The development and use of vascular targeted therapy in ovarian cancer Dana M. Chase, David J. Chaplin, Bradley J. Monk  Gynecologic Oncology  Volume 145, Issue 2, Pages 393-406 (May 2017) DOI: 10.1016/j.ygyno.2017.01.031 Copyright © 2017 The Authors Terms and Conditions

Fig. 1 Vascular targeted therapy. Tumors obtain oxygen and nutrients in two ways. (Left) In response to signals from the tumor, new blood vessels form on the periphery of tumors in a process called “angiogenesis” [28]. Angiogenic factors secreted by the tumor and their receptors on endothelial cells are targets for anti-angiogenic therapies. (Right) Nutrients and oxygen are provided to the inside of the tumor via established tumor vasculature. This process is inefficient because these vessels are fundamentally different from normal vessels in that they lack normal organization and structure and lack pericytes and smooth muscle support, all resulting in a poorly organized, leaky vascular network with high interstitial pressure [29,30]. Vascular endothelial cells are the target of vascular disrupting agents. Tubulin-binding agents cause microtubule depolymerization, which leads to cytoskeletal disruption [30]. Since tumor vessels lack pericyte and smooth muscle support, the endothelial cells round up and detach, compromising the integrity of the vessel and, ultimately, resulting in cessation of blood flow and tumor cell death. CA4P=combretastatin A4 phosphate. Adapted with permission from Folkman et al. [31]. Gynecologic Oncology 2017 145, 393-406DOI: (10.1016/j.ygyno.2017.01.031) Copyright © 2017 The Authors Terms and Conditions

Fig. 2 GOG-0186I. In the GOG-0186I phase II study, patients with perisistent or recurrent ovarian cancer (platinum-sensitive or platinum-resistant) were treated with CA4P+bevacizumab or bevacizumab alone. (A) Patients in the CA4P+bevacizumab arm had a significantly decreased risk of disease progression compared with those in the bevacizumab-alone arm (HR, 0.69, 90% CI, 0.47–1.00; P=0.05) [20] (B) With 61 events, there was no statistically signficant difference in risk of death between the two groups (HR, 0.85, 90% CI, 0.54–1.34) [20]. (C) The improved PFS in the CA4P+bevacizumab group was even more pronounced when the analysis was restricted to patients with measurable disease at baseline (HR=0.60, 95% CI, 0.38–0.95; P=0.027) [21], or (D) the difference in median OS was also more pronounced in these patients [21]. CA4P=combretastatin A4-phosphate; HR=hazard ratio; CI=confidence interval; PFS=progression-free survival; OS=overall survival. (Panels A and B reproduced with permission from Monk et al. [20]) Gynecologic Oncology 2017 145, 393-406DOI: (10.1016/j.ygyno.2017.01.031) Copyright © 2017 The Authors Terms and Conditions

Fig. 3 FOCUS study design [23]. aUp to four interim analyses (when 20, 40, 60, and 80 patients complete 3months of therapy). bInitiation of Part 2 driven by proof of concept of Part 1. PCC=Physician's Choice Chemotherapy (paclitaxel 80mg/m2 IV days 1, 8, 15, 22 q4w; OR paclitaxel 80mg/m2days 1, 8, 15 q4w; OR pegylated liposomal doxorubicin 40mg/m2 IV day 1 q4w); Bev=bevacizumab; CA4P=combretastatin A4 phosphate; PFS=progression-free survival; OS=overall survival; ORR=overall response rate; IV=intravenous; q4w=every 4weeks. Gynecologic Oncology 2017 145, 393-406DOI: (10.1016/j.ygyno.2017.01.031) Copyright © 2017 The Authors Terms and Conditions