ESMO 2014: Final Overall Survival Analysis of the Phase III Randomised Trial of Chemotherapy With and Without Bevacizumab for Advanced Cervical Cancer
Benefit conferred by the incorporation of bevacizumab sustained
Final overall survival (OS) data from the NRG Oncology - Gynecologic Oncology Group (GOG) study of chemotherapy with and without bevacizumab for advanced cervical cancer has showed that the benefit conferred by the incorporation of bevacizumab is sustained beyond 50 months as evidenced by the survival curves remaining separated.
The results were reported during the Proffered Paper session in Gynaecolgical cancers at ESMO Congress 2014 in Madrid, Spain by Dr Krishnansu Tewari of the Department of Obstetrics & Gynaecology, University of California, Irvine Medical Center, Orange, USA
On 14 August, 2014, the USA Food and Drug Administration approved bevacizumab with chemotherapy for women with recurrent, persistent, or metastatic cervical cancer. This regulatory milestone was due to GOG protocol 240 that met its primary endpoint with the arm administering chemotherapy plus bevacizumab resulting in significantly improved OS compared to chemotherapy alone. These results were publicly announced following a data freeze on 12 December, 2012 when 271 deaths had occurred.
At ESMO 2014, the study investigators reported planned final analysis of OS and a detailed updated toxicity analysis based on the protocol-specified 346 events. The study results that were previously presented during the 2013 Plenary session of the American Society of Clinical Oncology (ASCO) were from the second analysis. These results were also published in theNew England Journal of Medicineon 20 February 2014.
The GOG 240 is a phase III randomised clinical trial using a 2x2 factorial design to determine whether chemotherapy plus bevacizumab and/or the non-platinum chemotherapy doublet (topotecan plus paclitaxel) improves OS in women with recurrent/persistent and metastatic cervical cancer.
The primary endpoints were OS and toxicity and secondary endpoints progression-free survival (PFS) and response.
The study investigators calculated that they will have to enrol approximately 450 patients with approximately 346 deaths expected to provide the study with 90% power to detect a reduction in the risk of death of at least 30% with either experimental treatment, with the one-sided type I error rate limited to 2.5% for each regimen.
The median age was 49 years and groups were well-balanced for disease status (70-73% recurrent), prior chemoradiation (74-75%), and in-field pelvic recurrence (53-54%).
When 348 events had occurred (2 more than the pre-specified number estimated for final analysis), the regimens administering bevacizumab continued to demonstrate a significant improvement in OS over chemotherapy alone: 16.8 vs 13.3 months; hazard ratio (HR) 0.765 (p=0.0068). The benefit conferred by the incorporation of bevacizumab is sustained beyond 50 months as evidenced continued separation of the survival curves.
Gastrointestinal (GI) perforations were reported in 3.2% of patients receiving bevacizumab, all of whom had prior radiotherapy. GI-vaginal fistula occurred in 8.2% of patients treated with bevacizumab vs 0.9% of those treated with chemotherapy alone. Grade 3 plus venous thromboembolic events were reported in 10.6% in the chemotherapy plus bevacizumab arm vs 5.4% in the chemotherapy alone arm.
Bevacizumab is the first targeted agent to be granted regulatory approval in the USA for treatment of cervical cancer.
Dr Sandro Pignata, who discussed the study results, said that strengths of the study are first improvement in OS after several years in this setting, first biological drug approved for cervical cancer, and clear demonstration that targeting angiogenesis is important in this disease.
However, there was a significant toxicity rate in the study with GI fistula in 8.6%, GI perforations in 3.2%, thromboembolism > grade 3 in 8.2% of patients, bleeding > grade 3 in 4.5% and death in 3.3% of patients. There was no analysis reported for risk factors related to toxicity and it is urgently needed in term of disease in the pelvis, previous radiotherapy, performance status, … Dr Pignata said that the use of the drug in patients unselected for clinical trials may require special attention.
Bevacizumab is a significant advance in the therapy of metastatic cervical cancer, but management of toxic events is still an open issue. The question is if the results could be generalizable in high incidence, but poor resource countries. According to Dr Pignata, resources still need to be directed with priority on screening and prevention of cervical cancer.
The GOG 240 was sponsored by the USA National Cancer Institute (NCI). Genentech, the drug manufacturer, provided support for the trial under the Cooperative Research and Development Agreement with the NCI for the clinical development of bevacizumab.