Cediranib, an experimental, potent tyrosine kinase inhibitor (TKI) of VEGFR 1, 2, and 3, improved response rate and median progression-free survival (PFS) when added to conventional chemotherapy in a phase II study of patients with relapsed or metastatic cervical cancer, reported Paul Symonds, MD, at the 2014 ESMO Congress.
The findings confirm the benefit of adding an angiogenesis inhibitor to chemotherapy in cervical cancer, first demonstrated with bevacizumab (Avastin). In August, the FDA approved bevacizumab in advanced cervical cancer based on a pivotal study demonstrating that the drug improved overall survival when used in combination with chemotherapy (N Engl J Med
In the phase II CIRCCa study, 69 patients with histologically proven metastatic or relapsed cervical cancer unsuitable for radiotherapy or surgery were randomized in a 1:1 ratio to 20 mg of cediranib daily or matched placebo on top of conventional chemotherapy with weekly carboplatin and paclitaxel for a maximum of six cycles and then until disease progression or lack of tolerability. To be eligible, patients could not have received previous chemotherapy with the exception of cisplatin administered with radiotherapy as a primary treatment. As part of the study, plasma VEGFR-2 levels were measured at baseline and again at 28 days after the start of chemotherapy.
Thirteen percent of patients enrolled had local relapse only, 30% had extra pelvic metastases only, and 57% had both. Around 83% had received one line of previous treatment. Seventy-nine percent of patients completed six cycles of chemotherapy. Twenty-two percent of patients in the placebo arm and 17% in the cediranib arm stopped the study drug for treatment-related reasons.
Patients randomized to cediranib in addition to chemotherapy had a greater overall response rate (complete response plus partial response) than those treated with chemotherapy alone (66% vs 42%; P
= .03). “It’s worth saying that the 42% response rate in the standard chemotherapy arm was better than we expected,” said Symonds, a professor of Clinical Oncology at the University of Leicester, Leicester, UK. There were three complete responses in the cediranib arm and none in the placebo arm.
There was also a modest but statistically significant increase in median PFS (35 weeks vs 30 weeks) with cediranib, for a hazard ratio of 0.61 (P
= .046). Median OS was not significantly different between the cediranib and placebo groups (59 weeks vs 63 weeks; P
= .401) but the study was not powered to detect a difference in OS, said Symonds. After an initial rapid decline in OS, a significant number of patients in each arm were still alive and progression free from 1 year on after randomization, he noted.
One month into treatment, a marked reduction in median blood levels of VEGFR-2 was observed in the cediranib arm compared with the standard chemotherapy arm (median change in log10
VEGFR-2 from baseline: -0.036 vs +0.067; P
The overall rate of grade 2-4 adverse events during the study drug period was 19% in the cediranib group and 9% in the placebo group (P
= .240). Patients randomized to cediranib experienced more grade 2-4 diarrhea (50% vs 18%; P
=.005) and hypertension (34% vs 12%; P
= .038) than those randomized to placebo. “These side effects were easy to control. Diarrhea is controlled by loperamide,” said Symonds. Hypertension was controlled satisfactorily with calcium channel blockers and other standard antihypertensive agents. Grade 3/4 neutropenia also occurred more often in recipients of cediranib versus placebo (31% vs 9%; P
Regarding the next step with the research, Symonds said, “Our future plan is individual patient analysis looking at outcome versus VEGFR levels.”
Blood samples will also be examined for correlation of outcome with other tumor biomarkers. “These TKIs actually block a fair number of receptors. We want to find out why a significant number of these patients live far longer than you would expect—beyond 2 years without progression,” said Symonds. “VEGFR has been shown to be easy to target. I think we’ll get other targets from this study.”
Symonds P, Gourley C, Davidson S, et al. CIRCCa: A randomised double blind phase II trial of carboplatin-paclitaxel plus cediranib versus carboplatin-paclitaxel plus placebo in metastatic/recurrent cervical cancer. Presented at: ESMO Congress 2014; September 26-30, 2014; Madrid, Spain. Abstract LBA25.
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