CHICAGO—Adding bevacizumab to standard chemotherapy prolongs overall survival for women with advanced cervical cancer by an average of four months compared with chemotherapy alone, according to a randomized Phase III study reported as Abstract 3 at the American Society of Clinical Oncology Annual Meeting.
This represents the first time a targeted therapy has significantly prolonged overall survival for women with metastatic or relapsed cervical cancer. “Women with advanced cervical cancer do not have many options. We finally have a drug that helps women live longer,” said lead author Krishnansu Sujata Tewari, MD, Professor of Obstetrics and Gynecology at the University of California, Irvine.
“This is also possibly a first step toward 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.”
The Discussant for the study, Gottfried Konecny, MD, Associate Professor in the Department of Medicine, Hematology/Oncology at the UCLA's David Geffen School of Medicine, said, “The exciting thing is we have a good target of VEGF in cervical cancer. The study showed clinically meaningful and important improvement in extending survival up to 17 months. I think this study can be seen as practice-changing.”
Chemotherapy regimens are largely ineffective against advanced cervical cancer, Tewari noted. As a result, approximately 4,000 women in the U.S. die of the disease each year. Worldwide, cervical cancer takes an even higher toll, claiming 250,000 lives every year.
This study, performed by the Gynecologic Oncology Group, is the first to show that a targeted anti-angiogenic drug can prolong survival for women with gynecologic cancers.
The standard regimen of cisplatin plus paclitaxel is associated with a median overall survival time of less than 12 months, Tewari noted. “Cervical cancer affects young women in the prime of their lives. It does not respond to standard chemotherapy with cisplatin and paclitaxel. When patients don't respond, they die.”
Treatments are highly limited for those patients whose disease progresses, he continued. These patients often become resistant to cisplatin. “We need new therapeutic options.”
These tumors are highly angiogenic, he explained. “If we block angiogenesis, we can cure the cancer.” There is preclinical data showing inhibition of VEGF in cervical cancer, and a Phase II single-agent study demonstrated that bevacizumab has activity in this disease.
He added that in May, the National Comprehensive Cancer Network began considering putting a combination of chemotherapy plus bevacizumab into its treatment guidelines for cervical cancer.
In the four-armed trial, 452 women, median age of 47, with recurrent or metastatic cervical cancer were randomly assigned to treatment with a chemotherapy regimen alone or combined with 15 mg/kg of bevacizumab. The chemotherapy regimens were cisplatin at 50 mg/m2 plus paclitaxel at 135 to 175 mg/m2 and topotecan at 0.75 mg/m2 on days 1-3 plus paclitaxel at 175 mg/m2 on day 1.
Treatment was given on 21-day cycles until a complete response, unacceptable toxicity, or disease progression.
More than 70 percent of patients in both groups had received prior platinum-based therapy. The groups were well matched with regard to age, histology, race, disease stage, previous use of platinum as a radiosensitizer, and performance status, he said.
The study included a non-cisplatin chemotherapy arm because of concerns of resistance with repeated cisplatin treatment. A Phase II trial of topotecan plus paclitaxel had previously shown activity in cervical cancer.
After a median follow-up of 21 months, the median overall survival was 17.0 months in the chemotherapy-plus-bevacizumab group (227 patients) compared with 13.3 months in the chemotherapy-alone group (225 patients), which is a clinically meaningful difference, Tewari reported. There were no significant differences in survival between the two chemotherapy arms.
The median progression-free survival (PFS) time was 8.2 months in the chemotherapy-plus-bevacizumab arm and 5.9 months for patients receiving chemotherapy alone. There was a significant decrease in the hazard of progression, he said.
The median overall survival (OS) time for patients who received cisplatin plus paclitaxel plus bevacizumab was 17.5 months compared with 14.3 months for those who received cisplatin plus paclitaxel. Similarly, the median overall survival time for patients who received topotecan plus paclitaxel plus bevacizumab was 16.2 months compared with 12.7 months for those who received topotecan plus paclitaxel.
The response rates were higher in patients who received bevacizumab (48% vs. 36%) and responses lasted longer. There were 28 complete responses in the patients who received bevacizumab and 14 in the chemotherapy-alone group.
Bevacizumab use was considered a positive prognostic factor for patients in the age group of 48-56, who had a performance status of 1, who received prior platinum therapy, who had recurrent/resistant disease, and who had pelvic disease. “Perhaps most importantly, when the disease was in the previously irradiated pelvis, bevacizumab was still effective,” Tewari said.
