Ludwig Center for Cancer Immunotherapy, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Lancet Oncol. 2010 Feb;11(2):155-64. doi: 10.1016/S1470-2045(09)70334-1. Epub 2009 Dec 8.
Ipilimumab is a human monoclonal antibody that blocks cytotoxic T-lymphocyte antigen 4 and has shown promising activity in advanced melanoma. We aimed to ascertain the antitumour efficacy of ipilimumab in patients with advanced melanoma.
We undertook a randomised, double-blind, phase 2 trial in 66 centres from 12 countries. 217 patients with previously treated stage III (unresectable) or stage IV melanoma were randomly assigned a fixed dose of ipilimumab of either 10 mg/kg (n=73), 3 mg/kg (n=72), or 0.3 mg/kg (n=72) every 3 weeks for four cycles (induction) followed by maintenance therapy every 3 months. Randomisation was done with a permuted block procedure, stratified on the basis of type of previous treatment. The primary endpoint was best overall response rate (the proportion of patients with a complete or partial response, according to modified WHO criteria). Efficacy analyses were done by intention to treat, whereas safety analyses included patients who received at least one dose of ipilimumab. This study is registered with ClinicalTrials.gov, number NCT00289640.
The best overall response rate was 11.1% (95% CI 4.9-20.7) for 10 mg/kg, 4.2% (0.9-11.7) for 3 mg/kg, and 0% (0.0-4.9) for 0.3 mg/kg (p=0.0015; trend test). Immune-related adverse events of any grade arose in 50 of 71, 46 of 71, and 19 of 72 patients at doses of 10 mg/kg, 3 mg/kg, and 0.3 mg/kg, respectively; the most common grade 3-4 adverse events were gastrointestinal immune-related events (11 in the 10 mg/kg group, two in the 3 mg/kg group, none in the 0.3 mg/kg group) and diarrhoea (ten in the 10 mg/kg group, one in the 3 mg/kg group, none in the 0.3 mg/kg group).
Ipilimumab elicited a dose-dependent effect on efficacy and safety measures in pretreated patients with advanced melanoma, lending support to further studies at a dose of 10 mg/kg.
Bristol-Myers Squibb.
伊匹单抗是一种人源化单克隆抗体，可阻断细胞毒性 T 淋巴细胞相关抗原 4，在晚期黑色素瘤中显示出良好的疗效。我们旨在确定伊匹单抗在晚期黑色素瘤患者中的抗肿瘤疗效。
我们在 12 个国家的 66 个中心进行了一项随机、双盲、二期临床试验。217 例既往接受过治疗的 III 期（不可切除）或 IV 期黑色素瘤患者按每 3 周一次的固定剂量随机分配至伊匹单抗 10 mg/kg（n=73）、3 mg/kg（n=72）或 0.3 mg/kg（n=72）组，共 4 个周期（诱导期），然后每 3 个月进行维持治疗。随机分组采用置换块法，按既往治疗类型分层。主要终点是最佳总缓解率（按改良 WHO 标准评估的完全或部分缓解患者比例）。疗效分析采用意向治疗，安全性分析包括至少接受一剂伊匹单抗的患者。本研究在 ClinicalTrials.gov 注册，编号为 NCT00289640。
10 mg/kg、3 mg/kg 和 0.3 mg/kg 组的最佳总缓解率分别为 11.1%（95%CI 4.9-20.7）、4.2%（0.9-11.7）和 0%（0.0-4.9）（p=0.0015；趋势检验）。10 mg/kg、3 mg/kg 和 0.3 mg/kg 组分别有 50/71、46/71 和 19/72 例患者出现任何级别的免疫相关不良事件；最常见的 3-4 级不良事件为胃肠道免疫相关事件（10 mg/kg 组 11 例，3 mg/kg 组 2 例，0.3 mg/kg 组无）和腹泻（10 mg/kg 组 10 例，3 mg/kg 组 1 例，0.3 mg/kg 组无）。
伊匹单抗在既往治疗的晚期黑色素瘤患者中对疗效和安全性指标产生了剂量依赖性影响，支持进一步研究 10 mg/kg 剂量的疗效。
百时美施贵宝公司。
