PMID- 28950290 OWN - NLM STAT- MEDLINE DCOM- 20180502 LR - 20240426 IS - 1569-8041 (Electronic) IS - 0923-7534 (Print) IS - 0923-7534 (Linking) VI - 28 IP - 12 DP - 2017 Dec 1 TI - Meta-analysis of individual patient safety data from six randomized, placebo-controlled trials with the antiangiogenic VEGFR2-binding monoclonal antibody ramucirumab. PG - 2932-2942 LID - 10.1093/annonc/mdx514 [doi] AB - 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). CI - (c) The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. FAU - Arnold, D AU - Arnold D AD - Oncology, Instituto CUF de Oncologia (I.C.O.), Lisbon, Portugal. FAU - Fuchs, C S AU - Fuchs CS AD - Internal Medicine, Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA. FAU - Tabernero, J AU - Tabernero J AD - Medical Oncology Department, Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Universitat Autonoma de Barcelona, Barcelona, Spain. FAU - Ohtsu, A AU - Ohtsu A AD - Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan. FAU - Zhu, A X AU - Zhu AX AD - Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, USA. FAU - Garon, E B AU - Garon EB AD - Hematology Oncology, David Geffen School of Medicine at UCLA Translational Research in Oncology-US Network, Santa Monica, USA. FAU - Mackey, J R AU - Mackey JR AD - Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Canada. FAU - Paz-Ares, L AU - Paz-Ares L AD - Medical Oncology Department, Hospital Universitario Doce de Octubre, Madrid, Spain. FAU - Baron, A D AU - Baron AD AD - Division of Hematology Oncology, California Pacific Medical Center, San Francisco, USA. FAU - Okusaka, T AU - Okusaka T AD - Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan. FAU - Yoshino, T AU - Yoshino T AD - Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan. FAU - Yoon, H H AU - Yoon HH AD - Division of Medical Oncology, Mayo Clinic, Rochester, USA. FAU - Das, M AU - Das M AD - Oncology, Eli Lilly and Company, Indianapolis, USA. FAU - Ferry, D AU - Ferry D AD - Oncology, Eli Lilly and Company, Bridgewater, USA. FAU - Zhang, Y AU - Zhang Y AD - Oncology, Eli Lilly and Company, Bridgewater, USA. FAU - Lin, Y AU - Lin Y AD - Oncology, Eli Lilly and Company, Indianapolis, USA. FAU - Binder, P AU - Binder P AD - Oncology, Eli Lilly and Company, Bridgewater, USA. FAU - Sashegyi, A AU - Sashegyi A AD - Oncology, Eli Lilly and Company, Indianapolis, USA. FAU - Chau, I AU - Chau I AD - Department of Medicine, Royal Marsden Hospital, Sutton, UK. LA - eng SI - ClinicalTrials.gov/NCT01140347 SI - ClinicalTrials.gov/NCT00703326 PT - Journal Article PT - Meta-Analysis PT - Review PL - England TA - Ann Oncol JT - Annals of oncology : official journal of the European Society for Medical Oncology JID - 9007735 RN - 0 (Angiogenesis Inhibitors) RN - 0 (Antibodies, Monoclonal) RN - 0 (Antibodies, Monoclonal, Humanized) RN - 0 (Antineoplastic Agents, Immunological) RN - EC 2.7.10.1 (KDR protein, human) RN - EC 2.7.10.1 (Vascular Endothelial Growth Factor Receptor-2) SB - IM MH - Angiogenesis Inhibitors/adverse effects/immunology/therapeutic use MH - Antibodies, Monoclonal/administration & dosage/*adverse effects/immunology/*therapeutic use MH - Antibodies, Monoclonal, Humanized MH - Antineoplastic Agents, Immunological/adverse effects/immunology/therapeutic use MH - Antineoplastic Combined Chemotherapy Protocols/adverse effects/immunology/therapeutic use MH - Clinical Trials, Phase III as Topic MH - Humans MH - Randomized Controlled Trials as Topic MH - Risk Assessment MH - Vascular Endothelial Growth Factor Receptor-2/immunology MH - Ramucirumab PMC - PMC5834052 OTO - NOTNLM OT - VEGF OT - VEGFR OT - adverse events OT - antiangiogenic OT - meta-analysis OT - ramucirumab EDAT- 2017/09/28 06:00 MHDA- 2018/05/03 06:00 PMCR- 2017/09/10 CRDT- 2017/09/27 06:00 PHST- 2017/09/28 06:00 [pubmed] PHST- 2018/05/03 06:00 [medline] PHST- 2017/09/27 06:00 [entrez] PHST- 2017/09/10 00:00 [pmc-release] AID - S0923-7534(19)35384-0 [pii] AID - mdx514 [pii] AID - 10.1093/annonc/mdx514 [doi] PST - ppublish SO - Ann Oncol. 2017 Dec 1;28(12):2932-2942. doi: 10.1093/annonc/mdx514.