雷莫芦单抗联合多西他赛对比安慰剂联合多西他赛二线治疗铂类化疗后进展的 IV 期非小细胞肺癌（REVEL）：一项多中心、双盲、随机 III 期临床试验。
Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial.
机构信息
David Geffen School of Medicine at UCLA/Translational Research in Oncology-US Network, Los Angeles, CA, USA.
Institute of Oncology Ion Chiricuta and University of Medicine and Pharmacy Iuliu Hatieganu, Cluj-Napoca, Romania.
出版信息
Lancet. 2014 Aug 23;384(9944):665-73. doi: 10.1016/S0140-6736(14)60845-X. Epub 2014 Jun 2.
BACKGROUND
Ramucirumab is a human IgG1 monoclonal antibody that targets the extracellular domain of VEGFR-2. We aimed to assess efficacy and safety of treatment with docetaxel plus ramucirumab or placebo as second-line treatment for patients with stage IV non-small-cell-lung cancer (NSCLC) after platinum-based therapy.
METHODS
In this multicentre, double-blind, randomised phase 3 trial (REVEL), we enrolled patients with squamous or non-squamous NSCLC who had progressed during or after a first-line platinum-based chemotherapy regimen. Patients were randomly allocated (1:1) with a centralised, interactive voice-response system (stratified by sex, region, performance status, and previous maintenance therapy [yes vs no]) to receive docetaxel 75 mg/m(2) and either ramucirumab (10 mg/kg) or placebo on day 1 of a 21 day cycle until disease progression, unacceptable toxicity, withdrawal, or death. The primary endpoint was overall survival in all patients allocated to treatment. We assessed adverse events according to treatment received. This study is registered with ClinicalTrials.gov, number NCT01168973.
FINDINGS
Between Dec 3, 2010, and Jan 24, 2013, we screened 1825 patients, of whom 1253 patients were randomly allocated to treatment. Median overall survival was 10·5 months (IQR 5·1-21·2) for 628 patients allocated ramucirumab plus docetaxel and 9·1 months (4·2-18·0) for 625 patients who received placebo plus docetaxel (hazard ratio 0·86, 95% CI 0·75-0·98; p=0·023). Median progression-free survival was 4·5 months (IQR 2·3-8·3) for the ramucirumab group compared with 3·0 months (1·4-6·9) for the control group (0·76, 0·68-0·86; p<0·0001). We noted treatment-emergent adverse events in 613 (98%) of 627 patients in the ramucirumab safety population and 594 (95%) of 618 patients in the control safety population. The most common grade 3 or worse adverse events were neutropenia (306 patients [49%] in the ramucirumab group vs 246 [40%] in the control group), febrile neutropenia (100 [16%] vs 62 [10%]), fatigue (88 [14%] vs 65 [10%]), leucopenia (86 [14%] vs 77 [12%]), and hypertension (35 [6%] vs 13 [2%]). The numbers of deaths from adverse events (31 [5%] vs 35 [6%]) and grade 3 or worse pulmonary haemorrhage (eight [1%] vs eight [1%]) did not differ between groups. Toxicities were manageable with appropriate dose reductions and supportive care.
INTERPRETATION
Ramucirumab plus docetaxel improves survival as second-line treatment of patients with stage IV NSCLC.
FUNDING
Eli Lilly.
背景
雷莫芦单抗是一种针对 VEGFR-2 细胞外结构域的人源 IgG1 单克隆抗体。我们旨在评估多西他赛联合雷莫芦单抗或安慰剂二线治疗铂类化疗后进展的 IV 期非小细胞肺癌（NSCLC）患者的疗效和安全性。
方法
在这项多中心、双盲、随机 3 期试验（REVEL）中，我们招募了在一线铂类化疗方案中进展或之后进展的鳞状或非鳞状 NSCLC 患者。患者以中央交互语音响应系统（按性别、区域、表现状态和先前维持治疗[是/否]分层）随机分配（1:1）接受多西他赛 75mg/m²和雷莫芦单抗（10mg/kg）或安慰剂，每 21 天为一个周期，直至疾病进展、不可接受的毒性、退出或死亡。所有接受治疗的患者的主要终点是总生存期。我们根据接受的治疗评估不良事件。这项研究在 ClinicalTrials.gov 上注册，编号为 NCT01168973。
结果
2010 年 12 月 3 日至 2013 年 1 月 24 日期间，我们筛查了 1825 名患者，其中 1253 名患者被随机分配接受治疗。628 名接受雷莫芦单抗联合多西他赛治疗的患者中位总生存期为 10.5 个月（IQR 5.1-21.2），625 名接受安慰剂联合多西他赛治疗的患者中位总生存期为 9.1 个月（4.2-18.0）（风险比 0.86，95%CI 0.75-0.98；p=0.023）。雷莫芦单抗组中位无进展生存期为 4.5 个月（IQR 2.3-8.3），而对照组为 3.0 个月（1.4-6.9）（0.76，0.68-0.86；p<0.0001）。我们在雷莫芦单抗安全性人群的 627 名（98%）患者和对照组的 618 名（95%）患者中注意到治疗中出现的不良事件。最常见的 3 级或更严重不良事件是中性粒细胞减少症（雷莫芦单抗组 306 例[49%]，对照组 246 例[40%]）、发热性中性粒细胞减少症（雷莫芦单抗组 100 例[16%]，对照组 62 例[10%]）、疲劳（雷莫芦单抗组 88 例[14%]，对照组 65 例[10%]）、白细胞减少症（雷莫芦单抗组 86 例[14%]，对照组 77 例[12%]）和高血压（雷莫芦单抗组 35 例[6%]，对照组 13 例[2%]）。两组因不良事件（雷莫芦单抗组 31 例[5%]，对照组 35 例[6%]）和 3 级或更严重肺出血（雷莫芦单抗组 8 例[1%]，对照组 8 例[1%]）导致的死亡人数没有差异。通过适当减少剂量和支持性护理，可以控制毒性。
解释
雷莫芦单抗联合多西他赛可改善 IV 期 NSCLC 患者的二线治疗后的生存。
资金来源
礼来公司。
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