Angiogenesis-Targeting Agents Poised to Become a Mainstay of Gynecologic Cancer Treatment

Robert A. Burger, MD

Antiangiogenic agents hold promise in gynecologic cancers, as evidenced by their single-agent activity in malignancies including ovarian cancer, recurrent endometrial cancer, and cervical cancer.

While the compounds are still considered experimental in these diseases, their single-agent activity is something that has not been demonstrated even in many of the solid tumors in which they are approved to treat metastatic disease. As a result, a number of anti-VEGF drugs are being investigated in clinical trials for these gynecologic conditions as a complement, or follow-up, to standard cytotoxic therapy.

Bevacizumab (Avastin) is the furthest along in the development process, and already has been routinely employed for years by oncologists in the treatment of ovarian cancer. Decision Resources, a company that provides analysis and data about the healthcare industry, found in a recent survey¹ that 70% of oncologists use bevacizumab in their firstline treatment of patients with ovarian cancer— even though the FDA has not approved the agent for use in the disease. Bevacizumab is approved for the treatment of metastatic colorectal cancer, non-squamous non-small cell lung cancer, glioblastoma, and metastatic renal cell carcinoma.

Robert A. Burger, MD, a professor and director of the Women’s Cancer Center at Fox Chase in Philadelphia, has been involved in phase II and III clinical trials of bevacizumab in ovarian cancer. In the trials, Burger and colleagues demonstrated that the drug confers a progression-free survival advantage to patients with the disease, both in the firstand second-line settings. The results were notable enough to result in bevacizumab’s inclusion in National Comprehensive Cancer Network (NCCN) guidelines for the treatment of ovarian cancer.

In an interview with OncologyLive, Burger discussed the reasons for the widespread off-label use of bevacizumab in this population, remaining questions about the benefits the drug offers, and potential barriers to its FDA approval as an ovarian cancer therapy (Table).

He also discussed other orally administered antiangiogenic agents that are being investigated in clinical trials for the treatment of gynecologic cancers.

“The important thing to realize is that continued research is paramount,” Burger said. “We have a lot to learn about duration and timing; whether agents need to be given in combination with cytotoxic drugs or if they would be better used alone as bridges between cytotoxic regimens; and whether we can combine or sequence multiple classes of antiangiogenic therapy. It will be very important for us to identify, ahead of time, which patients will or will not benefit from these approaches, using laboratory science.”

Table. Anti-VEGF Agents Under Development

Monoclonal antibodies

Agent

Target(s)

Key trials

Participants

(est. enrollment)

Phase

Bevacizumab (Avastin)

VEGF-A

Carboplatin, paclitaxel, and gemcitabine with or without bevacizumab after surgery in recurrent ovarian epithelial cancer, primary peritoneal cavity cancer, or fallopian tube cancer (NCT00565851)

660

III

Carboplatin and paclitaxel or oxaliplatin and capecitabine, with or without bevacizumab, as first-line therapy in newly diagnosed stage II-IV or recurrent stage I epithelial ovarian cancer/ fallopian tube cancer (NCT01081262)

332

III

Ramucirumab^a

VEGFR2

Ramucirumab monotherapy in persistent or recurrent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma (NCT00721162)

60

II

Tyrosine kinase inhibitors

Agent

Target(s)

Key trials

Participants

(est. enrollment)

Phase

Sunitinib (Sutent)

VEGFR + PDGFR

Sunitinib in recurrent ovarian clear cell carcinoma (NCT01824615)

30

II

Sorafenib^a (Nexavar)

VEGFR, PDGFR, Raf

Sorafenib plus bevacizumab in recurrent/refractory epithelial ovarian cancer, primary peritoneal cancer or fallopian tube cancer (NCT00436215)

55

II

Pazopanib^a (Votrient)

VEGFR + PDGFR

Pazopanib monotherapy after first-line chemotherapy in ovarian, fallopian tube, or primary peritoneal cancer (NCT00866697)

940

III

Cediranib (AZD2171)

