Elsevier

Gynecologic Oncology

Volume 132, Issue 2, February 2014, Pages 496-505
Gynecologic Oncology

Review
Incorporation of anti-angiogenesis therapy in the management of advanced ovarian carcinoma—Mechanistics, review of phase III randomized clinical trials, and regulatory implications

https://doi.org/10.1016/j.ygyno.2013.11.029Get rights and content

Highlights

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    To date, eight phase 3 randomized trials using anti-angiogenic agents have shown positive results in ovarian cancer.

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    Anti-angiogenesis agents active in ovarian carcinoma include monoclonal antibodies as well as drugs that inhibit receptor tyrosine kinases.

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    Both vascular endothelial growth factor (VEGF)-dependent and non-VEGF-dependent angiogenic pathways may be targeted in ovarian cancer.

Abstract

Despite survival gains achieved nearly two decades ago with combination platinum- and taxane-based intravenous chemotherapy, overall survival curves have remained relatively unchanged during the 21st century using newer cytotoxic agents. Although combined intravenous–intraperitoneal (IV–IP) chemotherapy is promising, tolerability remains a significant issue. An emphasis has been placed on exploring dose dense schedules and targeted agents. Vascular endothelial growth factor (VEGF) has emerged as an important therapeutic target in several solid tumors including ovarian carcinoma. The monoclonal antibody, bevacizumab, binds VEGF, thus preventing activation of the VEGF receptor (VEGFR) leading to inhibition of tumor angiogenesis. To date eight phase 3 randomized controlled trials incorporating anti-angiogenesis therapy in the treatment of newly diagnosed and recurrent ovarian carcinoma have met their primary endpoints. Four of these trials included bevacizumab and were reported from 2010 to 2012. During 2013, the other four studies were reported, each studying one of the following novel anti-angiogenesis agents: pazopanib, cediranib, trebananib, and nintedanib. Importantly, none of these drugs have been approved by the United States Food and Drug Administration (US FDA) for the treatment of ovarian cancer. The purpose of this review will be to highlight both VEGF-dependent and non-VEGF dependent angiogenic pathways in ovarian cancer and discuss the phase 3 experiences and regulatory implications of targeting the tumor microenviroment with anti-angiogenesis therapy.

Introduction

Epithelial ovarian cancer (EOC) accounts for 25% of all malignancies affecting the female genital tract, and is the most lethal gynecologic malignancy. In the United States alone, a projected 22,240 new cases will be diagnosed in 2013, with 14,030 deaths [1]. Worldwide, there are 225,000 new cases diagnosed annually and 140,000 deaths. Advanced stage EOC is managed with surgical cytoreduction, followed by platinum- and taxane-based combination chemotherapy on a 21-day schedule [2]. In some centers, chemotherapy is administered via a combined intraperitoneal–intravenous (IV–IP) route. Over the past 12 months, a weekly, dose-dense schedule for paclitaxel has become increasingly popular. Unfortunately, the greatest hurdle is acquired drug resistance leading to recurrent disease through selection of platinum-resistant clones [3]. For patients with platinum-refractory and platinum-resistant tumors, available cytotoxic options are associated with limited responses and clinically insignificant gains in survival.

Importantly, platinum-resistance may be a surrogate concept reflecting chemotherapy-resistance. Even for those patients with potentially platinum-sensitive disease (relapse 6–12 months following completion of therapy) and those with ‘very’ platinum-sensitive tumors (relapse beyond 12 months), retreatment with platinum is unlikely to result in a durable remission. The development of tolerable and active non-cytotoxic therapies has emerged as a leading priority in ovarian cancer (OC) pharmacologic research programs. Molecular (or biologic) therapies may target specific biomarkers in an enriched population, or those non-specific, ubiquitous, processes found in the cancer microenvironment. Tumor neovascularization and angiogenesis constitute cardinal processes amenable to pharmacologic perturbation.

There are now 8 positive phase 3 randomized clinical trials in EOC involving five unique anti-angiogenesis agents. In this review we discuss the development of anti-angiogenesis therapy and consider the oncologic and regulatory implications of the phase 3 experiences in detail. It should be recognized that despite the remarkable progress that has been gained in this field, to date no anti-angiogenesis drugs approved by the US FDA lists EOC as an indication on the label.

Section snippets

Tumor microenvironment

Platinum resistance is well defined and relies on altered drug metabolism, repair of sub-lethal DNA damage, and inhibition of apoptosis [4], [5]. The concept of platinum-sensitive recurrence catalyzed interest in alternate cellular interactions explaining sensitivity with platinum re-challenge, with the tumor microenvironment emerging as an active area of investigation.

