Roxanne Nelson

September 29, 2014

MADRID — Adding the investigational agent cediranib (under development by AstraZeneca) to standard chemotherapy might be beneficial for patients with metastatic or recurrent cervical cancer, according to the phase 2 CIRCCa study, presented here at the European Society for Medical Oncology (ESMO) Congress 2014.

Tumor shrinkage was greater in women who received cediranib plus chemotherapy than in those who received placebo plus chemotherapy (66% vs 42%). There was a modest but significant increase in median progression-free survival with cediranib (35 vs 30 weeks), but the difference in median overall survival was not significant.

Dr. Paul Symonds

"There are a significant number of patients alive without tumor progression," said lead author Paul Symonds, MD, from the Department Cancer Studies and Molecular Medicine at the University of Leicester in the United Kingdom. He was speaking at a press briefing held in advance of his presentation.

Dr. Symonds said that in Europe, about 70% of cervical cancer patients can be cured with standard treatments such as surgery, chemotherapy, and radiation therapy. However, patients with recurrent or metastatic disease generally have a very poor prognosis. Those who receive standard treatment tend to have a "miserable outlook," said Dr. Symonds, with a response rate of about 30%.

Overall survival is usually less than a year, and high tumor angiogenesis, along with high levels of intratumoral vascular endothelial growth factor (VEGF), are adverse prognostic features.

Cediranib is a potent oral inhibitor of VEGF-receptor tyrosine kinases. It has previously shown activity in recurrent ovarian cancer; results were described as "ground-breaking" at last year's ESMO meeting. However, results from a phase 3 clinical trial of metastatic colorectal cancer indicated that cediranib is inferior to bevacizumab (Avastin), and results from a phase 3 glioblastoma trial were disappointing.

Second Antiangiogenic Agent

This is the second recent trial to show the benefit of adding an antiangiogenic drug to chemotherapy in cervical cancer, said Andrés Poveda, MD, head of the gynecological oncology clinic at Fundación Instituto Valenciano de Oncología in Valencia, Spain

"For 2 decades, advances in treatment for patients with advanced cervical cancer had been slow and scarce," Dr. Poveda said in an ESMO statement. "Between 1989 and 2009, modifications of chemotherapy regimens resulted in an increased survival rate of just 4 months."

Then bevacizumab was evaluated for this indication. "The first study to include an antiangiogenic drug, bevacizumab, obtained spectacular results, offering a survival benefit of 4 months in one study, which is the equivalent to that obtained over the previous 20 years," said Dr. Poveda.

"The FDA recently approved the use of bevacizumab, as it completely changed clinical practice," he added.

Both bevacizumab and cediranib are antiangiogenic drugs, but "they work in different ways," said Dr. Symonds. "They have the same target but are very different." Cediranib is an oral tyrosine kinase inhibitor that targets VEGF-1, 2, and 3, whereas bevacizumab is a monoclonal antibody that targets VEGF-A and is administered intravenously.

Dr. Symonds said that his team plans to conduct an individual patient analysis to look at outcome and VGEF levels. "We will also be looking at different biomarkers. We want to find out why a significant number of patients live far longer than we thought they would," he reported.

Higher Response Rates, More Toxicity

In this phase 2 trial, Dr. Symonds and his colleagues randomized 69 patients with advanced cervical cancer — 13% with local relapse, 30% with extra pelvic metastases, and 57% with both. The majority (83%) had received 1 previous treatment, and 79% completed 6 cycles of chemotherapy.

Half of the patients received carboplatin AUC5 plus paclitaxel 175 mg/m² thrice weekly, for a maximum of 6 cycles, plus 20 mg cediranib daily, and half received placebo until disease progression. Plasma VEGFR-2 levels were measured at baseline and 28 days into chemotherapy.

Median overall survival was better in the placebo group than in the cediranib group (63 vs 59 weeks; hazard ratio, 0.93; P = .401). However, overall response rate (complete and partial) was worse with placebo than with cediranib (42% vs 66%; P = .030).

Discontinuation for treatment-related reasons was similar in the placebo and cediranib groups (22% vs 17%).

Adverse events were less common in the placebo than in the cediranib group, including grade 2/3/4 diarrhea (18% vs 50%; P = .005) and hypertension (12% vs 34%; P = .038). Dr. Symonds acknowledged that there was more diarrhea and hypertension, but explained that they were easy to control.

This study "confirms that taking antiangiogenic agents is important in cervical cancer," said Sandro Pignata, MD, from the National Cancer Institute in Naples, Italy.

Weaknesses of the study are the small progression-free survival advantage and the fact that some patients had greater than grade 2 diarrhea, he pointed out.

"A phase 3 trial is needed, but we need to evaluate which comparator should be used," Dr. Pignata said.

This research was supported by Cancer Research UK and ECMC, and conducted with support from an investigator-sponsored study collaboration between AstraZeneca and the NCRN. Dr. Symonds has disclosed no relevant financial relationships. Several of his coauthors report relationships with industry, as noted in the abstract.

European Society for Medical Oncology (ESMO) Congress 2014: Abstract LBA25_PR. Presented September 28, 2014.

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