Bevacizumab in the Treatment of Advanced Ovarian Cancer

Ovarian cancer is the fifth leading cause of cancer-related death in females in the United States.1 There will be an estimated 22,280 new cases and 15,500 deaths related to ovarian cancer in 2012.¹ The prognosis of advanced ovarian cancer is poor, with a 5-year survival rate of 5% to 20%. A platinum-based doublet chemotherapy post cytoreductive surgery has been the standard of care for the past decade. A breakthrough came when vascular endothelial growth factor (VEGF) and angiogenesis were found to be associated with prognosis and overall survival.² Previous phase 2 trials have shown positive efficacy data for bevacizumab, a humanized monoclonal antibody of VEGF, in the treatment of recurrent and/or refractory ovarian cancer.^3,4 In 2011, results were published from 2 large phase 3 randomized trials (GOG 2185 and ICON76) exploring bevacizumab as first-line therapy. Around the same time, a cost-benefit study involving bevacizumab was reported. This article reviews these latest advances in managing ovarian cancer.

Clinical Trials
GOG 218 Trial⁵
The Gynecologic Oncology Group 218 (GOG 218) trial was a double-blind, placebo-controlled, randomized phase 3 trial in patients with newly diagnosed stage III (incompletely resectable) or stage IV epithelial ov­arian, primary peritoneal, or fallopian tube cancer. Ad­ditional eligibility criteria included maximal debulking surgery within 12 weeks, a GOG performance score of 0 to 2, and no history of clinically significant vascular events or evidence of intestinal obstruction. A total of 1873 pa­tients post surgical debulking were randomized into 3 groups. Group 1 (con­trol group, n = 625) received IV paclitaxel 175 mg/m2 and carboplatin AUC 6 every 3 weeks in cycles 1 through 6, plus placebo in cycles 2 through 22. Group 2 (bevacizumab-initiation group, n = 625) re­ceived the same chemo­ther­apy plus bevacizumab 15 mg/kg in cycles 2 through 6, plus placebo in cycles 7 through 22. Group 3 (bevaci­zu­mab-throughout group, n = 623) received chemotherapy plus bevacizu­mab in cycles 2 through 22. The primary end point, initially overall survival (OS), was modified to progression-free survival (PFS). Only 19% of patients over­all completed the planned treatment (16%, 17%, and 24% in the control, bevacizumab-initiation, and beva­cizumab-throughout groups, re­spec­tively). After a median follow-up of 17.4 months, the median PFS was 10.3 months in the control group, 11.2 months in the bevacizumab-initiation group, and 14.1 months in the bevaciz­u­mab-throughout group. The difference in progression or death was statistically significant between the be­va­cizumab-throughout group and the control group (hazard ratio [HR], 0.717; 95% confidence interval [CI], 0.625-0.824; P <.001) but not between the bevacizumab-initiation group and the control group (HR, 0.908; 95% CI, 0.795-1.040; P = .16). The OS was 39.3 months, 38.7 months, and 39.7 months for the control group, bevacizumab-initiation group, and bevacizumab-throughout group, respectively; there was no significant difference between either of the bevacizumab-treated groups and the control group. Up­dated data analyses of PFS and OS after 47% of the patients had died were consistent with those from original analyses. Quality of life (QOL) was similar among different groups. Hyper­tension requiring therapy was more often seen in the bevacizumab-initiation group (16.5%) and bevacizumab-throughout group (22.9%) than in the control group (7.2%).

ICON7 Trial⁶
The International Collaboration on Ovarian Neoplasms 7 (ICON7) trial, conducted by the Gynecologic Cancer InterGroup, was a randomized trial in patients with newly diagnosed, high-risk, early-stage or advanced epithelial ovarian, primary peritoneal, or fallopian tube cancer. Unlike the GOG 218 study, this study did not use a placebo or double-blind approach. Patients were randomized to receive IV paclitaxel 175 mg/m2 and carboplatin AUC 5 or 6 every 3 weeks for 6 cycles (n = 764), or chemotherapy with concurrent bevacizumab 7.5 mg/kg every 3 weeks for 5 or 6 cycles, followed by another 12 cycles or until disease progression (n = 764). The primary end point was PFS; 70% of patients were stage IIIC or IV. More than 90% of patients in both groups completed chemotherapy, and those patients in the bevacizumab group who began chemotherapy more than 4 weeks after surgery received a median of 17 cycles of bevacizumab. After disease progression, only 3% of patients received further antiangiogenic treatment. At 36 months after randomization, PFS in the bevacizumab group was 21.8 months, significantly longer than the 20.3 months in the chemotherapy group (HR, 0.81; CI, 0.70-0.94; P = .004). The median OS was not reached. However, an updated subgroup analysis of patients at high risk for progression, which accounts for 30% of this patient population, revealed statistically significant differences of OS between the bevacizumab group and the chemotherapy group (HR, 0.64; CI, 0.48-0.85; P = .002). As in the GOG 218 trial, QOL was improved in both groups, but the difference was not significant.

