Zosia Chustecka

June 02, 2013

CHICAGO, Illinois — Women with metastatic or recurrent cervical cancer had significantly prolonged survival when bevacizumab (Avastin, Genentech/Roche) was added to chemotherapy in a phase 3 trial reported during the plenary session here at the 2013 Annual Meeting of the American Society of Clinical Oncology (ASCO®).

The results were hailed as practice-changing, and the manufacturer has filed for approval of advanced cervical cancer as a new indication for bevacizumab. The drug is already marketed for use in a number of solid tumors, including colorectal and lung cancer.

The median overall survival was 17 months for women receiving the combination, compared with 13.3 months for women receiving chemotherapy alone (hazard ratio, 0.71; P = .0035).

This is the first time that a targeted agent has shown an improvement in survival in this cancer, noted lead author Krishnansu Sujata Tewari, MD, professor of obstetrics and gynecology at the University of California, Irvine.

"Women with advanced cervical cancer don't have many options," she commented. "We finally have a drug that helps women live longer."

"This is also possibly a first step towards turning cervical cancer into a chronic disease, helping women live longer and allowing time for additional treatments that could further slow the cancer's progression and improve survival," Dr. Tewari commented in a statement.

Practice-Changing Data

The trial was conducted by the Gynecologic Oncology Group and was funded by the National Cancer Institute (NCI). The improved survival with bevacizumab was made public earlier this year on recommendation of the trial's data safety monitoring committee.

These findings "are likely to change clinical practice and provide an opportunity to improve outcome in patients with recurrent cervical cancer who have previously had very limited treatment options," Dr. Tewari said.

According to NCI estimates, 12,000 women in the United States were diagnosed with cervical cancer in 2012, and 4000 died from the disease. The incidence is much higher is underdeveloped countries, where there is no regular screening, and worldwide cervical cancer is the third most common cancer in women. Worldwide, an estimated 500,000 women are diagnosed with cervical cancer each year, and 250,000 die.

Results from the Trial

Known as GOG 240, the trial involved 452 patients with pretreated metastatic, recurrent, or persistent cervical cancer who were enrolled from 2009 to 2012 in the United States and Spain.

The were 4 arms in the trial: patients were randomly assigned to receive either topotecan or cisplatin in combination with paclitaxel, and also to have bevacizumab added or not added to the chemotherapy.

In an analysis conducted in 2012, topotecan plus paclitaxel was not found to be superior to the standard therapy of cisplatin plus paclitaxel, and the investigators and patients were notified of the finding at that time, according to the NCI.

Detailed results on the addition of bevacizumab to chemotherapy were presented at the meeting.

Bevacizumab was administered at the same time as the chemotherapy, at a dose of 15 mg/kg intravenously once every 3 weeks until disease progression or unacceptable toxicity occurred.

In addition to showing a "highly statistically significant" difference in overall survival — women receiving bevacizumab lived for a median of 3.7 months longer — the response rate was significantly better with bevacizumab than without it (48% vs 36%; P = .00807), as was progression-free survival (8.2 vs 5.9 months: P = .0002).

"This was a triple-header," Dr. Tewari noted. All 3 end points were significantly better when bevacizumab was added.

"These data are very favorable, compared with what bevacizumab has achieved in the treatment of other cancers," said Gottfried Konecny, MD, from the David Geffen School of Medicine at the University of California, Los Angeles.

In a discussion of the results, he noted that pivotal studies of colorectal, lung, and renal cancers have shown improvement in progression-free survival with bevacizumab, but there was a mixed signal in overall survival. For breast and ovarian cancers, there was improvement in progression-free survival but no overall survival advantage.

Dr. Konecny said that the results seen in cervical cancer are "clinically meaningful," and agreed that the findings are practice-changing.

However, he noted that most of the burden of cervical cancer is found in less-developed countries, and wondered whether they will be able to afford such an advance in treatment.

"This proof-of-concept study shows that angiogenesis is very critical in cervical cancer," Dr. Konecny explained. "There is a real biology here; in the future, we may be able to target it with an oral drug," he added.

"It is pertinent now to investigate other VEGF inhibitors" and such targeted agents in earlier stages of cervical cancer, he said.

The addition of bevacizumab to chemotherapy led to more adverse effects, such as grade 3/4 bleeding (5% vs 1%), thrombosis/embolism (9% vs 2%), and gastrointestinal fistula (3% vs 0%). The adverse effects in the bevacizumab group were consistent with the known adverse-effect profile of the drug, the researchers note.

Although there was a numerical decrease in quality-of-life scores in patients who received bevacizumab, the difference was not clinically meaningful or statistically significant, Dr. Konecny noted.

The GOG 240 trial was sponsored by the NCI. Genentech, Inc., provided support for the trial under the Cooperative Research and Development Agreement (CRADA) with the NCI for the clinical development of bevacizumab.

2013 Annual Meeting of the American Society of Clinical Oncology: Abstract 3. Presented June 2, 2013.

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