Platinum-Resistant Recurrent Ovarian Cancer Treatment +/- Bevacizumab
Overview Of The Study
The study aims to elucidate the efficacy of bevacizumab therapy in patients with platinum-resistant ovarian cancer whose disease has already progressed after bevacizumab plus chemotherapy therapy.
The study is a multicenter, open-label, phase II trial (JGOG3023). Subjects were randomized 1:1 to single-agent chemotherapy. The primary endpoint was investigator-assessed progression-free survival (PFS) according to RECIST version 1.1. Secondary endpoints were overall survival (OS), objective response rate (ORR), and response rate according to Gynecological Cancer Intergroup cancer antigen 125 criteria.
A total of 103 patients were given chemotherapy plus bevacizumab. Results showed that bevacizumab was effective beyond progressive disease and AEs were manageable. However, further verification is suggested.
Ovarian Cancer
Each year, the incidence of ovarian cancer increases all around the globe. This is mostly due to the fact that most cases are already diagnosed at advanced stages. Most patients also have poor prognosis.
Ovarian cancer standard of care includes surgery plus chemotherapy with platinum and taxane agents. The issue with this is that 25% of patients at first relapse experience platinum resistance. It’s also found that almost all patients who experience recurrence or progressive disease develop platinum-resistant disease.
The problem with platinum resistant recurring ovarian cancer is that it has a poor prognosis. It also has a short OS (less than 12 months). Treatment options for these cases are limited and do not prolong survival.
Treatments for Platinum-resistant Ovarian Cancer
The commonly used treatments are PLD, topotecan, paclitaxel, and gemcitabine. The overall response rates of these treatments are no greater than 15%. Thus, there is a huge need for better new treatments for platinum-resistant ovarian cancer.
What is Bevacizumab?
Bevacizumab is a recombinant humanized monoclonal antibody. It contains murine complementarity-determining and human framework regions.
Bevacizumab targets a cancer cell protein called vascular endothelial growth factor (VEGF). This protein is the reason why cancers grow blood vessels—and get nourishment from blood. Bevacizumab blocks this protein and stops cancer cells from growing blood vessels. This starves the cancer cells and blocks their growth. As of today, it’s the standard treatment for ovarian cancer.
Trials have already proved the effectiveness of bevacizumab beyond progressive disease in locally recurrent or metastatic breast cancer and in advanced or recurrent colorectal cancer. However, there’s not enough data on its efficacy when it comes to re-treatment after progression of disease in ovarian cancer. There are also no clinical trials of bevacizumab beyond progressive disease in patients with platinum-resistant recurrent ovarian cancer.
This study is performed to investigate the efficacy of chemotherapy with or without bevacizumab in patients with platinum-resistant recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who were previously treated with bevacizumab for front-line or platinum-sensitive ovarian cancer.
Study design
The study started from June 2015 to November 2019. The first two years were planned for enrollment but were extended to 3.5 years to reach the sample size required. The follow-up period was six months after the completion of patient registration.
In total, 103 patients were enrolled and allocated to the chemotherapy group (n = 51) and chemotherapy + bevacizumab group (n = 52). All of these patients were included in the ITT analysis set.
Two patients in the chemotherapy + bevacizumab group were discontinued before starting protocol treatment. Two patients were misallocated to the chemotherapy group and received bevacizumab. These patients were included in the chemotherapy group for efficacy analyses and in the chemotherapy + bevacizumab group for safety analyses.
One patient allocated to the chemotherapy + bevacizumab group received chemotherapy alone (without bevacizumab). This patient was included in the chemotherapy + bevacizumab group for efficacy analysis and the chemotherapy group for safety analysis.
The efficacy analyses were done using the ITT set. For the safety analysis, 50 patients (chemotherapy group) and 51 patients (chemotherapy + bevacizumab group) were included in the SAS.
Patients with platinum-resistant recurrent ovarian cancer and recurrence after bevacizumab therapy in combination with chemotherapy were randomly assigned 1:1 by dynamic randomization to treatment with single-agent chemotherapy plus bevacizumab.
Inclusion criteria are patients ages 20 and up with a history of confirmed epithelial ovarian, fallopian tube, or primary peritoneal carcinoma. They should also be treated with h ≥3 cycles of bevacizumab + platinum chemotherapy; progression occurred <6 mo after completion of platinum treatment.
Patients with a measurable lesion confirmed by diagnostic imaging or with a cancer antigen (CA)125 level more than 2 times higher than normal were considered eligible.
The attending physician selected 1 of the following single-agent chemotherapy drugs for patients in both groups: PLD, topotecan, paclitaxel, or GEM.
Randomization was performed according to the following stratification factors: a number of regimens received previously (1 or 2 vs 3), time to recurrence or disease progression from the last day of platinum-drug administration (during treatment vs <3 mo vs ≥3 mo), and anticancer agent (PLD vs topotecan vs paclitaxel vs GEM).
All patients provided written informed consent. The study was also conducted in accordance with the International Conference on Harmonization Guidelines for Good Clinical Practice, the Ethical Guideline for Medical and Health Research involving Human Subjects, the Declaration of Helsinki, and applicable local laws and regulations.
Results
Results show that OS was longer in the chemotherapy + bevacizumab group than in the chemotherapy group. Despite no statistically significant improvement in OS, the researchers conclude that the endpoint would have been met if they had a larger sample size.
ORR in this study was approximately twice as high in the chemotherapy + bevacizumab group (25.0%) than in the chemotherapy group (13.7%; P = .0599). This finding supports the additive effect of bevacizumab in single-agent chemotherapy.
The results of this phase II study demonstrated the efficacy and manageable toxicity of continuing bevacizumab beyond progressive disease in patients with platinum-resistant recurrent ovarian cancer previously treated with bevacizumab for front-line or platinum-sensitive recurrent ovarian cancer. However, although an improvement in PFS was observed, further verification is required.
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