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Cost-effectiveness Analysis⁷
Bevacizumab is a high-cost drug, currently priced at $2801.52/400 mg.8 Based on preliminary results, Cohn and colleagues conducted a cost-effectiveness analysis comparing the 3 treatment arms of the GOG 218 study. Actual and estimated costs of treatment and the potential cost of complications in each arm were included for analysis. The incremental cost-effectiveness ratio (ICER) per progression-free life-year saved (PF-LYS) was estimated. For 600 patients evaluated on each arm, the cost of chemotherapy alone was $2.5 million, which was significantly increased to $78.3 million when bevacizumab was added to chemotherapy for 16 cycles. These costs resulted in an ICER of $401,088 per PF-LYS for patients in the bevacizumab-throughout group. Sens­i-t­i­­vity analysis revealed that if the cost of bevacizumab were decreased by 25%, the ICER per PF-LYS dropped to below $100,000 for the bevacizumab-throughout arm. The authors concluded that in the GOG 218 trial, adding bevacizumab to chemotherapy in the treatment of advanced ovarian cancer was not cost-effective, and maintenance with bevacizumab was associated with significant direct and indirect costs.

Discussion
These phase 3 trials demonstrated that only extended use, but not the short-term use of bevacizumab, in combination with chemotherapy, improved PFS in patients with newly diagnosed ovarian cancer. However, the GOG 218 trial failed to demonstrate statistically significant OS benefit. The ICON7 trial showed no improved median OS but did show a substantial OS benefit in a subgroup analysis. Based on the results, bevacizumab was approved in Europe as first-line treatment with chemotherapy in the treatment of advanced ovarian cancer. In the United States, it is unknown if the Food and Drug Administration (FDA) will grant approval of bevacizumab in the treatment of advanced ovarian cancer without OS benefit. The current National Comprehensive Cancer Network (NCCN) guidelines have not included a bevacizumab-based regimen as first-line therapy.⁹

It is not clear why the PFS difference was not transformed to OS benefit in the GOG 218 trial, especially since the patient population in the GOG 218 trial is similar to the subgroup of patients who had improved OS upon treatment in the ICON7 trial. Cross-over effect cannot be ruled out. The percentage of patients in the GOG 218 trial receiving postprogression antiangiogenic therapy has not been determined, while it is known that 3% of patients in the ICON7 trial received subsequent antiangiogenic therapy.¹⁰ It is possible that if a significant number of patients in the chemotherapy-only group of the GOG 218 trial received postprogression antiangiogenic therapy, the OS benefit of bevacizumab treatment could be masked.

The optimal bevacizumab dose and treatment duration remain unclear, based on the results of these 2 large trials. In the ICON7 trial, the dose of bevacizumab was 7.5 mg/kg every 3 weeks for 5 or 6 cycles, and patients received bevacizumab for an additional 12 cycles postchemotherapy or until disease progression. In contrast, patients in the GOG 218 trial received 15 mg/kg bevacizumab every 3 weeks, and patients were allowed an additional 16 cycles of bevacizumab after chemotherapy completion. Despite the dosing difference of bevacizumab, the absolute PFS gain from bevacizumab in the GOG 218 trial (3.8 months) was close to that of patients with high risk for progression in the ICON7 trial (3.5 months). These findings suggest that the 7.5 mg/kg bevacizumab dose may achieve efficacy similar to the efficacy of the 15 mg/kg dose. The dose change could make a significant difference in terms of cost. A recent pharmacoeconomic analysis demonstrated that the bevacizumab-throughout approach was not cost-effective based on the GOG 218 trial. It is important for patients and providers to give serious consideration to the high cost of bevacizumab before they make decisions to incorporate bevacizumab into treatment. For most patients, the financial hurdles must be cleared before treatment can be initiated.

It is also unknown if efficacy of bevacizumab-based IV chemotherapy is comparable to the current standard of care as intraperitoneal (IP) therapy in advanced ovarian cancer especially for patients with optimal reduction. To address this question, the ongoing GOG 252 clinical trial randomized patients with advanced ovarian cancer to either IV carboplatin/paclitaxel with bevacizumab, IV paclitaxel plus IP carboplatin with bevacizumab, or IV paclitaxel plus IP carboplatin/paclitaxel with bevacizumab. All patients receive bevacizumab 15 mg/kg with chemotherapy and additional 16 cycles.11 Another ongoing trial, GOG 262, repeats dose-intense paclitaxel with IV carboplatin, but allows bevacizumab 15 mg/kg as an option, to be combined with chemo­therapy to treat stage II through IV ovarian cancer patients.¹²

Summary
Recent results from the GOG 218 and ICON7 trials demonstrated that adding maintenance bevacizumab to chemotherapy improved PFS among patients with newly diagnosed advanced ovarian cancer. However, there was no significant difference in OS between the bevacizumab group and chemotherapy group in the GOG 218 trial, and the final results of OS from the ICON7 trial are still pending. Based on these findings, the European Com­mission approved the new indication of bevacizumab to be used as the first-line therapy for untreated advanced ovarian cancer. However, it is not clear whether the FDA will grant approval of bevacizumab in the treatment of advanced ovarian cancer. Recently, a pharmaco­economic analysis concluded that the use of bevacizumab was not cost-effective based on the GOG 218 study. The 2012 NCCN guidelines have not yet included bevacizumab as first-line therapy for patients with advanced ovarian cancer. Oncologists and clinical pharmacists need to take this information into careful consideration before incorporating bevacizumab with chemo­therapy. Fu­ture studies are focusing on including bevacizumab in IP therapy for patients with advanced ovarian cancer and discovering potential markers to identify individuals most likely to achieve clinical benefit.

References

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