Assessing the risk-benefit profile of ramucirumab in patients with advanced solid tumors: A meta-analysis of randomized controlled trials

Abstract

Background Ramucirumab is a widely used cancer drug having gained six regulatory approvals in various advanced solid tumors. Thus, assessing the risk-benefit profile of such a commonly used drug across multiple tumor types is necessary to inform clinical and reimbursement decisions. To objectively assess the risks and benefits of ramucirumab in patients with advanced solid tumors, we performed a systematic review and meta-analysis of published randomized controlled trials (RCTs). Methods A systematic search of PubMed, the Cochrane Library, Google Scholar and conference abstracts for all RCTs of ramucirumab in patients with advanced solid cancer was conducted according to the PRISMA guidelines. Data on treatment-related serious adverse events (SAEs), fatal adverse events (FAEs), primary endpoint, gains in median overall survival (OS), progression-free survival (PFS) with their hazard ratios (HR) and 95% confidence intervals (CIs) and quality of life (QOL) were extracted from each RCT. Summary relative risks (RR) with 95% CI for SAEs and FAEs were calculated by pooling data across the RCTs using random-effects model. Treatment benefit was evaluated descriptively in terms of median and HR with 95% CI of OS and PFS gains as well as improvements in QOL. ESMO-Magnitude of Clinical Benefit Scale (MCBS), a validated tool, was used to objectively quantify clinical benefit of ramucirumab in approved settings. Findings Ten RCTs met our inclusion criteria. Compared with the control arm, the use of ramucirumab was associated with a significantly increased risk of developing SAE (RR 1.13, 95% CI 1.05–1.21, incidence 37.5% v 33.5%). The increase in risk of FAE (RR 1.41, 95% CI 0.96–2.07, incidence 1.8% v 1.3%) was not statistically significant. Using the ESMO MCBS tool, clinical benefit with ramucirumab was not substantial in any indication, five of six approvals scoring a “negligible benefit” score of 1 or 2. QOL was either not reported (30%) or not improved (70%) in these RCTs. Interpretation In this meta-analysis of RCTs, use of ramucirumab in patients with advanced cancer was associated with increased risk of treatment related serious and possibly fatal adverse events but the magnitude of clinical benefit from ramucirumab was mostly negligible with no trial reporting an improvement in QOL. These relative risks and benefits should be considered in clinical and regulatory decision making. Funding None.

Current Status of Monoclonal Antibodies-Based Therapies in Castration-Resistant Prostate Cancer: A Systematic Review and Meta-Analysis of Clinical Trials

“…The incidence of adverse events was similar to expectations. Ramucirumab has shown improvement in OS in RCTs on other solid tumors [ 74 ]. Another trial by McHugh et al (2020) has also shown no activity of cixutumumab with temsirolimus [ 45 ].…”

Targeting Angiogenesis in Breast Cancer: Current Evidence and Future Perspectives of Novel Anti-Angiogenic Approaches

“…Ramucirumab approval was thereafter expanded to combination treatment with chemotherapy for gastric cancer, non-small cell lung cancer (NSCLC), and colon cancer. The drug is also approved as monotherapy for hepatocellular carcinoma (HCC), and most recently in combination with erlotinib for patients with epidermal growth factor receptor (EGFR)-positive NSCLC (Effing and Gyawali, 2020).…”

Hypoxia-induced therapy resistance: Available hypoxia-targeting strategies and current advances in head and neck cancer

“…Additionally, since access to bevacizumab is limited in some regions or circumstances, more affordable biosimilars have been developed some of which have already been approved for advanced non-small cell lung cancer and metastatic colorectal cancer (Bevacizumab Updates – Big Molecule Watch) [76] . Other monoclonal antibodies with anti-angiogenic properties include ramucirumab (Cyramza), which targets VEGFR-2 and has been approved for the treatment of metastatic gastric cancer and hepatocellular cancer as monotherapy, and for non-small cell lung cancer, colorectal cancer and gastric cancer in combination with chemotherapy [ 47 , 77 , 78 ].…”