CHICAGO – Adding the antiangiogenic agent bevacizumab to chemotherapy improves overall survival in women who have advanced cervical cancer, according to findings of a randomized phase III trial of the Gynecologic Oncology Group.
In the trial – Gynecologic Oncology Group (GOG) protocol 240 – women who received bevacizumab (Avastin) in addition to chemotherapy lived about 4 months longer than their counterparts who received chemotherapy alone, lead investigator Dr. Krishnansu S. Tewari reported in the plenary session at the annual meeting of the American Society of Clinical Oncology.
The adverse effects seen were largely consistent with previous experience in other cancers with bevacizumab, a vascular endothelial growth factor (VEGF) inhibitor.
"This study met its primary endpoint," said Dr. Tewari, a professor of obstetrics and gynecology at the University of California, Irvine. "Bevacizumab is the first molecularly targeted agent to improve overall survival in a gynecologic cancer."
"Moving forward, the incorporation of anti-VEGF therapy into primary treatment for locally advanced disease should be considered ..." he said. Also, "these data open up doors to study other classes of antiangiogenesis agents – both VEGF-dependent molecules as well as non–VEGF-dependent molecules."
Invited discussant Dr. Gottfried E. Konecny of the University of California, Los Angeles, commented, "Progression-free and overall survival improvements through bevacizumab in advanced cervical cancer as shown in the GOG 240 study are clinically meaningful. Adverse events and toxicities are manageable and, I believe, class specific."
In his opinion, as only about a fifth of the patients had metastatic disease, it is uncertain whether the drug benefits that population. And the data suggest bevacizumab may have less benefit in patients with adenocarcinoma tumors as compared with squamous tumors.
For future research, "most important is the identification and validation of response predictors," according to Dr. Konecny.
"Extending the global reach of antiangiogenic therapies for advanced cervical cancer is critical," he concluded, noting that the countries with highest incidence and mortality rates for this disease also have the lowest annual health care spending. "I think GOG 240 can be seen as a practice-changing study. But we urgently need to develop antiangiogenic treatment strategies that will benefit the global population."
The trial was open to women who had chemotherapy-naive, recurrent, persistent, or metastatic cervical cancer. They were randomized in dual factorial design according to chemotherapy doublet (cisplatin plus paclitaxel vs. topotecan plus paclitaxel) and receipt of bevacizumab (yes vs. no), which was provided by Roche/Genentech, manufacturer of the recombinant monoclonal antibody. Treatment was on an open-label basis, and crossover was not allowed.
Bevacizumab is approved by the Food and Drug Administration for selected indications in colorectal, renal, and lung cancer, and in glioblastoma.
An interim analysis concluded that the topotecan-paclitaxel regimen was not superior (or inferior) to the cisplatin-paclitaxel regimen that has been the standard in this setting, Dr. Tewari reported.
With longer follow-up, to a median of 20.8 months, women who received added bevacizumab had a longer median overall survival than did their counterparts who received chemotherapy alone (17.0 vs. 13.3 months; hazard ratio, 0.71; P = .0035).
Bevacizumab conferred a significant survival benefit when added to cisplatin-paclitaxel chemotherapy (HR, 0.68; P = .03) but not when added to topotecan-paclitaxel chemotherapy (HR, 0.74; P = .09).
"The effect of bevacizumab was sustained with multiple prognostic factors, including when the disease was in the previously irradiated pelvis," Dr. Tewari noted when reporting subgroup analyses.
Women who received added bevacizumab also had a longer median progression-free survival (8.2 vs. 5.9 months; HR, 0.67; P = .0002) and a higher response rate (48% vs. 36%, P = .008).
Adding bevacizumab led to significantly higher rates of grade 3/4 gastrointestinal fistula (3% vs. 0%), genitourinary fistula (2% vs. 0%), and thromboembolism (8% vs. 1%); grade 2 or higher hypertension (25% vs. 2%); and grade 4 or higher neutropenia (35% vs. 26%).
"We saw no new adverse events in this patient population, which includes patients who had been heavily irradiated," Dr. Tewari commented. There were four deaths each in the groups treated with and without bevacizumab.
Addition of bevacizumab did not compromise health-related quality of life as assessed with the FACT(Functional Assessment of Cancer Therapy) – Cervical Cancer Trial Outcome Index.
Dr. Tewari disclosed no relevant conflicts of interest. Dr. Konecny disclosed that he receives honoraria from Genentech and Sanofi, and research funding from Amgen and Pfizer.