Differential Antitumor Activity of Aflibercept and Bevacizumab in Patient-Derived Xenograft Models of Colorectal Cancer

Abstract

The recombinant fusion protein aflibercept (ziv-aflibercept in the United States) binds VEGF-A, VEGF-B, and placental growth factor (PlGF). The monoclonal antibody bevacizumab binds VEGF-A. Recent studies hypothesized that dual targeting of VEGF/PlGF is more beneficial than targeting either ligand. We compared activity of aflibercept versus bevacizumab in 48 patient-derived xenograft (PDX) colorectal cancer models. Nude mice engrafted subcutaneously with PDX colorectal cancer tumors received biweekly aflibercept, bevacizumab, or vehicle injections. Differential activity between aflibercept and bevacizumab, determined by mouse (m), human (h), VEGF-A, and PlGF levels in untreated tumors, was measured. Aflibercept induced complete tumor stasis in 31 of 48 models and bevacizumab in 2 of 48. Based on statistical analysis, aflibercept was more active than bevacizumab in 39 of 48 models; in 9 of 39 of these models, bevacizumab was considered inactive. In 9 of 48 remaining models, aflibercept and bevacizumab had similar activity. Tumor levels of hVEGF-A (range 776-56,039 pg/mg total protein) were $16-to 1,777-fold greater than mVEGF-A (range 8-159 pg/mg total protein). Tumor levels of mPlGF (range 104-1,837 pg/mg total protein) were higher than hPlGF (range 0-543 pg/mg total protein) in 47 of 48 models. Tumor cells were the major source of VEGF; PlGF was primarily produced by tumor stroma. Because tumor levels of hVEGF-A were far greater than mVEGF-A, bevacizumab's inability to bind mVEGF-A is unlikely to explain higher and more consistent aflibercept activity. Neutralizing PlGF and VEGFR-1 activation may be a factor and should be investigated in future studies. In these colorectal cancer PDX models, aflibercept demonstrated greater antitumor activity than bevacizumab. Mol Cancer Ther; 13(6); 1636-44. Ó2014 AACR.

Efficacy and safety of aflibercept in metastatic colorectal cancer pretreated with bevacizumab: A report of five cases

“…However, there is available data from pre-clinical studies that have made a comparative assessment of the activity of the two drugs. A recent study with mCRC tumour tissue models extracted from patients and xenografted mice (PDX cancer models) revealed differences in tumour growth control between the antiangiogenic treatments bevacizumab and aflibercept; the latter was revealed to be more effective in preventing tumour growth (25). Chiron et al (26) verified this data, also using PDX models, and revealed that administrating aflibercept during cancer progression following bevacizumab treatment facilitates maintenance of tumour growth inhibition, thus achieving a greater response compared with bevacizumab maintenance following tumour progression (26).…”

“…This superior activity may be explained by the effect aflibercept has on VEGF and PIGF, since it better neutralises the resistance mechanisms that are activated by the tumour compared with bevacizumab (27,28). In addition, it has been suggested that PIGF presence in patient serum may aid in the prediction of the optimal time for switching to antiangiogenic therapy prior to tumour progression taking place (25). …”

Aflibercept: A Review in Metastatic Colorectal Cancer

“…Aflibercept appears to have greater anti-VEGF [10] and antitumor [20] activity than bevacizumab. The binding affinity of aflibercept to human VEGF-A 165 isoform was &118-fold higher than that of bevacizumab [10].…”

“…Furthermore, aflibercept blocked human PIGF-2 induced VEGFR-1 activation and HUVEC migration, whereas bevacizumab does not bind to P1GF-2 and therefore showed no such activity [10]. In mice bearing human colorectal cancer xenografts, aflibercept induced complete tumour stasis in 31 of 48 animals, whereas bevacizumab in 2 of 48; aflibercept also significantly (p \ 0.05) inhibited tumour growth versus bevacizumab in 39 of 48 animals, including in nine animals in which bevacizumab was inactive [20]. In this model, aflibercept down-regulated a number of angiogenesis-promoting genes and that may be associated with its increased antitumour activity relative to bevacizumab [21].…”

Aflibercept: side effects in focus

“…Молекула афли-берцепта обладает большей связующей способностью в сравнении с бевацизумабом в отношении VEGFA [5][6][7][8][9][10][11].…”