TRC105 is an anti-
endoglin antibody currently being tested in combination with
VEGF inhibitors. In the phase Ib trial, 38 patients were treated with both
TRC105 and
bevacizumab (BEV), and improved clinical outcomes were observed, despite the fact that 30 patients (79%) were refractory to prior anti-
VEGF therapy. Plasma samples were tested for angiogenic and inflammatory
biomarkers at baseline and on-treatment. To provide broader context of this combination
biomarker study, direct cross-study comparisons were made to
biomarker studies previously conducted in patients treated with either BEV or
TRC105 monotherapy. Upon treatment with BEV and
TRC105, pharmacodynamic changes in response to both BEV (PlGF increase) and
TRC105 (soluble
endoglin increase) were noted. In addition, distinct patterns of change were identified (similar, opposing, neutralizing). Similar patterns were observed when the combination elicited similar effects to those observed with monotherapy treatment (i.e., decreases of Ang-2, increases of
IL6 and VCAM-1). Opposing patterns were observed when the combination led to opposing effects compared with monotherapy treatment (i.e., TGFβ1,
PDGF-AA and
PDGF-BB, PAI-1). Lastly, neutralizing patterns were observed when one drug led to increase, whereas the other drug led to decrease, and the combination elicited no overall effect on the marker (i.e.,
VEGF-A,
VEGF-D, and
IGFBP-3). Patients achieving partial responses or stable disease from the combination exhibited significantly lower expression of
E-Cadherin, HGF,
ICAM-1, and TSP-2 at baseline. Taken together, the novel
biomarker modulations identified may deepen our understanding of the underlying biology in patients treated with BEV and
TRC105 compared with either drug alone. Mol
Cancer Ther; 17(10); 2248-56. ©2018 AACR.