Abstract A2: Exploratory textural CT evaluation of the combination of TRC105 (anti-endoglin monoclonal antibody; MAb) and bevacizumab (BEV) indicates partial response by Choi criteria in BEV refractory advanced cancer patients (pts) and identifies candidate markers of response.

Abstract

Abstract Background: Endoglin (CD105) is an endothelial cell membrane receptor, highly expressed on angiogenic tumor vessels, that is essential for angiogenesis and upregulated by hypoxia and VEGF inhibition. TRC105 is an anti-endoglin MAb that potentiates VEGF inhibitors in preclinical models. TRC105 10 mg/kg weekly was well tolerated with BEV 10 mg/kg q2wk and the combination demonstrated activity in BEV and VEGF TKI refractory pts. This study assessed radiographic responses to TRC105 + BEV using Choi criteria and tumor morphology by applying novel quantitative textural analysis (QTA: TexRad -University of Sussex, UK) in pts with durable stable disease by RECIST, to determine predictive markers of response. Methods: Contrast enhanced CT scans from 5 pts with advanced solid tumors who demonstrated stable disease by RECIST in a trial of escalating doses of TRC105 (3, 6, 8 or 10 mg/kg/wk) plus BEV were reviewed. Seventeen target lesions were selected from baseline scans and assessed for target lesion diameter, whole lesion density, and tumor volume at baseline and follow-up. QTA analysis was assessed on the same target lesions using six different filter levels at baseline and on follow-up scans. The results were correlated to anatomic tumor response using non-parametric evaluation and regression analysis. Statistical significance was defined as a two-tailed p < 0.05. Results: Scans from 5 patients (median age 56; M:F 2:3; median 4 prior regimens; 3 metastatic colorectal and 2 ovarian cancer) 4 of whom progressed following VEGF inhibitor treatment were selected and demonstrated stable disease by RECIST for at least 4 months (range: 4-14 months) of treatment with TRC105 + BEV. Four of five patients (80%) had partial responses by Choi criteria. Predictive markers of tumor response on baseline scans included 1) elevated mean pixel density (median values of responder (R) vs non responder (NR): 27.2 vs -4.3) that correlated with subsequent tumor size reduction, 2) elevated entropy (a measure of tumor heterogeneity; median R vs NR: 5.1 vs 4.7) that correlated with subsequent decrease in mean tumor volume, and 3) low kurtosis (a measure of tumor heterogeneity; median R vs NR: 0.2 vs 1.1) that correlated with subsequent reduction in lesion density (p<0.01). Mean positive pixel values (an indicator of hypoxia) on follow-up scans correlated with decreased tumor density. Conclusions: Assessment of radiographic response using Choi criteria identified VEGF inhibitor refractory patients who demonstrated partial response to the combination of TRC105 + BEV. Using novel QTA measures, markers of tumor heterogeneity and hypoxia correlated with individual lesion responses and are worthy of prospective evaluation as predictive imaging biomarkers. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A2. Citation Format: Ron L. Korn, Michael S. Gordon, Lee S. Rosen, Francisco Robert, Daniela Matei, Jonathan W. Goldman, David S. Mendelson, E. Gabriela Chiorean, Robert Matthew Strother, Ben K. Seon, Delia Alvarez, Bonne J. Adams, Charles P. Theuer. Exploratory textural CT evaluation of the combination of TRC105 (anti-endoglin monoclonal antibody; MAb) and bevacizumab (BEV) indicates partial response by Choi criteria in BEV refractory advanced cancer patients (pts) and identifies candidate markers of response. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A2.