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

D Arnold, C S Fuchs, J Tabernero, A Ohtsu, A X Zhu, E B Garon, J R Mackey, L Paz-Ares, A D Baron, T Okusaka, T Yoshino, H H Yoon, M Das, D Ferry, Y Zhang, Y Lin, P Binder, A Sashegyi, I Chau, D Arnold, C S Fuchs, J Tabernero, A Ohtsu, A X Zhu, E B Garon, J R Mackey, L Paz-Ares, A D Baron, T Okusaka, T Yoshino, H H Yoon, M Das, D Ferry, Y Zhang, Y Lin, P Binder, A Sashegyi, I Chau

Abstract

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).

Keywords: VEGF; VEGFR; adverse events; antiangiogenic; meta-analysis; ramucirumab.

© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology.

Figures

Figure 1.
Figure 1.
Forest plots of the incidence and relative risk of ATE, VTE, and bleeding adverse events in completed phase III ramucirumab clinical trials. ATE, arterial thromboembolic events; CI, confidence interval; VTE, venous thromboembolic events; RR, relative risk.
Figure 1.
Figure 1.
Forest plots of the incidence and relative risk of ATE, VTE, and bleeding adverse events in completed phase III ramucirumab clinical trials. ATE, arterial thromboembolic events; CI, confidence interval; VTE, venous thromboembolic events; RR, relative risk.

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