VEGFR + PDGFR + FGFR

Cediranib monotherapy in recurrent/persistent ovarian epithelial, peritoneal cavity, or fallopian tube cancer (NCT00278343)

64

II

Nintedaniba (BIBF 1120)

VEGFR + PDGFR + FGFR

Nintedanib or placebo in combination with paclitaxel in first-line ovarian cancer LUME-Ovar1 (NCT01015118)

1375

III

Peptibodies

Agent

Target(s)

Key trials

Participants

(est. enrollment)

Phase

Trebananib (AMG 386)

Ang1 and Ang2

Trebananib or placebo in combination with paclitaxel and carboplatin in ovarian cancer TRINOVA-3 (NCT01493505)

2000

III

^aStudy is ongoing but not recruiting participants.

FGFR indicates fibroblast growth factor receptor; PDGFR, platelet-derived growth factor receptor; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor.

OncologyLive: What is the mechanism of action of antiangiogenic agents?

Burger: Angiogenesis is defined by the development of new microcirculation in the microenvironment of the tumor. A primary regulatory pathway for angiogenesis is controlled by the vascular endothelial growth factor [VEGF] pathway. A number of anti-VEGF agents have been evaluated in gynecologic malignancies; some target the ligand, including bevacizumab as well as VEGF Trap, also known as aflibercept, a decoy receptor that has a higher affinity for VEGF-A than bevacizumab. There are also several agents that target VEGF receptors R1, R2, and some cross talk with other angiogenic pathways, including those regulated by PDGFR and FGFR.

How, and when, did the trend toward off-label use of bevacizumab in ovarian cancer begin?

The FDA approved bevacizumab in colorectal cancer in the early 2000s, and two phase II trials of bevacizumab in ovarian cancer^2,3 were launched at about the same time. By the time those trials were mature, bevacizumab had also been approved by the FDA, on high-level evidence, in nonsmall cell lung cancer.

Results of the phase II trials were published in 2007. They were trials of bevacizumab as monotherapy, demonstrating significant activity in recurrent ovarian cancer and almost equivalent activity in platinum-resistant and platinum-sensitive recurrent disease. This was remarkable, considering that single-agent activity hadn’t been identified for even some of the metastatic disease sites in which the drug had been FDA-approved.

Based on the phase II results and the commercial availability of the drug, oncologists began using bevacizumab to treat ovarian cancer.

Phase III trials later supported the findings from the earlier studies. In late 2011, two trials of firstline bevacizumab plus chemotherapy, followed by extended therapy with bevacizumab alone (GOG- 0218 and ICON7),^4,5 were reported. These showed a significant prolongation in progression-free survival in patients with ovarian cancer.

How is bevacizumab used in patients with ovarian cancer?

Bevacizumab is used mostly in patients with recurrent epithelial ovarian cancer, and that’s where it has been recommended as a preferred agent for clinical practice in the NCCN guidelines [at a level 2B].

I would say it would be less frequently used in patients in the front line, based on lack of consensus in the NCCN. The category level in the NCCN guidelines for use of bevacizumab in the front line is 3, which means that some members of the panel felt it should be used as a preferred component of therapy and others disagreed; there was no consensus on this.

How has bevacizumab been shown to help this population of patients?

I think the most interesting thing about the use of bevacizumab is that it probably is agnostic to prior types of therapy. The benefit reflects the pharmacology of bevacizumab and similar antiangiogenic agents, in which it is common to observe evidence of local progression of measurable lesions, without evidence of additional metastatic sites while the tumor is essentially incarcerated. Yet, upon discontinuation of these agents, it is common to see rapid disease progression including other sites, indicating that the brake on angiogenesis had still been important despite evidence of early progression.

In the initial management of advanced ovarian cancer, we don’t have a good idea of which patients stand to benefit long term, and we’re searching for an answer in the lab. Outside that arena, we’ve at least identified some hypothesis-generating factors, including a subset of patients with suboptimally debulked stage 3 or 4 disease. Such patients represented one-third of the population in the ICON7 trial, and a posthoc analysis demonstrated a significant overall survival advantage, which would lead one to believe that this may be the population to concentrate on. Maybe patients with more aggressive disease have more highly angiogenic tumors and are more likely to benefit. But this has yet to be confirmed.

