Bevacizumab Improves Overall Survival in Patients with Advanced Cervical Cancer

The addition of bevacizumab to the chemotherapeutic regimens of cisplatin-paclitaxel or topotecan-paclitaxel resulted in improved overall survival among patients with advanced cervical cancer, according to results of a recent study [N Engl J Med. 2014;370:734-743].

Treatment options have been limited in women with advanced cervical cancer who have already received platinum-based chemoradiotherapy. Bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor A, had previously shown single-agent activity in heavily pretreated, recurrent cervical carcinoma.

Krishnansu S. Tewari, MD, University of California, Irvine, Medical Center, and colleagues conducted GOG (Gynecologic Oncology Group) 240, a phase 3, randomized trial to evaluate the addition of bevacizumab to nonplatinum combination chemotherapy in the treatment of advanced cervical cancer.

The primary end points were overall survival and the frequency and severity of adverse events. Progression-free survival and response rate were secondary end points. The study was based on the intent-to-treat principle, and the researchers used the log-rank test and a Cox proportional-hazards model in their analysis. Health-related quality of life (HRQoL) was assessed using the FACT-Cx-TOI survey that measured physical and functional well-being; pain was evaluated via the Brief Pain Inventory; and neurotoxicity was evaluated using the neurotoxicity subscale short form.

Patients with metastatic, persistent, or recurrent cervical cancer were eligible for the study. Between April 2009 and January 2012, 452 women from institutions in the United States and Spain were enrolled. They were randomized to 1 of 4 regimens: (1) cisplatin plus paclitaxel (n=114); (2) topotecan plus paclitaxel (n=111); (3) cisplatin-paclitaxel with the addition of bevacizumab (n=115); and (4) topotecan-paclitaxel plus bevacizumab (n=112). Regimens were repeated at 21-day intervals and continued until disease progressed, unacceptable adverse events, or the patient had a complete response. After the discontinuation of treatment, disease was assessed every 3 months for 2 years, then every 6 months for 3 years, until disease progression occurred.

A total of 97% of patients discontinued study treatment, primarily due to disease progression (51% of patients who received chemotherapy without bevacizumab, and 38% of patients who received a bevacizumab regimen). Adverse events caused discontinuation in more patients who took a bevacizumab regimen (25% versus 16%).

Results from the interim analysis after a median follow-up of 12.5 months showed that 62% of patients were still alive. The topotecan-paclitaxel regimen was associated with a significantly higher risk of progression compared with cisplatin-paclitaxel, with or without bevacizumab (hazard ratio [HR], 1.39; 95% confidence interval [CI], 1.09-1.77), although overall survival was not significantly affected (HR for death, 1.2; 99% CI, 0.82-1.76).

After a median follow-up of 20.8 months, 271 patients had died (60%). The addition of bevacizumab was associated with a significant improvement in overall survival compared with chemotherapy alone (17 months vs 13.3 months; HR for death, 0.71; 98% CI, 0.54-0.95). Significant improvement in progression-free survival was also observed (8.2 vs 5.9 months; HR for disease progression, 0.67; 95% CI, 0.54-0.82).

Results also showed response rates were significantly higher for patients who received bevacizumab compared with patients who did not (48% vs 36%). Among patients who received bevacizumab, 28 experienced a complete response compared with 14 patients who had received chemotherapy alone. Response rates for the cisplatin-paclitaxel-bevacizumab group were 50% compared with 45% for the cisplatin-paclitaxel group, and 47% for the topotecan-paclitaxel-bevacizumab group compared with 27% for the topotecan-paclitaxel group. HRQoL was not adversely affected by the addition of bevacizumab.

Hypertension of grade 2 or more was significantly more common in regimens containing bevacizumab (25% vs 2%; P<.001), although no patients discontinued for this reason. Gastrointestinal or genitourinary fistulas of grade 3 or more and thromboembolic events of grade 3 or higher were significantly increased with bevacizumab-associated regimens (6% vs 0%; P=.002; and 8% vs 1%; P=.0001, respectively).

In conclusion, Dr. Tewari said in an interview with First Report Managed Care, “The near 4-month improvement in overall survival is not only statistically significant in terms of the clinical trial design, but it is also clinically meaningful. Because the survival gains were not accompanied by a significant deterioration in quality of life, we may finally be on the cusp of converting what was previously a rapidly downward spiral into a more chronic condition, in which the gains in median survival time will allow for a critical window through which patients may potentially benefit from other antiangiogenesis agents and/or novel immunotherapies. Both classes of drugs are currently being studied in this population by the [National Cancer Institute] and other [associations]. The London Guardian recently reported that, based on this trial, bevacizumab has been approved for advanced cervical cancer for women in England. We are also hoping for regulatory approval in the United States and in [more of] Europe.”