BJ Rimel, MD, discuss the current literature surrounding antiangiogenesis agents in ovarian cancer.
BJ Rimel, MD
Antiangiogenesis agents target tumor vascular biology which is a known driving force in ovarian cancer. Many of these agents have been studied in ovarian cancer with some important successes. Specifically, bevacizumab, cediranib, pazopanib, and trebananib have shown positive effects either alone or in combination with other drugs.
The timing and length of use of these agents is still being studied as there have been some benefits seen in upfront, maintenance and recurrent settings. Toxicity remains an issue with this class of agents and physicians should carefully select patients for these drugs. This article will discuss the current literature surrounding antiangiogenesis agents in ovarian cancer.
Ovarian cancer remains the most lethal gynecologic malignancy in the United States.1 Despite advances in the delivery of platinum- and taxane-based chemotherapy such as intraperitoneal cisplatin and dose-dense paclitaxel, overall survival (OS) has remained largely constant for the last 10 years. Even the addition of other cytotoxic agents in combination or in sequence has not improved outcomes.2
Basic science accomplishments have led to the elucidation of some of the mechanisms of cancer promotion in ovarian cancer. Angiogenesis is now known to be a major biologic pathway in ovarian cancer progression and metastasis but remains complex with multiple actors, including vascular endothelial growth factor and its three receptors (VEGFR 1, 2, and 3), platelet-derived growth factor receptor, the angiopoietin pathway, and integrins that stabilize tumor blood vessels.3-5 Specifically, high levels of vascular endothelial growth factor are noted in ovarian cancer.6 In addition, the angiopoietin pathway is also involved in angiogenesis in ovarian cancer.7
Drugs developed to interfere with these pathways have also been studied in ovarian cancer. Recently, the first biologic therapy in ovarian cancer, bevacizumab (Avastin), was approved for use by the FDA.8 Several other antiangiogenesis agents have been studied in ovarian cancer, with varying success. This review will focus on the study of antiangiogenesis agents in ovarian cancer with special emphasis on those drugs that have shown benefit.
Aflibercept, Ramucirumab, Volociximab—Not Ready for Primetime
Aflibercept works as a VEGF-trap, removing circulating VEGF. This drug was an obvious choice for study in recurrent ovarian cancer with ascites. Colombo et al demonstrated a repeat paracentesis response rate of 62%.9
However, a randomized phase 2 study in platinum-resistant ovarian cancer did not meet its primary endpoint for response with only 4.6% of patients responding.10 Similarly, a phase 2 study of ramucirumab, an anti-VEGFR2 antibody, had a best response rate of only 5%.11 Attempts to use anti-integrin antibodies to disrupt ovarian cancer angiogenesis have also been lackluster.
A phase 2 study of the anti-integrin α5β1 antibody, volociximab, in platinum-resistant ovarian cancer involved 16 patients who demonstrated no responses.12 Unfortunately, none of these 3 agents indicated significant activity in ovarian cancer.
Bevacizumab—Up Front, Maintenance, or Recurrence?
The most studied antiangiogenesis agent in ovarian cancer is bevacizumab. Bevacizumab is a monoclonal antibody to VEGF and acts to bind and sequester the ligand. This therapy has been studied in the upfront and recurrent settings, both alone and in combination with cytotoxic therapy. It has recently received approval from the Food and Drug Administration (FDA) for use in recurrent ovarian cancer.
There are 2 large phase 3 studies of bevacizumab in combination with platinum-taxane therapy in the upfront setting, GOG 218 and ICON 7.13,14 Both included women at high risk for recurrence and both included a maintenance arm that extended the bevacizumab treatments past the completion of the chemotherapy.
However, there were some significant differences in these studies. ICON 7 included women with stage IC ovarian cancer as well as advanced stage. The bevacizumab dose was 7.5mg/kg every 21 days. GOG 218 included patients in stage 3 or 4, included a placebo arm, and perhaps most strikingly, twice the amount of bevacizumab at 15mg/kg. Both studies demonstrated improved progression-free survival (PFS) but not improved OS, with an increase of 2.3 months seen in ICON 7 with bevacizumab and 3.8 months in GOG 218.
Bevacizumab has also been studied in combination with chemotherapy in platinum-sensitive ovarian cancer. The OCEANS study was a large double-blinded phase 3 study which randomized 484 platinum-sensitive ovarian cancer patients to either gemcitabine/carboplatin/bevacizumab followed by maintenance bevacizumab or gemcitabine/carboplatin/placebo followed by maintenance placebo.15 Both groups were given 6 cycles of the cytotoxic therapy and continued on maintenance treatment until progression. The study demonstrated a 4-month improvement in PFS with addition of bevacizumab but no improvement in OS.
The AURELIA study evaluated bevacizumab in platinum-resistant ovarian cancer, a group with limited responses to traditional cytotoxic chemotherapy.16 In this randomized open label phase 3 study, women with platinum-resistant ovarian cancer were randomized to the investigators’ choice of single agent non-platinum chemotherapy combined with bevacizumab versus chemotherapy alone. Options for chemotherapy were pre-specified and included weekly paclitaxel, liposomal doxorubicin or topotecan. Median PFS was improved by 3.3 months in the group who received bevacizumab. There was no significant difference in OS. It is important to note, however, that a third of patients treated with chemotherapy alone went on to receive single-agent bevacizumab at the time of progression.
