Meta-analysis of individual patient safety data from six randomized, placebo-controlled trials with the antiangiogenic VEGFR2-binding monoclonal antibody ramucirumab.

View/ Open
Publication Date
2017-12Author
Arnold, D
Fuchs, CS
Tabernero, J
Ohtsu, A
Zhu, AX
Garon, EB
Mackey, JR
Paz-Ares, L
Baron, AD
Okusaka, T
Yoshino, T
Yoon, HH
Das, M
Ferry, D
Zhang, Y
Lin, Y
Binder, P
Sashegyi, A
Chau, I
Type
Journal Article
Metadata
Show full item recordAbstract
<h4>Background</h4>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.<h4>Materials and methods</h4>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.<h4>Results</h4>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.<h4>Conclusions</h4>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).
Collections
Licenseref URL
https://creativecommons.org/licenses/by-nc/4.0Version of record
Subject
Humans
Vascular Endothelial Growth Factor Receptor-2
Angiogenesis Inhibitors
Antineoplastic Combined Chemotherapy Protocols
Antibodies, Monoclonal
Risk Assessment
Randomized Controlled Trials as Topic
Clinical Trials, Phase III as Topic
Antibodies, Monoclonal, Humanized
Antineoplastic Agents, Immunological
Language
eng
License start date
2017-12
Citation
Annals of oncology : official journal of the European Society for Medical Oncology, 2017, 28 (12), pp. 2932 - 2942