Metastatic intra-peritoneal dissemination of OC relies on the ability of floating cells to survive, proliferate and disseminate

Angiogenesis and discovery of VEGF

In 1939, Ide and Warren were the first to suggest that tumors release specific factors capable of stimulating the growth of blood vessels [13]. In 1971, the American cellular biologist and pediatric surgeon, Moses Judah Folkman (1933–2008, Fig. 1), published his hypothesis in the New England Journal of Medicine that tumor growth is angiogenesis dependent and that inhibition of angiogenesis could be therapeutic [14]. This landmark manuscript also introduced the term anti-angiogenesis to mean the

Targeting angiogenesis pathways

Currently, the VEGF pathway is the most widely studied angiogenic pathway in carcinogenesis, and is comprised of VEGF-A (also known as VEGF) and the two receptor tyrosine kinases, VEGFR1 (Flt-1) and VEGFR2 (Flk-1) (Fig. 2) [19]. Principally, the angiogenic and permeability properties of VEGF are mediated by VEGFR2 binding [19]. Strategies to block the VEGF pathway include ligand binding and sequestration as well as inhibition of the intracytoplasmic tyrosine kinase domain.

The angiopoietin (Ang)

Phase 2 studies

The tumor vasculature in EOC is highly disorganized and leaky, with relatively poor blood flow, perpetuating tumor hypoxia, growth factor expression, and potentially interfering with delivery of cytotoxic chemotherapy [41]. Not surprisingly, the first efforts to study anti-angiogenesis therapy in EOC occurred in populations with recurrent disease. Bevacizumab has been the most studied anti-angiogenic agent. The immediate mechanism of action of bevacizumab is to bind and sequester VEGF,

Phase 3 randomized clinical trials 1–4: GOG 218, ICON7, OCEANS, AURELIA (bevacizumab)

Based on the phase 2 experiences of Burger et al. (on behalf of the GOG), Cannistra et al., and Garcia et al., in which response rates (RR) exceeding 20% and 6-month PFS of 40–50% were documented (Table 1), bevacizumab (Avastin) was the first anti-angiogenesis agent to be advanced into the phase 3 randomized trial design for advanced EOC. To date, four pivotal trials have been completed, two in the primary setting and two for patients with recurrent disease (Table 2) [57], [58], [59], [60], [61]

Phase 3 randomized clinical trial 5: AGO-OVAR16 (pazopanib)

Pazopanib (Votrient), an oral tyrosine kinase inhibitor, exhibits its anti-angiogenic properties via inhibition of VEGFR, PDGFR and c-Kit signaling. Encouraged by the phase 2 results (Table 1), the Arbeitsgemeinschaft Gynaekologische Onkologie (AGO) launched a phase 3 randomized trial of maintenance daily pazopanib (800 mg) vs. placebo for up to two years following primary platinum-based combination chemotherapy for advanced disease (AGO-OVAR16, aka POIZE). At the 2013 Annual Meeting of the

Phase 3 randomized clinical trial 6: ICON-6 (cediranib)

Cediranib (Recentin) is a potent oral inhibitor of all 3 VEGFR tyrosine kinases (VEGFR1, 2, 3), with 800–5000 fold selectivity for the VEGFR2. Prior phase 2 studies indicated single agent activity in patients with recurrent EOC (Table 1), catalyzing development and completion of ICON 6, a randomized, double blind, 3-arm phase 3 trial of cediranib in patients with platinum sensitive recurrent ovarian cancer [49], [64] (Table 2). Data, presented at the 2013 ESMO annual meeting, indicated a

Phase 3 randomized clinical trial 7: TRINOVA-1 (trebananib)

Trebananib (AMG 386) is an anti-angiogenic peptibody, fusing an anti-angiogenic protein to the Fc region of an antibody. This peptibody inhibits Ang1/Ang2 binding to the Tie2 receptor, resulting in inhibition of a parallel angiogenic pathway [31]. Given the promising randomized phase II data by Karlan et al. using trebananib in recurrent disease (Table 1), the phase 3 randomized, double blind trial, TRINOVA-1 (NCT01204749), was developed comparing weekly paclitaxel in combination with

Phase 3 randomized clinical trial 8: AGO-OVAR12/LUME-Ovar 1 (nintedanib)

Nintedanib (Vargatef) is an oral trifunctional angiokinase inhibitor with activity against VEGFR, fibroblast growth factor receptor (FGFR), and platelet derived growth factor receptor (PDGFR). In the AGO-OVAR12/LUME-Ovar 1 phase 3 randomized placebo-controlled trial, postoperative patients with newly diagnosed FIGO stage IIB–IV OC were randomized 2:1 to carboplatin and paclitaxel with and without nintedanib 200 mg twice daily [66]. Monotherapy with nintedanib/placebo was scheduled for up to 120 

Cost-effectiveness

In our current health care climate, efforts have been directed to control costs while improving patient outcomes. As part of the American Recovery and Reinvestment Act of 2009, the government allocated $1.1 billion toward comparative effectiveness research, within which falls cost-effectiveness studies. In 2011, Cohn et al. conducted a cost-effectiveness analysis of bevacizumab in the treatment of primary ovarian cancer using a decision analysis program [69]. In the paper the authors determined

