title: 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.
authors.affiliation: Authors' Affiliations: Sanofi Oncology, Translational & Experimental Medicine; Sanofi Oncology, Pharmacology, Vitry-sur-Seine, France; Sanofi Oncology, Clinical Development; Sanofi Oncology, Translational & Experimental Medicine, Cambridge, Massachusetts; and Oncotest GmbH, Freiburg, Germany Marielle.Chiron@Sanofi.com.
authors.forename: Marielle
authors.initials: M
authors.lastname: Chiron
authors.affiliation: Authors' Affiliations: Sanofi Oncology, Translational & Experimental Medicine; Sanofi Oncology, Pharmacology, Vitry-sur-Seine, France; Sanofi Oncology, Clinical Development; Sanofi Oncology, Translational & Experimental Medicine, Cambridge, Massachusetts; and Oncotest GmbH, Freiburg, Germany.
authors.forename: Rebecca G
authors.initials: RG
authors.lastname: Bagley
authors.affiliation: Authors' Affiliations: Sanofi Oncology, Translational & Experimental Medicine; Sanofi Oncology, Pharmacology, Vitry-sur-Seine, France; Sanofi Oncology, Clinical Development; Sanofi Oncology, Translational & Experimental Medicine, Cambridge, Massachusetts; and Oncotest GmbH, Freiburg, Germany.
authors.forename: Jack
authors.initials: J
authors.lastname: Pollard
authors.affiliation: Authors' Affiliations: Sanofi Oncology, Translational & Experimental Medicine; Sanofi Oncology, Pharmacology, Vitry-sur-Seine, France; Sanofi Oncology, Clinical Development; Sanofi Oncology, Translational & Experimental Medicine, Cambridge, Massachusetts; and Oncotest GmbH, Freiburg, Germany.
authors.forename: Parminder K
authors.initials: PK
authors.lastname: Mankoo
authors.affiliation: Authors' Affiliations: Sanofi Oncology, Translational & Experimental Medicine; Sanofi Oncology, Pharmacology, Vitry-sur-Seine, France; Sanofi Oncology, Clinical Development; Sanofi Oncology, Translational & Experimental Medicine, Cambridge, Massachusetts; and Oncotest GmbH, Freiburg, Germany.
authors.forename: Christophe
authors.initials: C
authors.lastname: Henry
authors.affiliation: Authors' Affiliations: Sanofi Oncology, Translational & Experimental Medicine; Sanofi Oncology, Pharmacology, Vitry-sur-Seine, France; Sanofi Oncology, Clinical Development; Sanofi Oncology, Translational & Experimental Medicine, Cambridge, Massachusetts; and Oncotest GmbH, Freiburg, Germany.
authors.forename: Loïc
authors.initials: L
authors.lastname: Vincent
authors.affiliation: Authors' Affiliations: Sanofi Oncology, Translational & Experimental Medicine; Sanofi Oncology, Pharmacology, Vitry-sur-Seine, France; Sanofi Oncology, Clinical Development; Sanofi Oncology, Translational & Experimental Medicine, Cambridge, Massachusetts; and Oncotest GmbH, Freiburg, Germany.
authors.forename: Catherine
authors.initials: C
authors.lastname: Geslin
authors.affiliation: Authors' Affiliations: Sanofi Oncology, Translational & Experimental Medicine; Sanofi Oncology, Pharmacology, Vitry-sur-Seine, France; Sanofi Oncology, Clinical Development; Sanofi Oncology, Translational & Experimental Medicine, Cambridge, Massachusetts; and Oncotest GmbH, Freiburg, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Baltes
authors.affiliation: Authors' Affiliations: Sanofi Oncology, Translational & Experimental Medicine; Sanofi Oncology, Pharmacology, Vitry-sur-Seine, France; Sanofi Oncology, Clinical Development; Sanofi Oncology, Translational & Experimental Medicine, Cambridge, Massachusetts; and Oncotest GmbH, Freiburg, Germany.
authors.forename: Donald A
authors.initials: DA
authors.lastname: Bergstrom
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage*; D000068258:Bevacizumab; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D004357:Drug Synergism; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000037:antagonists & inhibitors; D040262:Receptors, Vascular Endothelial Growth Factor / Q000008:administration & dosage*; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; C000608036:PGF protein, human; C000608037:Pgf protein, mouse; D011257:Pregnancy Proteins; D011993:Recombinant Fusion Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000072483:Placenta Growth Factor; C533178:aflibercept; D000068258:Bevacizumab; D040262:Receptors, Vascular Endothelial Growth Factor