School of Medicine, National and Kapodistrian University of Athens, Alexandra Hospital, Athens, Greece.
Heidelberg Medical University, Heidelberg, Germany.
Lancet Oncol. 2017 Oct;18(10):1327-1337. doi: 10.1016/S1470-2045(17)30578-8. Epub 2017 Aug 23.
The phase 3 ENDEAVOR trial was a head-to-head comparison of two proteasome inhibitors in patients with relapsed or refractory multiple myeloma. Progression-free survival was previously reported to be significantly longer with carfilzomib administered in combination with dexamethasone than with bortezomib and dexamethasone in an interim analysis. The aim of this second interim analysis was to compare overall survival between the two treatment groups.
ENDEAVOR was a phase 3, open-label, randomised controlled trial in patients with relapsed or refractory multiple myeloma. Patients were recruited from 198 hospitals and outpatient clinics in 27 countries in Europe, North America, South America, and the Asia-Pacific region. Patients were aged 18 years or older, had relapsed or refractory multiple myeloma, and had received between one and three previous lines of therapy. Patients were randomly assigned (1:1) to receive carfilzomib and dexamethasone (carfilzomib group) or bortezomib and dexamethasone (bortezomib group) through a blocked randomisation scheme (block size of four), stratified by International Staging System stage, previous lines of treatment, previous proteasome inhibitor therapy, and planned route of bortezomib delivery if assigned to the bortezomib group. Carfilzomib (20 mg/m on days 1 and 2 of cycle 1; 56 mg/m thereafter) was given as a 30-min intravenous infusion on days 1, 2, 8, 9, 15, and 16 of 28-day cycles; bortezomib (1·3 mg/m) was given as an intravenous bolus or subcutaneous injection on days 1, 4, 8, and 11 of 21-day cycles. Dexamethasone (20 mg oral or intravenous infusion) was given on days 1, 2, 8, 9, 15, 16, 22, and 23 in the carfilzomib group and on days 1, 2, 4, 5, 8, 9, 11, and 12 in the bortezomib group. The primary endpoint of ENDEAVOR, progression-free survival, has been previously reported. A stratified log-rank test was used to compare overall survival between treatment groups for this prospectively planned second interim analysis. Efficacy assessments were done in all randomly assigned patients (the intention-to-treat population) and the safety analysis included patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT01568866, and is no longer enrolling patients.
Between June 20, 2012, and June 30, 2014, 1096 patients were assessed for eligibility, of whom 929 were randomly assigned (464 to the carfilzomib group and 465 to the bortezomib group). The cutoff date for this prespecified interim analysis was Jan 3, 2017. Median overall survival was 47·6 months (95% CI 42·5-not evaluable) in the carfilzomib group versus 40·0 months (32·6-42·3) in the bortezomib group (hazard ratio 0·791 [95% CI 0·648-0·964], one-sided p=0·010). Grade 3 or worse adverse events were reported in 377 (81%) of 463 patients in the carfilzomib group and 324 (71%) of 456 patients in the bortezomib group, and serious adverse events in 273 (59%) patients in the carfilzomib group and 182 (40%) in the bortezomib group. The most frequent grade 3 or worse adverse events were anaemia (76 [16%] of 463 patients in the carfilzomib group vs 46 [10%] of 456 patients in the bortezomib group), hypertension (67 [15%] vs 15 [3%]), pneumonia (42 [9%] vs 39 [9%]), thrombocytopenia (41 [9%] vs 43 [9%]), fatigue (31 [7%] vs 35 [8%]), dyspnoea (29 [6%] vs ten [2%]), decreased lymphocyte count (29 [6%] vs nine [2%]), diarrhoea (18 [4%] vs 39 [9%]), and peripheral neuropathy (six [1%] vs 28 [6%]). Treatment-related deaths occurred in five (1%) of 463 patients in the carfilzomib group (pneumonia [n=2], interstitial lung disease [n=1], septic shock [n=1], and unknown [n=1]) and two (<1%) of 456 patients in the bortezomib group (cardiac arrest [n=1] and pneumonia [n=1]).
Carfilzomib provided a significant and clinically meaningful reduction in the risk of death compared with bortezomib. To our knowledge, carfilzomib is the first and only multiple myeloma treatment that extends overall survival in the relapsed setting over the current standard of care. This study is informative for deciding which proteasome inhibitor to use for treating this disease.
Onyx Pharmaceuticals Inc, an Amgen Inc subsidiary.
