The safety and efficacy of bevacizumab added to pegylated liposomal doxorubicin and carboplatin was investigated in a Phase 2 trial in women with platinum-sensitive, recurrent ovarian cancer.5 The objective response rate was 78.3% (CI, 63.6–89.1). Of the 54 patients enrolled, 15 had serious adverse events (AE): 13 drug-related, including gastrointestinal, infectious, injury/procedural, respiratory, and vascular complications. Therapy was stopped by 39 patients due to an AE (22 patients), choice/violation (14 patients), and disease progression (3 patients).
The VEGF pathway was targeted at multiple points in a Phase 2 study that combined bevacizumab with sorafenib, which inhibits VEGFR2 and Raf kinase.6 Patients with epithelial ovarian cancer who were naïve to treatment with bevacizumab received sorafenib 200mg twice daily with bevacizumab 5mg/kg every two weeks on a 28-day cycle. Partial responses were achieved by 6 of 25 patients, and these responses lasted a median of 15.5 months (mean 15, range 5–22). Stabilized disease occurred in 16 of 25 patients (median 5 months; mean 6.8). Toxicities of grade 3 or 4 included hypertension (47%), thrombosis (13%), elevated liver enzymes (7%), anal fissure (3%), headache (3%), and hand-foot syndrome (3%).
Other Antiangiogenesis Agents
Results of a Phase 2 discontinuation trial of the antiangiogenesis agent cabozantinib were reported in 2011.7 Cabozantinib simultaneously targets both VEGFR2 and MET, which is an oncogene that possesses tyrosine kinase activity and is over-expressed in advanced ovarian cancer. Women with recurrent, progressive ovarian cancer that were platinum-resistant (up to two prior regimens) or platinum-sensitive (up to three prior regimens) were treated with cabozantinib 100mg daily over a 12-week lead-in. Patients who had a partial response received open-label cabozantinib, while those with stable disease were randomized to either cabozantinib or placebo. However, the randomization was halted due to the high rate of clinical activity, as the overall response rate (ORR) was 24%, including 18% of platinum-resistant patients and 29% of platinum-sensitive patients. The most common AEs of grade 3 or higher were hand-foot syndrome (10%), diarrhea (8%), and fatigue (4%).
Aflibercept is a fusion protein that binds the VEGF ligand, serving as a decoy receptor for VEGF binding at high affinity. It also has strong binding affinity for placental growth factor, which interacts with neuropilin-1 and neuropilin-2, providing more potential regulation of vasculature associated with tumors. A Phase 2 study enrolled 49 patients with recurrent or persistent epithelial ovarian cancer and treated them with aflibercept 6mg/kg and docetaxel 75mg/m2 once every 21 days.8 A total of 54% of the patients achieved an objective response, and responses to the treatment were confirmed in 15 of 33 (45%) of the platinum-resistant patients, and in 10 of 13 (77%) of the platinum-sensitive patients. Grade 1–2 hypertension in five (11%) patients and grade 2 hypotension in one (2%) patient were directly associated with aflibercept.