Anti-angiogenesis Targeting Agents in Recurrent Ovarian Cancer: Now There Are Two?
Anti-angiogenesis Targeting Agents in Recurrent Ovarian Cancer: Now There Are Two?
Abstract & Commentary
By Robert L. Coleman, MD, Professor, University of Texas; M.D. Anderson Cancer Center, Houston, is Associate Editor for OB/GYN Clinical Alert.
Dr. Coleman is a consultant to GlaxoSmithKline, Eli Lilly Co., Abbott Laboratories, Sanofi-Aventis, and Pfizer; and serves on the speakers bureaus for GlaxoSmithKline, Eli Lilly Co., and OrthoBiotech.
Synopsis: While true efficacy was not demonstrated, cediranib warrants further study in combination with chemotherapy due to its demonstrated response rate, shorter half-life, and toxicity profile.
Source: Matulonis U, et al. Cediranib, an oral inhibitor of vascular endothelial growth factor receptor kinases, is an active drug in recurrent epithelial ovarian, fallopian tube, and peritoneal cancer. J Clin Oncol 2009;27:5601-5606.
Angiogenesis is an important process, which sustains ovarian cancer growth. Cediranib, a potent, oral tyrosine kinase inhibitor (TKI) of vascular endothelial growth factor receptor (VEGFR) 1, 2, and 3, and c-kit, has shown promise in other solid tumors, including non-small cell lung cancer. The current study aimed to define the response characteristics, survival, and toxicity of cediranib administered as a single agent to women with recurrent ovarian, fallopian tube, and primary peritoneal cancer. Patients eligible for this phase II open-label study included those with measurable disease and up to two prior courses of chemotherapy, although this was a modification of initial eligibility limited to elevated CA-125 and no measurable disease (n = 10 patients). Patients with prior exposure to vascular endothelial growth factor (VEGF)-targeted agents and those with uncontrolled hypertension or proteinuria were excluded from the trial. The primary endpoint was response (RECIST and GCIG criteria) and was conducted in a two-stage process with decision rules for platinum-sensitive (treatment-free interval > 6 months) and platinum-resistant disease cohorts. In all, 46 patients were enrolled. The overall response rate was 17%, with a median progression-free survival of 5.2 months. At 6 months, 17% of patients were progression-free. Mean overall survival was 16.3 months. Eleven patients were removed from the study due to toxicity without assessment of response. This prompted a dose reduction of 33% for subsequent enrollees. Grade 3 toxicities observed were: hypertension (46%), fatigue (24%), and diarrhea (13%). Grade 2 hypothyroidism was seen in 43% of patients and one patient had a CNS hemorrhage. There were no bowel perforations. Based on the response characteristics, cediranib has significant activity in ovarian cancer and merits the planned investigation in combination with chemotherapy.
Commentary
VEGF and VEGFRs are important to the growth and proliferation of many solid tumors including ovarian cancer. The first compound to demonstrate substantial single-agent activity in this disease was bevacizumab, and this observation has prompted an explosion of clinical trials of other VEGF/VEGFR-targeted agents, both alone and in combination with chemotherapy. To date, ligand (VEGF)-targeted strategies have produced higher response rates than oral TKIs to VEGFRs, but the shorter half-life of these agents and their oral administration have distinct clinical advantages. The current report brings a new agent to the clinical domain, which is a viable competitor to the VEGF-ligand-based strategies, such as bevacizumab and aflibercept. It is impressive that objective responses were observed; however, true efficacy should also consider the propensity to delay progression. In this regard, the agent appears on par with bevacizumab. The toxicity portfolio for cediranib is less well developed but appears to share a spectrum observed with other anti-VEGF agents, with the exception of hypothyroidism and bowel perforation. Nevertheless, the clinical activity of cediranib is sufficient to warrant further investigation. This is currently underway in the European Union in a phase III study of paclitaxel and carboplatin, with and without cediranib, and followed by maintenance cediranib or placebo (ICON-6).
Additional Reading
- Burger RA, et al. 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;25:5165-5171.
- Cannistra SA, et al. Phase II study of bevacizumab in patients with platinum-resistant ovarian cancer or peritoneal serous cancer. J Clin Oncol 2007;25:5180-5186.
- Hennessy BT, et al. Ovarian cancer. Lancet 2009;374:1371-1382.
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