Bevacizumab: The First Agent to Remarkably Improve Survival in Recurrent Cervical Cancer

Highlights from ASCO 2013 Annual Meeting

Bevacizumab significantly improved overall survival (OS) when added to chemotherapy in women with recurrent or metastatic cervical cancer, according to a planned interim analysis of the Gynecologic Oncology Group (GOG) 240 study presented at the Plenary session of 2013 Annual Meeting of the American Society for Clinical Oncology (ASCO), held May 30 – June 3 in Chicago, USA (Plenary abstract 3). This is the first time that a targeted agent has demonstrated such an improvement in gynecologic cancers.

This patient category has very few therapeutic options. The standard of care, a chemotherapy regimen consisted of cisplatin plus paclitaxel is associated with median OS of less than 12 months.

Dr Krishnansu Sujata Tewari of the University of California, Irvine, Medical Center reported during the ASCO Plenary Session that there is ample preclinical rationale for inhibiting VEGF in cervical cancer, and a phase II single-agent study demonstrated bevacizumab’s activity in this disease.

The study design and results

The GOG 240 study used a 2×2 factorial design; patients were assigned to either of two chemotherapy regimens involving cisplatin plus paclitaxel or topotecan and paclitaxel, and then randomly assigned to receive 15 mg/kg of bevacizumab or not. Treatment cycles were repeated every 21 days until disease progression, unacceptable toxicity, or complete response. More than 70% of patients in both groups had received prior platinum-based therapy; the groups were well matched with regard to age, histology, race, disease stage, and performance status.

The initial interim analysis showed that the topotecan-paclitaxel regimen was neither superior nor inferior to the cisplatin-paclitaxel regimen, while the second interim analysis did show superiority when bevacizumab was added to either chemotherapy regimen. In fact, the survival analysis conducted earlier in 2013 led ASCO to make an exception and allow the release of the abstract into the public domain well in advance of its presentation.

A total of 225 patients received chemotherapy alone and 227 received chemotherapy along with bevacizumab. With a median follow-up of 20.8 months, the median OS was 17 months with bevacizumab and 13.3 months without it, for a hazard ratio of death of 0.71 (97.6%, CI [0.54, 0.94]; p=0.0035).

The improvement in overall survival of 3.7 months was characterized by the study authors as clinically meaningful.

Bevacizumab also improved progression-free survival (PFS) over chemotherapy alone. The median PFS in the bevacizumab group was 8.2 months, compared with 5.9 months in the chemotherapy alone group, for a hazard ratio of 0.67 (95% CI [0.54, 0.82]; p=0.0002). The response rate was also better with bevacizumab, at 48% vs. 36% (p=0.00807); there were 28 complete responses in the patients who received bevacizumab and 14 in the chemotherapy-alone group.

The advantage seen with bevacizumab persisted in some subsets of patients, including those between the ages of 48 and 56, those with recurrent/persistent disease (although not among the 76 patients with metastatic disease), and those with squamous histology. Dr Tewari pointed out that bevacizumab was effective even in the presence of the disease in previously irradiated pelvis.

The median OS for those patients who received cisplatin plus paclitaxel was 14.3 months, significantly less than the 17.5 months for those who received cisplatin, paclitaxel, and bevacizumab (p=0.0348). Similarly, the median OS for those who received topotecan plus paclitaxel was 12.7 months, compared with 16.2 months when bevacizumab was added to that regimen (p=0.0896).

Side effects

There were four adverse-event deaths in each group. Patients who received bevacizumab experienced more occurrences of 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%). According to the study presenter, although both thromboembolic events and fistula were increased in the bevacizumab arms, these rates were relatively low, below 10%

The magnitude of the study results

Dr Tewari concluded that these results justify further study of this and related agents and also noted that the huge worldwide burden (especially in developing countries) associated with cervical cancer should play an important role in future research. There was no cost-benefit analysis accompanied with the current study results presentation and Dr Tewari underlined that such survival gains seen 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 the therapy to those who are in the greatest need.

How a discussant not involved in the study characterized the results?

Dr Gottfried Konecny of the David Geffen School of Medicine at the University of California, Los Angeles, was the abstract discussant during the Plenary Session. He said that the GOG 240 can be seen as a practice-changing study. He noted that the results may not be applicable to patients with metastases, given that only 17% of those in this trial had metastatic disease. He emphasized that would be important to move testing of bevacizumab into earlier disease stages.

In a post-Plenary discussion session, Dr Terwari said that he hopes that the manufacturer of bevacizumab will open a dialogue with the US Food and Drug Administration to work toward the drug’s approval in this setting.