What is the drug’s safety profile?

The majority of patients treated with bevacizumab as a single agent tolerate therapy very well without any noticeable side effects, although some can develop muscular and joint manifestations, especially with prolonged treatment. In the phase III trials, the rate of clinically significant hypertension requiring medical management was in the range of 20% to 25%, so obviously that has to be monitored. What’s been most concerning is a rate of about 2% to 5% of potentially life-threatening complications, including gastrointestinal perforation and arterial-vascular complications such as stroke and heart attack. There are well-defined risk factors for arterial-vascular complications, but not so for gastrointestinal perforation. So when you look at this from a risk-benefit standpoint, you have to weigh the potential for very serious complications, which fortunately occur at low frequency, against potential benefit.

How long should patients with ovarian cancer stay on bevacizumab?

There have been four phase III trials of bevacizumab in ovarian cancer. The two front-line trials were designed with a predefined maximum number of treatment cycles beyond chemotherapy, whereas in the two second-line trials, the OCEANS trial⁶ and the AURELIA trial,⁷ maintenance therapy was continued until disease progression. The major difference in the results of those trials was about a 50% prolongation of progression-free survival when bevacizumab was continued until disease progression, whereas when treatment was capped at a certain time point, results were less substantial.

No one really knows what the right answer is, but based on weighing all the evidence and understanding the biology of drugs like bevacizumab, it is rational to continue the drug until at least disease progression if it’s going to have any lasting benefit. Some would argue that it should be continued even beyond disease progression, which has yet to be proven in ovarian cancer but has been demonstrated in metastatic colorectal cancer.

Has bevacizumab been submitted for FDA approval in the treatment of ovarian cancer?

I have not heard of any effort to submit an application for FDA approval of bevacizumab in treating patients with ovarian cancer. The drug has received regulatory approval for use in Europe, because the European regulatory agencies consider progression-free survival a valid primary outcome measure in clinical trials on which to weigh decisions about the approval of drugs.

That is rare in the United States because, when you’re just looking at progression-free survival or response rate as an outcome measure, it’s difficult to know in the long run how much clinical benefit was really there. Median overall survival for patients with stage 3 and 4 ovarian cancer is now approximately four years. Most patients receive a multitude of regimens that individually contribute to that overall survival. To prove that a front-line or a second-line regimen that shows a significant prolongation in progression-free survival contributes to that overall survival benefit is statistically very challenging, and it’s becoming less possible.

Another challenge is that, because bevacizumab is used quite widely in the United States in the management of patients with recurrent ovarian cancer, it is covered by health insurance for that purpose. Submitting an application to the FDA could pose a risk to the patients who would ordinarily be covered, if that application failed. On the other hand, without FDA approval, even though this agent is used in a widespread fashion off-label, it still is subject to insurance discrimination. There are some pockets of this country where it’s not covered at all, and that doesn’t make it easy for patients who could stand to benefit.

Has there been any effort, outside clinical trials, to monitor bevacizumab’s benefit to patients with ovarian cancer?

That would normally be done as postapproval follow- ups, like phase IV studies. It’s not being done to my knowledge, and I don’t think that there’s a registry, the way there has been for colorectal cancer.

In the absence of approval, there have been basically just historical cohort studies that have been published, which are consistent with what has been seen in the controlled trials, and there are also some follow-up studies that have been conducted that are generating more prospective data. So there’s a trial being conducted in Europe where bevacizumab is being used in front line for a much longer time period than was used in the two front-line phase III trials.

What should community oncologists know about using bevacizumab in the treatment of ovarian cancer?

