Zhu M, Tang R, Doshi S, Oliner K S, Dubey S, Jiang Y, Donehower R C, Iveson T, Loh E Y, Zhang Y
Translational Sciences, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
Global Clinical Development, Amgen Inc., South San Francisco, CA, USA.
Br J Cancer. 2015 Feb 3;112(3):429-37. doi: 10.1038/bjc.2014.649. Epub 2015 Jan 13.
Rilotumumab, an investigational, monoclonal antibody, inhibits MET-mediated signalling. In a randomized phase 2 trial of rilotumumab±epirubicin/cisplatin/capecitabine in gastric or oesophagogastric junction cancer, patients receiving rilotumumab showed a trend towards improved survival, especially in MET-positive patients, but no clear dose-response relationship was observed. Exposure-response and biomarker analyses were used for dose selection and to differentiate patient subpopulations that may benefit most from treatment. Here, we analyse rilotumumab exposure-survival and exposure-safety and the impact of MET expression on these relationships.
Individual rilotumumab exposure parameters were generated using population pharmacokinetic modelling. Relationships among rilotumumab dose (7.5 and 15 mg kg(-1)), exposure, and clinical outcomes (progression-free survival (PFS) and overall survival (OS)) were evaluated with Cox regression models and Kaplan-Meier plots. MET status and other baseline covariates were evaluated in subgroup and multivariate analyses. Treatment-emergent adverse events were summarised by exposure.
Among MET-positive patients, higher rilotumumab exposure, vs placebo and low exposure, was associated with improved median PFS (80% CI: 7.0 (5.7-9.7) vs 4.4 (2.9-4.9) and 5.5 (4.2-6.8) months) and OS (13.4 (10.6-18.6) vs 5.7 (4.7-10.2) and 8.1 (6.9-11.1) months) without increased toxicity. No rilotumumab benefit was seen among MET-negative patients.
Rilotumumab had an exposure-dependent treatment effect in patients with MET-positive gastric or oesophagogastric junction cancer.
瑞罗西单抗是一种处于研究阶段的单克隆抗体，可抑制MET介导的信号传导。在一项针对胃或食管胃交界癌患者使用瑞罗西单抗±表柔比星/顺铂/卡培他滨的随机2期试验中，接受瑞罗西单抗治疗的患者显示出总生存期改善的趋势，尤其是在MET阳性患者中，但未观察到明确的剂量反应关系。暴露-反应和生物标志物分析用于剂量选择以及区分可能从治疗中获益最大的患者亚组。在此，我们分析瑞罗西单抗的暴露-生存和暴露-安全性以及MET表达对这些关系的影响。
使用群体药代动力学模型生成个体瑞罗西单抗暴露参数。采用Cox回归模型和Kaplan-Meier曲线评估瑞罗西单抗剂量（7.5和15mg kg⁻¹）、暴露与临床结局（无进展生存期（PFS）和总生存期（OS））之间的关系。在亚组分析和多变量分析中评估MET状态及其他基线协变量。按暴露情况总结治疗期间出现的不良事件。
在MET阳性患者中，与安慰剂和低暴露相比，较高的瑞罗西单抗暴露与改善的中位PFS（80% CI：7.0（5.7 - 9.7）对4.4（2.9 - 4.9）和5.5（4.2 - 6.8）个月）和OS（13.4（10.6 - 18.6）对5.7（4.7 - 10.2）和8.1（6.9 - 11.1）个月）相关，且毒性未增加。在MET阴性患者中未观察到瑞罗西单抗的益处。
瑞罗西单抗对MET阳性胃或食管胃交界癌患者具有暴露依赖性治疗效果。
