Ramucirumab in the second-line treatment of metastatic colorectal cancer: a narrative review of literature from clinical trials

Abstract

The development of new anti-angiogenic agents targeting the vascular endothelial growth factor (VEGF) and epidermal growth factor receptor pathways has greatly expanded the therapeutic options for patients with metastatic colorectal cancer (mCRC). Although these new agents have considerably improved survival outcomes compared with conventional chemotherapeutic regimens, the optimal integration of these drugs into the management of patients with mCRC continues to develop. One particular challenge is the identification of patient subgroups that will benefit from treatment with a specific targeted agent. In RAISE, a phase III randomized, placebo-controlled clinical trial, the VEGF receptor 2 antagonist ramucirumab in combination with fluorouracil plus leucovorin and irinotecan demonstrated efficacy as a second-line treatment for patients with mCRC. Ramucirumab is approved for the treatment of patients with mCRC in Taiwan but, due to lack of reimbursement, is often reserved for use as a third-line or later treatment. This narrative review of prespecified and post-hoc analyses of the RAISE study data, and data from other ramucirumab trials and real-world studies, summarizes the efficacy and tolerability of ramucirumab in the second-line treatment of different subpopulations of patients with mCRC. The aim was to identify patients most likely to benefit from treatment with second-line ramucirumab, with a view to illustrating the potential benefit of integrating this regimen into Taiwanese or Asian treatment practice.

Keywords: Angiogenesis; VEGFR2 inhibition; colorectal cancer (CRC); narrative review; ramucirumab.

Figure 1

Forest plot showing overall survival in the general RAISE mCRC population and in patient subgroups. HRs and 95% CIs are shown for subgroups as defined by baseline patient and tumor characteristics (7,12,13,16-19). ^a, patients were grouped into four ramucirumab C_min,ss exposure quartiles: <25% (Q1), 25% to <50% (Q2), 50% to <75% (Q3), and ≥75% (Q4). Potential interactions between treatment-group and subgroup variables were significant at a two-sided α level of 0.10. CEA, carcinoembryonic antigen; CI, confidence interval; C_min,ss, minimum steady-state plasma concentration; FOLFIRI, fluorouracil/leucovorin/oxaliplatin; HR, hazard ratio; mCRC, metastatic colorectal cancer; OS, overall survival; PBO, placebo; RAM, ramucirumab; TTP, time to tumor progression; VEGF-D, vascular endothelial growth factor-D.

Figure 2

Forest plot showing progression-free survival in the general RAISE mCRC population and in patient subgroups. HRs and 95% CIs are shown for subgroups as defined by baseline patient and tumor characteristics (7,12,13,16-18). ^a, patients were grouped into four ramucirumab C_min,ss exposure quartiles: <25% (Q1), 25% to <50% (Q2), 50% to <75% (Q3), and ≥75% (Q4). Potential interactions between treatment-group and subgroup variables were significant at a two-sided α level of 0.10. CEA, carcinoembryonic antigen; CI, confidence interval; C_min,ss, minimum steady-state plasma concentration; FOLFIRI, fluorouracil/leucovorin/oxaliplatin; HR, hazard ratio; mCRC, metastatic colorectal cancer; PBO, placebo; PFS, progression-free survival; RAM, ramucirumab; TTP, time to tumor progression; VEGF-D, vascular endothelial growth factor-D.