They should strongly adhere to guidelines, especially related to safety, and they should understand the patient populations that demonstrated a benefit in the trials, and not stray from the exclusion criteria used in those trials. One of the key exclusion criteria used in the phase III trials was absence of evidence of intestinal obstruction, which is perhaps the greatest risk factor for gastrointestinal perforation. One of the reasons that the rates of GI perforation were unexpectedly low in the four phase III trials is likely the exclusion of patients who were at high risk of developing bowel perforations.

In monitoring patients, oncologists should also follow guidelines utilized in the trials, so that they can more readily detect any signs of potential major complications before they become life threatening.

Are there any other angiogenesis inhibitors that hold promise for the treatment of gynecologic cancers?

I think that we’ve seen a lot of consistency among the different classes of antiangiogenic agents. I’m not sure how well they’ll play together in the same sandbox, or whether they’ll be used sequentially or as alternatives. But we’re seeing very similar data for the multitargeted tyrosine kinase inhibitors that interact with VEGF receptors, not VEGF itself, and some other important angiogenic growth factor receptors.

The most compelling data were presented at ESMO with cediranib in the ICON6 trial, showing an overall survival advantage in patients with platinum-sensitive recurrent disease. Of course, one of the reasons this agent may have shown an overall survival advantage is a difference in the availability of postprogression therapies known to be active in managing recurrent disease.

A number of other phase III trials are being conducted. A trial of nintedanib is evaluating the drug versus placebo taken for 120 weeks by patients with newly diagnosed disease after the completion of standard chemotherapy. AGO-OVAR16 was the only trial to investigate an antiangiogenesis drug purely in the maintenance setting; patients with locally advanced disease took pazopanib or placebo for 24 months, with a significantly prolonged progression-free survival in the experimental group. Unlike for pure VEGF antagonists, use of angiogenic growth factor receptor tyrosine kinase inhibitors is commonly associated with more prominent adverse symptoms, mostly upper- and lower-gastrointestinal in origin.

Other agents targeting VEGF or its receptors either previously or currently under investigation include VEGF Trap, ramucirumab, sunitinib, sorafenib, motesanib, brivanib, and vandetanib.

Another important parallel pathway of angiogenesis involves angiopoietins and their receptors. The drug AMG-386, or trebananib, is an angiopoietin- targeted agent that has demonstrated significant prolongation of progression-free survival in a phase III trial of patients with platinum-resistant disease when used in combination with weekly paclitaxel. This agent is now undergoing a phase III trial (TRINOVA-3) in the front-line setting.

My hope is that one or more of these agents will eventually become FDA-approved, because I think this is an important general modality in the treatment of ovarian cancer.

References

1. Decision Resources. The majority of surveyed oncologists prescribe Avastin off-label to their ovarian cancer patients; however approximately half encounter access and reimbursement hurdles [press release]. Decision Resources website. www.decisionresources.com Published August 14, 2013. Accessed November 4, 2013.
2. Burger RA, Sill MW, Monk BJ, Greer BE, Sorosky JI. Phase II trial of bevacizumab in persistent or recurrent epithelial ovarian cancer or primary peritoneal cancer: A Gynecologic Oncology Group study. J Clin Oncol. 2007;25(33):5165- 5171.
3. Cannistra SA, Matulonis UA, Penson RT, et al. Phase II study of bevacizumab in patients with platinum-resistant ovarian cancer or peritoneal serous cancer. J Clin Oncol. 2007;25(33):5180-5186.
4. Burger RA, Brady MF, Bookman MA, et al. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med. 2011;365(26):2473-2483.
5. Perren TJ, Swart AM, Pfisterer J, et al. A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med. 2011;365(26):2484-2496.
6. Aghajanian C, Blank SV, Goff BA, et al. OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer [published online April 23, 2012]. J Clin Oncol. 2012;30(17):2039-2045.
7. Pujade-Lauraine E, Hilpert F, Weber B, et al. AURELIA: A randomized phase III trial evaluating bevacizumab plus chemotherapy for platinum-resistant recurrent ovarian cancer. J Clin Oncol. 2012;30(suppl; abstr LBA5002).