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

Beth Fand Incollingo
Published Online: Friday, January 3, 2014
Dr. Robert A. Burger

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)
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
Ramucirumaba 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)
Sunitinib (Sutent) VEGFR + PDGFR Sunitinib in recurrent ovarian clear cell carcinoma (NCT01824615) 30 II
Sorafeniba (Nexavar) VEGFR, PDGFR, Raf Sorafenib plus bevacizumab in recurrent/refractory epithelial ovarian cancer, primary peritoneal cancer or fallopian tube cancer (NCT00436215) 55 II
Pazopaniba (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
Agent Target(s) Key trials Participants
(est. enrollment)
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.

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