Critical Appraisal of Ramucirumab (IMC-1121B) for Cancer Treatment: From Benchside to Clinical Use

Abstract

Although antiangiogenic treatments have produced milestone advances in the treatment of several diseases, and have significantly extended the median survival of cancer patients, these agents share some weaknesses, including a limited impact on the overall cure rate, a fleeting effect because of redundant pathways or early appearance of resistance mechanisms, and the lack of predictive factors for treatment selection. Recent data suggest that antibodies targeting the vascular endothelial growth factor axis exert their activity through the inhibition of vascular endothelial growth factor receptor-2 phosphorylation, which has a pivotal role in the neoangiogenic process. Ramucirumab, a fully humanized monoclonal antibody specifically directed against the extracellular domain of the receptor, administered intravenously every 2 or 3 weeks, is emerging as a novel antiangiogenic opportunity. Starting with preclinical data and early clinical results, this concise review focuses on the development of the novel compound across multiple cancers (including gastrointestinal malignancies, breast cancer, lung carcinoma, and genitourinary tumors), and presents available data from randomized phase II and phase III trials. REGARD was the first phase III study to report on the efficacy of single-agent ramucirumab in patients with advanced cancer. Many other ongoing phase III trials are testing the efficacy of this interesting antiangiogenic compound as a single agent or in combination with chemotherapy in different cancer types.

Targeting Angiogenesis in Cancer Therapy: Moving Beyond Vascular Endothelial Growth Factor

“…In the phase III RAINBOW trial, the addition of ramucirumab significantly improved OS from 7.36 months to 9.63 months (HR: 0.807; 95% CI: 0.678-0.962; p 5 .0169) [30]. Ramucirumab has shown varying degrees of efficacy in renal, uterine, colorectal, and ovarian carcinoma [31,32]. Most recently, results of ramucirumab trials in NSCLC and breast cancer have been reported.…”

Ramucirumab – egy új gyógyszer az onkológiában

“…A VEGFR-2-ligand-kö-tődés következményeként a sejten belül több jelátviteli út aktiválódik és ennek következtében fokozódik a tumorangiogenezis [3]. Annak ellenére, hogy a VEGF-A receptorkötő affinitása a VEGFR-2-receptorhoz csak tizede a VEGFR-1-hez mutatott aktivitásnak, mégis a VEGFR-2-t tekintik a tumor-angiogenezis főszereplőjé-nek, mivel a foszforilációja által elindított intracelluláris jelátviteli kaszkád hatékonyabb intermediereket aktivál, mint a másik két receptor [4]. A VEGF-ellenes terápiák az onkológiai gyógyszerfejlesztések élvonalába kerültek [5].…”

Angiogenic inhibitors in gastric cancers and gastroesophageal junction carcinomas: A critical insight

“…Among many novel antiangiogenic drugs, ramucirumab, a fully human IgG 1 monoclonal antibody specifically directed against VEGFR-2, is emerging as a new therapeutic option [67]. The phase III, placebo-controlled, double-blinded REGARD trial was conducted with the aim of evaluating the safety and efficacy of ramucirumab as second-line treatment in 355 patients with advanced, unresectable gastric or GEJ cancers.…”