Modulation of Circulating Protein Biomarkers in Cancer Patients Receiving Bevacizumab and the Anti-Endoglin Antibody, TRC105

Abstract

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. .

Endoglin Targeting: Lessons Learned and Questions That Remain

“…CT scans also revealed favorable tumor morphology change, such as decreased tumor density [ 56 ]. The angiome biomarker panel was assessed across 37 patients (97%) at baseline, after bevacizumab lead-in monotherapy, after co-administration of both drugs for 3 weeks and at the end of treatment [ 57 ]. The modulation of certain pharmacodynamic biomarkers, such as bevacizumab-induced PlGF increases and TRC105-induced sEng increases, were observed and not affected by the presence of the other drug.…”

“…For example, bevacizumab treatment increased VEGF-D levels [ 58 ], while TRC105 monotherapy decreased VEGF-D [ 54 ]. In response to the combination of drugs, VEGF-D levels did not statistically differ, indicating compensatory VEGF-D signaling was inhibited, possibly accounting for delayed drug resistance [ 57 ].…”

A phase Ib study of the combination regorafenib with PF-03446962 in patients with refractory metastatic colorectal cancer (REGAL-1 trial)

“…All biomarkers were measured using the CiraScan multiplex platform (Aushon Biosystems, Inc., Billerica, MA, USA), except for BMP-9 and TGFβ-R3. TGFβ-R3 [10] and BMP-9 [11] were assessed as previously described.…”

Phase 1b trial of docetaxel, prednisone, and pazopanib in men with metastatic castration‐resistant prostate cancer

“…After processing, the samples were immediately frozen and stored at −80°C until use. All 23 angiogenic and inflammatory biomarkers (angiome analysis) were measured at baseline and cycle 3 day 1 using the Cirascan multiplex platform (Aushon BioSystems, Inc, Billerica, MA) except for BMP‐9, CD73, TGF‐β R3, and sHER3 (R&D Systems, Inc, Minneapolis, MN), as described previously …”