Trebananib (AMG 386) is a peptibody that targets the angiopoietin pathway.7 It interferes with the binding of both angiopoietin-1 and -2 and the Tie-2 receptor. A phase 2 study of trebananib at either 10mg or 3mg with weekly paclitaxel versus weekly paclitaxel alone demonstrated improved PFS in both the experimental arms of 7.2 and 5.7 months versus 4.6 months.17
Phase 3 studies of AMG 386 in combination with weekly paclitaxel have been similarly successful with increases of PFS in the AMG 386 group of 7.2 months compared with 5.4 months.18 Interim analysis of OS did not show statistically significant benefit (P = .19) but trended towards AMG 386 with median OS of 19.0 months in AMG 386 versus 17.3 months in placebo.
Pazopanib and Cediranib—Oral Drugs on the Horizon
Two oral tyrosine-kinase inhibitors (TKIs) that inhibit the angiogenesis pathways by disabling vascular endothelial growth factor (1, 2, and 3), platelet-derived growth factor receptor and fibroblast growth factor receptor are pazopanib and cediranib.19,20 Phase 2 studies of pazopanib were widely promising, leading to phase 3 trials in ovarian cancer.21
DuBois et al published the largest study of pazopanib in ovarian cancer to date.22 This study included 940 women who had a complete response to treatment after surgery and at least 5 cycles of platinum/taxane chemotherapy. Participants were then randomized to receive pazopanib or placebo for up to 2 years. The study demonstrated a remarkable improvement in median PFS of 5.6 months with maintenance pazopanib. Unfortunately, there was no difference in OS and about a third of women on the pazopanib arm discontinued therapy due to side effects. This discontinuation was even more pronounced in Asian women. Phase 2 studies of pazopanib in combination with cytotoxic chemotherapy are still ongoing.21
Cediranib has also had promising results in phase 2 studies with a clinical benefit rate of 30% in recurrent ovarian cancer patients without prior VEGF/VEGFR therapy.20 As a single agent there was a 17% partial response (PR) in this group, comparable with other therapies in recurrence. However, possibly due to its improved side effect profile, it has had more success.
A large phase 3 study of women with platinum-sensitive ovarian cancer (ICON 6) compared cediranib in combination with platinum-based chemotherapy and as a maintenance versus standard treatment with platinum-based chemotherapy alone.23 This placebo-controlled study randomized women 2:3:3 to placebo, cediranib at 20 mg every day during chemotherapy followed by placebo, to cediranib followed by maintenance cediranib for 18 months. The results were presented at the National Cancer Research Institute (NCRI) conference in abstract form and demonstrated improved PFS of 2 months and significantly improved OS as well by 2.7 months.
Cediranib has also been used recently in combination with other biologics to remarkable effect.24 Liu et al published the results of a phase 2 study comparing single agent olaparib versus olaparib/cediranib in women with platinum-sensitive ovarian cancer. Participants were stratified for BRCA mutation status. The response rate in this study was a remarkable 79.6% in the combination arm.
Use in the Clinic
Clinical use of these antiangiogenic agents in ovarian cancer requires an understanding of the toxicities that each present. Hypertension and proteinuria are fairly ubiquitous in this class of agents, with the exception of AMG 386, which seems to have edema as its main side effect.5,25,26 The vast majority of hypertension can be managed with antihypertensives. However, there are significantly more feared toxicities such as gastrointestinal perforation, fistula, and arterial thromboembolism. The scope and individual management of each is beyond the scope of this review, but clinicians should be careful in their counseling and selection of patients for these therapies.
In reviewing these agents several themes emerge. First, there is clearly an improved response to therapy and improved PFS in most studies, of about 3 to 4 months. Second, OS is not yet demonstrated in studies with bevacizumab, but there was an interesting trend in the AURELIA study. These results were strong and this study led to bevacizumab being approved by the FDA for use in combination with chemotherapy in platinum-resistant ovarian cancer.
It should be noted that bevacizumab is listed in the National Comprehensive Cancer Network (NCCN) guidelines as an option for upfront therapy in addition to recurrence. Cediranib in combination with chemotherapy and followed with maintenance therapy improved OS by 2.7 months in the ICON 6 study, making it the only antiangiogenesis agent as yet to improve this measure. However, this agent is still not available outside of a clinical trial. Third, these drugs are expensive and cost-effective analysis thus far has suggested that lower-dose regimens such as the bevacizumab dose used in ICON 7 may be better choices.27,28
But cost effectiveness in the setting of long-term maintenance use, such as the pazopanib study investigating up to 24 months of therapy has yet to be done. Lastly, it appears that further study is needed to determine the best time to use antiangiogenesis agents: at primary treatment, at recurrence, with another biologic agent, or as maintenance therapy, or maybe, just maybe, at all of these times.
About the author:
BJ Rimel, MD, is an associate director for Gynecologic Oncology Clinical Trials, Division of Gynecologic Oncology, Women’s Cancer Program, Cedars-Sinai Medical Center.
Address correspondence to: BJ Rimel, MD, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048, phone: 310-â€¨423-5800. e-mail: firstname.lastname@example.org.