Safety of Onartuzumab in Patients with Solid Tumors: Experience to Date from the Onartuzumab Clinical Trial Program

BackgroundOnartuzumab, a recombinant humanized monovalent monoclonal antibody directed against MET, the receptor for the hepatocyte growth factor, has been investigated for the treatment of solid tumors. This publication describes the safety profile of onartuzumab in patients with solid tumors using data from the global onartuzumab clinical development program.MethodsAdverse event (AE) and laboratory data from onartuzumab phase II/III studies were analyzed and coded into standardized terms according to industry standards. The severity of AEs was assessed using the NCI Common Toxicity Criteria, Version 4. Medical Dictionary for Regulatory Activities (MedDRA) AEs were grouped using the standardized MedDRA queries (SMQs) “gastrointestinal (GI) perforation”, “embolic and thrombotic events, venous (VTE)”, and “embolic and thrombotic events, arterial (ATE)”, and the Adverse Event Group Term (AEGT) “edema.” The safety evaluable populations (patients who received at least one dose of study treatment) for each study were included in this analysis.ResultsA total of 773 onartuzumab-treated patients from seven studies (phase II, n = 6; phase III, n = 1) were included. Edema and VTEs were reported in onartuzumab-treated patients in all seven studies. Edema events in onartuzumab arms were generally grade 1–2 in severity, observed more frequently than in control arms and at incidences ranging from 25.4−65.7% for all grades and from 1.2−14.1% for grade 3. Hypoalbuminemia was also more frequent in onartuzumab arms and observed at frequencies between 77.8% and 98.3%. The highest frequencies of all grade and grade ≥3 VTE events were 30.3% and 17.2%, respectively in onartuzumab arms. The cumulative incidence of all grade ATE events ranged from 0−5.6% (grade ≥3, 0−5.1%) in onartuzumab arms. The frequency of GI perforation was below 10% in all studies; the highest estimates were observed in studies with onartuzumab plus bevacizumab for all grades (0−6.2%) and grade ≥3 (0−6.2%).ConclusionsThe frequencies of VTE, ATE, GI perforation, hypoalbuminemia, and edema in clinical studies were higher in patients receiving onartuzumab than in control arms; these are considered to be expected events in patients receiving onartuzumab.

背景：Onartuzumab是靶向肝细胞生长因子受体MET的重组人源化单价单克隆抗体，目前已被探索用于实体瘤的治疗。本研究基于全球onartuzumab临床开发项目的数据，阐述了该药物在实体瘤患者中的安全性特征。
方法：对onartuzumab II/III期临床试验中的不良事件（Adverse Event, AE）及实验室检查数据进行分析，并按照行业标准编码为标准化术语。不良事件的严重程度依据美国国家癌症研究所通用毒性判定标准第4版（NCI Common Toxicity Criteria, Version 4）进行评估。将按医疗监管活动医学词典（Medical Dictionary for Regulatory Activities, MedDRA）收录的不良事件，通过标准化MedDRA查询（Standardized MedDRA Queries, SMQs）分为“胃肠道（gastrointestinal, GI）穿孔”“静脉血栓栓塞事件（venous thromboembolic events, VTE）”“动脉血栓栓塞事件（arterial thromboembolic events, ATE）”，并采用不良事件组术语（Adverse Event Group Term, AEGT）“水肿”进行归类。本分析纳入各项研究中接受过至少一剂研究治疗的安全性可评估人群。
结果：本分析共纳入7项临床试验中的773例onartuzumab治疗患者，其中II期试验6项、III期试验1项。7项试验的onartuzumab治疗组均报告了水肿与静脉血栓栓塞事件。onartuzumab治疗组的水肿事件多为1~2级严重程度，发生率高于对照组：所有级别水肿的发生率为25.4%~65.7%，3级水肿发生率为1.2%~14.1%。低白蛋白血症在onartuzumab治疗组中同样更为常见，发生率为77.8%~98.3%。onartuzumab治疗组的全级别VTE与≥3级VTE的最高发生率分别为30.3%与17.2%。onartuzumab治疗组的全级别ATE事件累积发生率为0~5.6%（≥3级为0~5.1%）。所有试验中胃肠道穿孔事件的发生率均低于10%；其中onartuzumab联合贝伐珠单抗的试验中，全级别与≥3级胃肠道穿孔的最高发生率分别为0~6.2%与0~6.2%。
结论：临床研究显示，接受onartuzumab治疗的患者的静脉血栓栓塞事件、动脉血栓栓塞事件、胃肠道穿孔、低白蛋白血症及水肿的发生率均高于对照组；上述不良事件被认为是onartuzumab治疗患者中可预期的不良事件。