Ramucirumab in metastatic colorectal cancer: evidence to date and place in therapy

Abstract

Colorectal cancer is the third most frequent cancer worldwide. Overall survival rates have improved greatly over the last few years due, at least in part, to the addition of targeted therapies to standard of care chemotherapy. Angiogenesis plays an important role in colorectal cancer, and therapies directed against the vascular endothelial growth factor (VEGF) axis have contributed significantly to improving the outcome of patients with metastatic colorectal cancer. Over the past few years, several new targeted antiangiogenic agents have been approved for this patient population, confirming the value of inhibiting tumour angiogenesis. The most recent among them is ramucirumab, a fully humanized monoclonal antibody that targets the extracellular domain of VEGF receptor 2. It has proven valuable in multiple tumour types including colorectal cancer. Several phase I and II clinical trials showed a favourable toxicity profile and promising clinical antitumour efficacy in colorectal cancer patients. In the phase III RAISE clinical trial, the addition of ramucirumab to FOLFIRI-based chemotherapy resulted in an improvement of overall survival in patients with metastatic colorectal cancer who had been previously treated with bevacizumab, oxaliplatin and a fluoropyrimidine. On the basis of these results, ramucirumab was approved by the US Food and Drug Administration for this setting. We present an overview of the key preclinical and clinical studies in the development of ramucirumab in the context of metastatic colorectal cancer.

Keywords: angiogenesis; colorectal cancer; metastatic; ramucirumab; vascular endothelial growth factor.

Figure 1.

Binding specificity of vascular endothelial growth factor family members and their receptors. VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor; PIGF, placenta growth factor; Flt, human receptor-type tyrosine kinase gene; NRP, neuropilin; KDR, Kinase Insert Domain Receptor.

Figure 2.

Kaplan–Meier estimate of progression-free survival for patients treated with ramucirumab + modified FOLFOX6 in a Phase II study [Garcia-Carbonero et al. 2014]. CI, confidence interval; mFOLFOX-6, modified FOLFOX-6 regimen; PFS, progression-free survival.

Figure 3.

Kaplan–Meier estimates of overall survival (A) and progression-free survival (B) in the intention-to-treat population for ramucirumab versus placebo Tabernero et al. [2015]. FOLFIRI, 180 mg/m² irinotecan followed by or concurrent with 400 mg/m² leucovorin, followed by 400 mg/m² fluorouracil given as an intravenous bolus then 2400 mg/m² given as a continuous infusion over 48 hours.