Ramucirumab, a human IgG1 monoclonal antibody receptor antagonist of vascular endothelial growth factor receptor 2 (VEGFR-2), has been approved for treatment in gastric/gastroesophageal junction, non-small cell lung, and metastatic colorectal cancers. A total of 6 global, randomized, double-blind, placebo-controlled, phase 3 trials across multiple tumor types and a large patient population have currently been completed. To further establish the safety profiles of ramucirumab, a meta-analysis has been performed based on the data from these 6 trials and the results are presented here.
Fixed-effects or mixed-effects models were used to conduct an individual patient meta-analysis across the 6 completed phase 3 trials and derive the relative risk (RR) and associated 95% confidence intervals (CIs) for all-grade and high-grade (Grade ≥3) adverse events (AEs) possibly related to VEGF pathway inhibition.
This meta-analysis included a total of 4996 treated patients (2748 patients in ramucirumab arms, 2248 in control arms). Proteinuria, gastrointestinal (GI) perforation, hypertension, wound-healing complications, infusion-related reactions, and low-grade (Grade 1-2) bleeding were observed at a higher percentage in the ramucirumab arms compared to control. However, our data did not demonstrate a definite increased risk with ramucirumab in high-grade bleeding (RR: 1.1, 95% CI 0.8-1.5), high-grade GI bleeding (RR: 1.1, 95% CI 0.7-1.7), 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), or arterial thromboembolic events (ATE, all-grade, RR: 0.8, 95% CI 0.5-1.3; high-grade, RR: 0.9, 95% CI 0.5-1.7).
The risk of developing certain AEs with ramucirumab is consistent with other antiangiogenic agents; and, the safety profile is consistent with the ramucirumab labels. Our results showed no clear evidence for an increased risk of high-grade bleeding, high-grade GI bleeding, VTE, or ATE in this large and patient level meta-analysis.
Clinical trial identification
REGARD = NCT00917384, RAINBOW = NCT01170663, REVEL = NCT01168973, RAISE = NCT01183780, REACH = NCT01140347, ROSE = NCT00703326
Legal entity responsible for the study
Eli Lilly and Company
Eli Lilly and Company Disclosure: D. Arnold: Honoraria/consultancy from Bayer, Biocompatibles, Boehringer Ingelheim, Eli Lilly and Company, Roche, Sanofi, and Servier; as well as honoraria presentations for Bayer, Eli Lilly and Company, Roche, and Servier. C.S. Fuchs: Consultant roles for Entrinsic Health, Genetech, Merck, Gilead Sciences, Sanofi, Dicerna, Five Prime Therapeutics, Merrimack, Bayer, Agios, Taiho, Kew, and Eli Lilly and Company. J. Tabernero: Consultant/advisory roles for Amgen, Bayer, Boehringer Ingelheim, Celgene, Chugai, Imclone, Eli Lilly and Company, MSD, Merck Serono, Novartis, Roche, Sanofi, Symphogen, and Taiho. A. Ohtsu: A.O. reports a grant from BMS. A.X. Zhu: Research support to his institution from Eli Lilly and Company. E.B. Garon: Grants to his institution from Eli Lilly and Company, AstraZeneca, Boehringer Ingelheim, BMS, Genentech, Merck, Mirati, Novartis, and Pfizer. L. Paz-Ares: Advisory roles for Eli Lilly and Company, Roche, MSD, BMS, AstraZeneca, Boehringer Ingelheim, Pfizer, Novartis, Clovis, and Amgen. T. Okusaka: Various relationships with Novartis, Pfizer, Taiho, Bayer, Chugai, Eli Lilly, Yakuruto Honsha, Ono, AZ, Merck Serono, Baxter, Nobelpharma, Nippon BI, Dainippon Simitomo, Eisai, OncoTherapy Science, Kyowa Hakko Kirin, Shizuoka, Nano Carrier, Zeria, & GSK. T. Yoshino: Grants from Boehringer Ingelheim GmbH. and GlaxoSmithKline. H.H. Yoon: Grants to his institution from Eli Lilly and Company. M. Das, D. Ferry, Y. Zhang, Y. Lin, P. Binder, A. Sashegyi: Employee and shareholder of Eli Lilly and Company. I. Chau: Various relationships with Sanofi Oncology, Eli Lilly and Company, Bristol Meyers Squibb, MSD, Bayer, Roche, Five Prime Therapeutics, Taiho, Pfizer, Amgen, Gilead Science, Janssen-Cilag, Merck-Serono, Novartis. All other authors have declared no conflicts of interest.