Background Ramucirumab, the human immunoglobulin G1 monoclonal antibody receptor antagonist of vascular endothelial growth factor receptor 2, has been approved for treating gastric/gastroesophageal junction, non-small-cell lung, and metastatic colorectal cancers. With the completion of six global, randomized, double-blind, placebo-controlled, phase III trials across multiple tumor types, an opportunity now exists to further establish the safety parameters of ramucirumab across a large patient population. Materials and methods An individual patient meta-analysis across the six completed phase III trials was conducted and the relative risk (RR) and associated 95% confidence intervals (CIs) were derived using fixed-effects or mixed-effects models for all-grade and high-grade adverse events (AEs) possibly related to vascular endothelial growth factor pathway inhibition. The number needed to harm was also calculable due to the placebo-controlled nature of all six registration standard trials. Results A total of 4996 treated patients (N = 2748 in the ramucirumab arm and N = 2248 in the control, placebo arm) were included in this meta-analysis. Arterial thromboembolic events [ATE; all-grade, RR: 0.8, 95% CI 0.5-1.3; high-grade (grade ≥3), RR: 0.9, 95% CI 0.5-1.7], venous thromboembolic events (VTE; all-grade, RR: 0.7, 95% CI 0.5-1.1; high-grade, RR: 0.7, 95% CI 0.4-1.2), high-grade bleeding (RR: 1.1, 95% CI 0.8-1.5), and high-grade gastrointestinal (GI) bleeding (RR: 1.1, 95% CI 0.7-1.7) did not demonstrate a definite increased risk with ramucirumab. A higher percentage of hypertension, proteinuria, low-grade (grade 1-2) bleeding, GI perforation, infusion-related reaction, and wound-healing complications were observed in the ramucirumab arm compared with the control arm. Conclusions Ramucirumab may be distinct among antiangiogenic agents in terms of ATE, VTE, high-grade bleeding, or high-grade GI bleeding by showing no clear evidence for an increased risk of these AEs in this meta-analysis of a large and diverse patient population. Ramucirumab is consistent with other angiogenic inhibitors in the risk of developing certain AEs. Clinical Trial Numbers: NCT00917384 (REGARD), NCT01170663 (RAINBOW), NCT01168973 (REVEL), NCT01183780 (RAISE), NCT01140347 (REACH), and NCT00703326 (ROSE).

中文翻译：

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对来自六项抗血管生成 VEGFR2 结合单克隆抗体雷莫芦单抗随机、安慰剂对照试验的个体患者安全性数据进行荟萃分析。


背景 Ramucirumab 是血管内皮生长因子受体 2 的人免疫球蛋白 G1 单克隆抗体受体拮抗剂，已被批准用于治疗胃/胃食管交界处、非小细胞肺癌和转移性结直肠癌。随着六项针对多种肿瘤类型的全球随机、双盲、安慰剂对照 III 期试验的完成，现在有机会进一步确定雷莫芦单抗在大量患者群体中的安全参数。材料和方法 对六项已完成的 III 期试验进行了个体患者荟萃分析，并使用所有级别和级别的固定效应或混合效应模型得出相对风险 (RR) 和相关的 95% 置信区间 (CI)。严重不良事件（AE）可能与血管内皮生长因子途径抑制有关。由于所有六项注册标准试验均采用安慰剂对照，因此造成伤害所需的人数也是可以计算的。结果 本荟萃分析共纳入 4996 名接受治疗的患者（雷莫芦单抗组 N = 2748 例，对照安慰剂组 N = 2248 例）。动脉血栓栓塞事件[ATE；所有级别，RR：0.8，95% CI 0.5-1.3；高级别（≥3 级），RR：0.9，95% CI 0.5-1.7]，静脉血栓栓塞事件（VTE；所有级别，RR：0.7，95% CI 0.5-1.1；高级别，RR：0.7， 95% CI 0.4-1.2）、重度出血（RR：1.1，95% CI 0.8-1.5）和重度胃肠道（GI）出血（RR：1.1，95% CI 0.7-1.7）没有表现出雷莫芦单抗确实增加了风险。与对照组相比，雷莫芦单抗组的高血压、蛋白尿、低度（1-2 级）出血、胃肠道穿孔、输液相关反应和伤口愈合并发症的比例较高。 结论 雷莫芦单抗在 ATE、VTE、重度出血或重度胃肠道出血方面可能与抗血管生成药物不同，因为在对大量不同患者群体进行的荟萃分析中没有显示出明确的证据表明这些 AE 的风险增加。在发生某些 AE 的风险方面，雷莫芦单抗与其他血管生成抑制剂一致。临床试验编号：NCT00917384 (REGARD)、NCT01170663 (RAINBOW)、NCT01168973 (REVEL)、NCT01183780 (RAISE)、NCT01140347 (REACH) 和 NCT00703326 (ROSE)。