ENDEAVOR 是一项头对头比较两种蛋白酶体抑制剂在复发或难治性多发性骨髓瘤患者中的疗效的 3 期临床试验。中期分析结果显示，与硼替佐米和地塞米松联合治疗组相比，卡非佐米联合地塞米松治疗组的无进展生存期显著延长。本次第二次中期分析旨在比较两组患者的总生存期。
ENDEAVOR 是一项在欧洲、北美、南美和亚太地区 27 个国家的 198 家医院和门诊进行的 3 期、开放标签、随机对照试验。纳入的患者年龄≥18 岁，诊断为复发或难治性多发性骨髓瘤，且接受过 1 至 3 线治疗。患者按照 1:1 比例随机（1 个 4 人组块）接受卡非佐米联合地塞米松（卡非佐米组）或硼替佐米联合地塞米松（硼替佐米组）治疗，分组依据国际分期系统（ISS）分期、先前治疗线数、先前蛋白酶体抑制剂治疗和如果分配至硼替佐米组则计划的硼替佐米给药途径。卡非佐米（第 1 周期 1 天和 2 天 20mg/m2；此后 56mg/m2）于 28 天周期第 1、2、8、9、15 和 16 天静脉输注 30 分钟；硼替佐米（1.3mg/m2）于 21 天周期第 1、4、8 和 11 天静脉推注或皮下注射。卡非佐米组第 1、2、8、9、15、16、22 和 23 天及硼替佐米组第 1、2、4、5、8、9、11 和 12 天给予地塞米松（20mg 口服或静脉滴注）。主要终点无进展生存期已在先前报道。本次前瞻性计划的第二次中期分析采用分层对数秩检验比较两组的总生存期。疗效评估在所有随机分组患者（意向治疗人群）中进行，安全性分析包括至少接受一剂研究治疗的患者。该试验在 ClinicalTrials.gov 注册，编号为 NCT01568866，不再招募患者。
2012 年 6 月 20 日至 2014 年 6 月 30 日，对 1096 名患者进行了入组评估，其中 929 名患者被随机分组（卡非佐米组 464 名，硼替佐米组 465 名）。本次预设的中期分析截止日期为 2017 年 1 月 3 日。卡非佐米组的中位总生存期为 47.6 个月（95%CI 42.5-无法评估），硼替佐米组为 40.0 个月（32.6-42.3）（风险比 0.791[95%CI 0.648-0.964]，单侧 p=0.010）。卡非佐米组 463 例患者中 377 例（81%）和硼替佐米组 456 例患者中 324 例（71%）报告了 3 级或更高级别的不良事件，卡非佐米组 273 例（59%）患者和硼替佐米组 182 例（40%）患者报告了严重不良事件。最常见的 3 级或更高级别的不良事件为贫血（卡非佐米组 463 例患者中 76 例[16%]，硼替佐米组 456 例患者中 46 例[10%]）、高血压（卡非佐米组 463 例患者中 67 例[15%]，硼替佐米组 456 例患者中 15 例[3%]）、肺炎（卡非佐米组 463 例患者中 42 例[9%]，硼替佐米组 456 例患者中 39 例[9%]）、血小板减少症（卡非佐米组 463 例患者中 41 例[9%]，硼替佐米组 456 例患者中 43 例[9%]）、疲劳（卡非佐米组 463 例患者中 31 例[7%]，硼替佐米组 456 例患者中 35 例[8%]）、呼吸困难（卡非佐米组 463 例患者中 29 例[6%]，硼替佐米组 456 例患者中 10 例[2%]）、淋巴细胞计数减少（卡非佐米组 463 例患者中 29 例[6%]，硼替佐米组 456 例患者中 9 例[2%]）、腹泻（卡非佐米组 463 例患者中 18 例[4%]，硼替佐米组 456 例患者中 39 例[9%]）和周围神经病（卡非佐米组 463 例患者中 6 例[1%]，硼替佐米组 456 例患者中 28 例[6%]）。卡非佐米组 5 例（1%）患者和硼替佐米组 2 例（<1%）患者发生与治疗相关的死亡（卡非佐米组：肺炎[2 例]、间质性肺病[1 例]、感染性休克[1 例]和未知[1 例]；硼替佐米组：心脏骤停[1 例]和肺炎[1 例]）。
卡非佐米与硼替佐米相比，显著降低了死亡风险，具有显著的临床意义。据我们所知，卡非佐米是复发患者中首个且唯一能延长总体生存时间的多发性骨髓瘤治疗药物。本研究为决定使用哪种蛋白酶体抑制剂治疗该疾病提供了信息。
Onyx Pharmaceuticals Inc，隶属于 Amgen Inc。
