.5 months (95 % CI, 8.8–14.2). Median overall survival was not reached. No grade 3 or 4 treatment-related toxicities were observed. The most common grade 2 adverse events were fatigue (19 %) and pneumonitis (8 %). Everolimus demonstrated a favorable toxicity profile and promising anti-tumor activity as a second-line therapy in metastatic renal cell carcinoma (RCC) patients previously treated with bevacizumab ± IFN

Пятилетняя общая выживаемость больных метастатическим раком почки, получавших эверолимус при прогрессировании на фоне лечения бевацизумабом: проспективное многоцентровое исследование CRAD001LRU02T

Background. In a CRAD001LRU02T study of everolimus for metastatic renal cell carcinoma patients previously treated with bevacizumab ±  interferon, median overall survival (OS) was 17.4 months (95 % confidence interval 13.5–21.3 month).Objective of final analysis was to evaluate 5-year OS and long-term toxicity in this study.Materials and methods. Survival data were collected from 37 patients with bevacizumab-refractory metastatic renal cell carcinoma who received everolimus in a completed prospective multicenter study. Patients were predominantly male, 89 % had ECOG performance status of 0/1, 51 % received previous bevacizumab in combination with interferon, and 38/62% had MSKCC favorable/intermediate risk disease.Results. The 5-year survival rate was 16.2% (95 % confidence interval 14.1–18.3 %), with a median follow-up of 5 years. The 1-, and 3-year OS rates were 81.0 and 43.0 %, respectively. The median duration of second-line of everolimus was 315 (range 61–569) days. 11 (29.7 %) patients received third-line therapy with a median duration of 3.6 months. Confirmed objective tumor responses were seen in 5 (14.0 %) patients. 70.0 % (n = 26) patients had a stable disease. 1 (2.7 %) patient achieved complete response after 4 years of therapy. One (2.7 %) patient  discontinued everolimus therapy on their own accord due to relapse of systemic lupus erythematosus and one (2.7 %)  patient had 14-days interruption of an everolimus therapy due to grade 3 hyperglycemia. No grade 4 treatment-related toxicity was found.Conclusions. Everolimus provided an estimated 5-year survival rate of 16.2 % for bevacizumab-resistant metastatic renal cell carcinoma. Prolonged everolimus was not associated with new types or increased severity of adverse events.Введение. В исследовании CRAD001LRU02T эффективности эверолимуса у больных метастатическим почечно-клеточным раком, получавших ранее терапию бевацизумабом в комбинации с интерфероном или без него, медиана общей выживаемости (ОВ) составила 17,4 мес (95 % доверительный интервал 13,5–21,3 мес).Цель работы – оценка 5-летней ОВ и отдаленной токсичности в этом исследовании.Материалы и методы. Данные по ОВ были получены у 37 пациентов, рефрактерных к терапии бевацизумабом и получивших эверолимус в рамках проспективного многоцентрового исследования. Большинство пациентов – мужчины, 89 % больных имели статус по шкале ECOG 0 / 1, 51 % пациентов получили предшествующую терапию бевацизумабом в комбинации с интерфероном. Благоприятный прогноз имели 38 % больных, промежуточный – 62 %.Результаты. При медиане наблюдения 5 лет 5-летняя ОВ составила 16,2 % (95 % доверительный интервал 14,1–18,3 %),  1- и 3-летняя ОВ – 81,0 и 43,0 % соответственно. Медиана продолжительности 2-й линии терапии эверолимусом составила 315 (61–569) сут. С медианой длительности 3,6 мес 3-ю линию терапии получили 11 (29,7 %) пациентов. Подтвержденные объективные ответы отмечены у 5 (14,0 %) больных. Стабилизация болезни наблюдалась у 70,0 % (n = 26) пациентов. Полного ответа спустя 4 года терапии достиг 1 (2,7 %) пациент. Из-за обострения системной красной волчанки 1 (2,7 %) больной по собственному желанию прекратил терапию эверолимусом и 1 (2,7 %) пациент имел перерыв в лечении в течение 14 сут в связи с развитием гипергликемии III степени токсичности. Нежелательных явлений IV степени тяжести не выявлено.Заключение. Терапия эверолимусом привела к 5-летней ОВ 16,2 % у больных метастатическим почечно-клеточным раком, ранее резистентных к терапии бевацизумабом. Длительная терапия эверолимусом не была ассоциирована с новыми видами выраженной токсичности или повышением частоты нежелательных явлений

Five-year overall survival of metastatic renal cell carcinoma patients treated with everolimus after progression on bevacizumab: a prospective multicenter study CRAD001LRU02T

Background. In a CRAD001LRU02T study of everolimus for metastatic renal cell carcinoma patients previously treated with bevacizumab ±  interferon, median overall survival (OS) was 17.4 months (95 % confidence interval 13.5–21.3 month).Objective of final analysis was to evaluate 5-year OS and long-term toxicity in this study.Materials and methods. Survival data were collected from 37 patients with bevacizumab-refractory metastatic renal cell carcinoma who received everolimus in a completed prospective multicenter study. Patients were predominantly male, 89 % had ECOG performance status of 0/1, 51 % received previous bevacizumab in combination with interferon, and 38/62% had MSKCC favorable/intermediate risk disease.Results. The 5-year survival rate was 16.2% (95 % confidence interval 14.1–18.3 %), with a median follow-up of 5 years. The 1-, and 3-year OS rates were 81.0 and 43.0 %, respectively. The median duration of second-line of everolimus was 315 (range 61–569) days. 11 (29.7 %) patients received third-line therapy with a median duration of 3.6 months. Confirmed objective tumor responses were seen in 5 (14.0 %) patients. 70.0 % (n = 26) patients had a stable disease. 1 (2.7 %) patient achieved complete response after 4 years of therapy. One (2.7 %) patient  discontinued everolimus therapy on their own accord due to relapse of systemic lupus erythematosus and one (2.7 %)  patient had 14-days interruption of an everolimus therapy due to grade 3 hyperglycemia. No grade 4 treatment-related toxicity was found.Conclusions. Everolimus provided an estimated 5-year survival rate of 16.2 % for bevacizumab-resistant metastatic renal cell carcinoma. Prolonged everolimus was not associated with new types or increased severity of adverse events