Phase III GOG-0218 trial of Avastin front-line in advanced ovarian cancer

GOG-0218 was a randomised(How subjects are assigned to a treatment arm in a study. The treatment a subject receives is determined by chance alone), double-blind(A study in which both the investigator and the participant are blind to (unaware of) the nature of the treatment the participant is receiving), placebo-controlled(A way of testing a medical therapy in which, in addition to a group of subjects that receives the treatment to be evaluated, a separate control group receives a sham "placebo" treatment which is specifically designed to have no real effect) phase III trial conducted by the Gynecology Oncology Group (GOG).¹

Primary endpoint: investigator-assessed PFS(The time from trial entry to disease progression or death from any cause)

Secondary endpoints

• OS(The time from trial entry to death from any cause)
• Safety
• QoL(A phrase used to refer to an individual’s total well-being)

Women with stage III or IV ovarian cancer with residual disease were randomised to one of three arms

• Arm I: 6 cycles of carboplatin/paclitaxel, combined with placebo from cycle 2, followed by continued placebo until progression(A carcinogenic process whereby genetically altered cells undergo a second (non-genetic) cell expansion resulting in uncontrollable growth) or for 16 further cycles to give a maximum duration of placebo of 15 months
• Arm II: 6 cycles of carboplatin/paclitaxel, combined with Avastin 15mg/kg every 3 weeks from cycle 2, followed by continued placebo until progression or for 16 further cycles to give a maximum duration of placebo of 15 months
• Arm III: 6 cycles of carboplatin/paclitaxel, combined with Avastin 15mg/kg every 3 weeks from cycle 2, followed by continued Avastin until progression or for 16 further cycles to give a maximum duration of Avastin of 15 months.

Patients eligible for the trial were required to have optimally debulked (macroscopic) stage III, suboptimally debulked stage III or stage IV epithelial ovarian, primary peritoneal or fallopian tube cancer.¹

No other prospective randomised phase III trial reported to date has evaluated different durations of Avastin therapy. Therefore, the GOG-0218 trial provides important new information on the optimal duration of Avastin therapy.

GOG-0218: Avastin front-line significantly improves PFS in advanced ovarian cancer patients with residual disease^2,3

The phase III GOG-0218 trial met its primary endpoint, showing a significant PFS improvement in patients with advanced ovarian cancer treated with front-line Avastin combined with chemotherapy followed by continued Avastin compared to control. Progression was defined based on radiological scans, symptomatic deterioration or CA-125 levels.

The PFS benefit was both clinically meaningful and statistically significant(Pertaining to an event that is unlikely to have occurred by chance) (median PFS 10.6 months and 14.7 months for arm I and arm III, respectively; HR(An estimate of relative risk of an event occurring)=0.70 (95% CI(A range of values used to indicate the reliability of an estimate (or a set of values within which there is a specified probability)): 0.61–0.81, p<0.0001).² PFS was not significantly improved in patients who received Avastin only in combination with chemotherapy, i.e. in whom Avastin was stopped when chemotherapy was withdrawn (arm I vs II).

Prespecified PFS analyses, all with a cut-off date of September 29, 2009, also showed statistically significant improvements in PFS over chemotherapy combined with placebo when Avastin was combined with chemotherapy and continued as a single agent

• Investigator-assessed PFS (without censoring for CA-125 progression or non-protocol therapy [NPT]): stratified(The process of dividing members of the population into homogeneous subgroups before sampling) HR of 0.71 (95% CI: 0.61–0.83, p<0.0001) with median PFS of 14.1 and 10.4 months, respectively.²
• Investigator-assessed PFS, censoring for CA-125 progression and NPT: stratified HR of 0.62 (95% CI: 0.52–0.75, p<0.0001) with median PFS of 18.2 and 12 months, respectively.²
• Analysis of PFS as determined by the independent review committee (censoring for NPT): stratified HR of 0.62 (95% CI: 0.50–0.77, p<0.0001) with median PFS of 13.1 and 19.1 months, respectively.²

In patients who received Avastin only in combination with chemotherapy, no statistically or clinically significant(A measure of the importance of a therapy, treatment or a related side effect that may impact clinical practice) benefit in PFS was observed in any analysis.²

GOG-0218: OS data are immature²

The reported OS analysis was performed when approximately 36% of the patients had died; therefore, data are immature.²

GOG-0218: efficacy(The capacity for beneficial change (or therapeutic effect) of a given intervention) summary

In summary, prespecified PFS analyses showed that the GOG-0218 trial met its primary endpoint, demonstrating a significant improvement in PFS with front-line Avastin combined with chemotherapy followed by continued single-agent Avastin until disease progression or for a maximum of 15 months versus chemotherapy alone in women with advanced ovarian cancer with residual disease.^1,2 Independent review demonstrated the robustness of the trial and confirmed the significant PFS benefit resulting from Avastin-based therapy.² OS results are not yet mature. Continuing single-agent Avastin after completion of chemotherapy is essential for optimal outcomes in women with advanced ovarian cancer.