Aflibercept More Active Than Bevacizumab in Patient-Derived Colorectal Cancer Xenografts

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Some evidence suggests that dual targeting of vascular endothelial growth factor (VEGF) and placental growth factor (which binds to VEGFR-1) might provide more effective antiangiogenic therapy. In a study reported in Molecular Cancer Therapeutics, Chiron and colleagues compared the antitumor effects of ziv-aflibercept (Zaltrap), which binds VEGF-A, VEGF-B, and placental growth factor, with those of the anti–VEGF-A antibody bevacizumab (Avastin) in patient-derived xenograft colorectal cancer models.

Tumors (47 adenocarcinomas) were freshly excised from primary (n = 9) or metastatic sites (n = 39) of 48 patients and engrafted and passaged subcutaneously into female NMRI nu/nu mice, which received biweekly aflibercept or bevacizumab. Complete tumor stasis was observed with aflibercept in 31 (65%) of 48 models (including 15 of 31 with KRAS-activating mutations) and with bevacizumab in 2 (4%) of 48.

Tumor cells were the major source of VEGF, whereas placental growth factor was primarily produced by tumor stroma. According to the investigators, the markedly higher human vs mouse VEGF-A levels observed in the tumors makes it unlikely that the results reflect an inability of bevacizumab to bind mouse VEGF-A.

The investigators concluded, “Neutralizing of [placental growth factor] and VEGFR-1 activation may be a factor [in this setting] and should be investigated in future studies. In these [colorectal cancer patient–derived xenograft] models, aflibercept demonstrated greater antitumor activity than bevacizumab…. [Since] many of the xenograft tumors were derived from [metastatic colorectal cancer] tumors, there is the suggestion that aflibercept may have activity in retarding the progression of later-stage disease.” ■

Chiron M, et al: Mol Cancer Ther. March 31, 2014 (early release online).




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