There was no sign of deterioration of health-related quality of life (QOL) with bevacizumab, he noted. “Patient-reported outcomes of physical function and well-being showed that the survival gains did not impair quality of life.”
Bevacizumab did lead to more adverse events, but “we found no new toxicities associated with bevacizumab. The toxicities were similar to what had been previously reported in other types of cancers,” he said. Patients who received bevacizumab experienced more thromboembolism (8% vs. 1%), gastrointestinal fistula of at least grade 3 (3% vs. 0%), genitourinary fistula of at least grade 3 (2% vs. 0%), hypertension of grade 2 or above (25% vs. 2%), and neutropenia of at least grade 4 (35% vs. 26%) compared with the chemotherapy-alone patients.
“Although both thromboembolic events and fistula were increased in the bevacizumab arms, these rates were relatively low—below 10 percent,” Tewari said. There were four deaths related to adverse events in each arm.
In conclusion, Tewari said, “This is the first molecularly targeted agent to improve overall survival in a gynecologic cancer. The effect of bevacizumab was sustained with prognostic factors.”
He noted that the international burden associated with cervical cancer should play an important role in future research: “The discovery of survival gains such as that concurred by anti-VEGF therapy needs to be followed by cost-effectiveness studies to best determine how to balance the societal burden and, at the same time, provide these therapies to those who are in the greatest need,” he said.
Bevacizumab, though, is an expensive drug, and other classes of anti-angiogenic drugs may be less expensive and as effective: “We were able to demonstrate that angiogenesis is a factor, which opens doors to studying other classes of these drugs.”
Carol Aghajanian, MD, an ASCO spokesperson and Chief of Gynecologic Medical Oncology Service at Memorial Sloan-Kettering Cancer Center, commented at a news briefing at the meeting that included all the plenary papers:
“Treatment options for women with recurrent or advanced disease have been insufficient for far too long. This study clearly shows how our nation's investment in clinical cancer research pays off, offering the first ever treatment to extend the lives of women with aggressive cervical cancer.”
The moderator of the news briefing, Jyoti D. Patel, MD, Associate Professor in Medicine-Hematology/Oncology at Northwestern University Feinberg School of Medicine, added: “This is the first time that an OS benefit has been shown in cervical cancer [with a targeted drug]. This is a paradigm shift. Patients live longer and feel better.”
“Over the last 25 years there has been no improvement in PFS,” Konecny noted. A critical review of efficacy of the standard of care in cervical cancer recently found a progression-free survival time of 3.7 months and overall survival of six to seven months. “Attempts to improve the dose or add in other agents do not improve OS,” he said.
Tumor angiogenesis is promising, with data from bevacizumab as a single agent in recurrent, persistent, or metastatic cervical cancer. VEGF is “an extraordinary target” based on its pathophysiological role in the disease, he said.
In Front-Line Setting
Other cancer studies have looked at bevacizumab in the front-line setting with mixed results. He noted that bevacizumab leads to improved PFS in all organ sites, but not an OS advantage in renal, gastric, pancreas, or prostate cancers.
“This is in contrast with cervical cancer in this study where there was a relevant reduction in hazard ratio for PFS and OS,” Konecny explained. “This is independent of the choice of chemotherapy. This demonstrates the data are favorable in cervical cancer when compared with bevacizumab in other cancers in the front-line setting.
“I applaud the researchers for their quality-of-life assessment,” he added, noting that there was no statistically significant deterioration in QOL.
The strengths of the Tewari study, said Konecny, include that “it was a placebo-controlled trial, the control arm did not underperform, the study contained a strong translational component, a detailed QOL assessment, and exploratory subset analyses. The limitations include no cost-benefit analysis yet.”
May Not Be Applicable for Patients with Metastatic Disease
The use of VEGF inhibitors may not be applicable to patients with metastatic disease, noted the study's Discussant, Gottfried Konecny, MD. Drug combinations may delay or overcome primary or secondary disease resistance. The future direction of research should be to investigate the role of other VEGF inhibitors as well.
“We have no validated predictors in hand,” he said, adding that it is important to study anti-angiogenic therapy in early cervical cancer because it may translate into a reduction in mortality.
In the Post-Plenary Discussion Session, both Tewari and Konecny said they hoped bevacizumab would be approved for these patients.