Regulatory implications: 8 positive trials, 5 novel agents, and no approved indication

Granted that 4 of the studies were reported in 2013, with 4 other positive pivotal trials encompassing the disease spectrum from newly diagnosed to platinum sensitive and platinum resistant recurrent disease, it is remarkable that we do not have a US FDA indication for anti-angiogenesis therapy in ovarian cancer. Given the high incidence of acquired drug resistance in EOC and lack of effective therapies for recurrent disease, one approach to overcome barriers would be to cite the Orphan Drug

Conflict of interest statement

The authors have no potential conflicts of interest to disclose. Our institution (University of California, Irvine) receives a grant from the Gynecologic Oncology Group to conduct GOG clinical trials and we have enrolled patients onto GOG 218 (discussed in this paper) as well as the current GOG 3001 trial involving trebananib (drug discussed in this paper).

References (70)

  • A. Gonzalez-Martin et al.

    Efficacy and safety results from OCTAVIA, a single-arm phase II study evaluating front-line bevacizumab, carboplatin and weekly paclitaxel for ovarian cancer

    Eur J Cancer

    (2013)
  • W.H. Gotlieb et al.

    Intravenous aflibercept for treatment of recurrent symptomatic malignant ascites in patients with advanced ovarian cancer: a phase 2, randomised, double-blind, placebo-controlled study

    Lancet Oncol

    (2012)
  • N. Colombo et al.

    A phase II study of aflibercept in patients with advanced epithelial ovarian cancer and symptomatic malignant ascites

    Gynecol Oncol

    (2012)
  • M. Friedlander et al.

    A phase II, open-label study evaluating pazopanib in patients with recurrent ovarian cancer

    Gynecol Oncol

    (2010)
  • R. Siegel et al.

    Cancer statistics, 2013

    CA Cancer J Clin

    (2013)
  • M. Bookman

    Trials with impact on clinical management: first line

    Int J Gynecol Cancer

    (2009)
  • J. Chien et al.

    Platinum-sensitive recurrence in ovarian cancer: the role of tumor microenvironment

    Front Oncol

    (2013)
  • L. Galluzzi et al.

    Molecular mechanisms of cisplatin resistance

    Oncogene

    (2012)
  • N. Said et al.

    Normalization of the ovarian cancer microenvironment by SPARC

    Mol Cancer Res

    (2007)
  • J. Kassis et al.

    Tumor microenvironment: what can effusions teach us?

    Diagn Cytopathol

    (2005)
  • D.A. Leinster et al.

    The peritoneal tumour microenvironment of high-grade serous ovarian cancer

    J Pathol

    (2012)
  • R.N. Eskander et al.

    Bevacizumab in the treatment of ovarian cancer

    Biologics

    (2011)
  • J. Folkman

    Tumor angiogenesis: therapeutic implications

    N Engl J Med

    (1971)
  • A.G.B.N. Ide et al.

    Vascularization of the Brown–Pearce rabbit epithelioma transplant as seen in the transparent ear chamber

    Am J Roentgenol

    (1939)
  • J.M.E. Folkman et al.

    Isolation of a tumor factor responsible for angiogenesis

    J Exp Med

    (1971)
  • N. Ferrara

    Molecular and biological properties of vascular endothelial growth factor

    J Mol Med (Berl)

    (1999)
  • N. Ferrara

    Vascular endothelial growth factor: molecular and biological aspects

    Curr Top Microbiol Immunol

    (1999)
  • N. Ferrara

    VEGF as a therapeutic target in cancer

    Oncology

    (2005)
  • N. Ferrara et al.

    Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene

    Nature

    (1996)
  • K.J. Kim et al.

    Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo

    Nature

    (1993)
  • P. Borgstrom et al.

    Neutralizing anti-vascular endothelial growth factor antibody completely inhibits angiogenesis and growth of human prostate carcinoma micro tumors in vivo

    Prostate

    (1998)
  • P. Borgstrom et al.

    Importance of VEGF for breast cancer angiogenesis in vivo: implications from intravital microscopy of combination treatments with an anti-VEGF neutralizing monoclonal antibody and doxorubicin

    Anticancer Res

    (1999)
  • P. Borgstrom et al.

    Complete inhibition of angiogenesis and growth of microtumors by anti-vascular endothelial growth factor neutralizing antibody: novel concepts of angiostatic therapy from intravital videomicroscopy

    Cancer Res

    (1996)
  • R.S. Warren et al.

    Regulation by vascular endothelial growth factor of human colon cancer tumorigenesis in a mouse model of experimental liver metastasis

    J Clin Invest

    (1995)
  • K. Margolin et al.

    Phase Ib trial of intravenous recombinant humanized monoclonal antibody to vascular endothelial growth factor in combination with chemotherapy in patients with advanced cancer: pharmacologic and long-term safety data

    J Clin Oncol

    (2001)

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