Selection of Second-line Anti-angiogenic Agents After Failure of Bevacizumab-containing First-line Chemotherapy in Metastatic Colorectal Cancer

Continuation of anti-angiogenic agents beyond progression in second-line therapy is recognized as a standard of care for patients with metastatic colorectal cancer, and there are 3 options based on the results of the phase III trials: bevacizumab (ML18147 trial), ramucirumab (RAISE trial), and aflibercept (VELOUR trial). However, the eligibility criteria of these three trials differed, and there are no established biomarkers for selecting the optimal agent. In a collaborative study of the RAISE trial, it was reported that vascular endothelial growth factor (VEGF)-D may be a predictive marker for remucirumab, which can prevent binding of VEGF-D to VEGF receptor, and establishment of the standard method for assessing VEGF-D is eagerly awaited. Although subset analysis in the ML18147 and VELOUR trials suggested that short progression-free survival (PFS) in first-line therapy with bevacizumab might have some adverse impacts on the efficacy of anti-angiogenic agent targeting VEGF ligands in second-line therapy, consistent hazard ratios in the subgroups divided by first-line PFS < and >= 9 months (0.84 [95% confidence interval, 0.69-1.02] and 0.89 [95% confidence interval, 0.72-1.09]) were observed in the RAISE trial. It is suggested that anti-angiogenic agents beyond progression can be selected by considering first-line PFS.