What is the role of front-line bevacizumab?

Bevacizumab is a humanized monoclonal antibody that binds vascular endothelial growth factor (VEGF) and prevents it from binding to its receptor. This blocks the growth and maintenance of tumour-associated blood vessels. In women with newly diagnosed EOC, postsurgical chemotherapy is given with a curative intent. Unfortunately, the vast majority of women still relapse. The incorporation of bevacizumab as part of the upfront treatment program was evaluated in 2 randomized studies.

The first study conducted by GOG 0218 was a phase III randomized placebo-controlled study involving 1873 women with stage III or IV EOC who had undergone surgical cytoreduction.28At a median follow-up of 17 months, there was a significant increase in the median PFS in patients receiving upfront followed by maintenance bevacizumab as compared to when chemotherapy alone is administered (14.1 versus 10.3 months, p<0.001). This translates into a significant reduction in the risk of disease progression or death (HR 0.72, 95% CI 0.63-0.82). There was no improvement in OS (39.7 versus 39.3 months for the maintenance bevacizumab and chemotherapy alone group respectively). PFS was not significantly increased in patients who did not receive maintenance bevacizumab (they received upfront with placebo maintenance) when compared with the chemotherapy alone group.

The second study by the International Collaborative on Ovarian Neoplasms (ICON7) randomly assigned 1528 previously untreated women with high-risk early stage (I or IIA, clear cell or grade 3) or advanced EOC to standard chemotherapy for 6 cycles with or without bevacizumab during chemotherapy, followed by maintenance treatment for 12 additional cycles.29Compared to standard chemotherapy, the incorporation of bevacizumab resulted in a significant improvement of the median PFS by 1.7 months at a follow-up of 42 months. For women with a high risk of progression (stage III with >1.0 cm residual disease at the end of surgery or stage IV), bevacizumab was associated with significant improvement in PFS (18.1 versus 14.5 months) and OS (36.6 versus 28.8 months). However, this analysis was a post hoc subgroup analysis. In the final survival analysis at a median follow-up of 49 months, there was no difference in median OS (58 months for both arms using restricted means analysis). Women with high risk of progression experienced a lengthening of survival by 4.8 months from 34.5 months to 39.3 months.

In both studies, bevacizumab-containing treatments were associated with greater toxicities. There were higher incidences of grade 3 and 4 adverse events (66% versus 56% in control group)29, hypertension and gastrointestinal- wall disruption.28-29Global QoL was not improved by the addition of bevacizumab.28-31

Cost-effectiveness Analyses

Actual cost data was not collected in GOG 0218 or ICON 7. However, independent modeled cost-effectiveness analyses using available data on PFS and OSreport that without improvement in OS, the use of bevacizumab as part of the front-line therapy for ovarian cancer is not cost effective. 21,32-35These analyses include an analysis by the UK NICE appraisal committee which reported a range of incremental cost-effectiveness ratios from 128,000 to 161,000 per QALY for the use of bevacizumab at its licensed dose of 15mg/kg body weight with a treatment duration of 15 months or time horizon of 25 years or both.21Treatment with maintenance bevacizumab leads to improved PFS but is associated with both direct and indirect costs.

Recommendations for Front-line Bevacizumab

The SCAN Workgroup has voted in favour of the adoption of the ESMO guidelines. ESMO guidelines recommend the use of upfront bevacizumab with chemotherapy followed by maintenance bevacizumab for patients with poor prognostic features as defined in the ICON 7 trial.22Bevacizumab is currently licensed by the European Medicines Agency (EMA) at a dosage of 15mg/kg for use with carboplatin and paclitaxel for less than 15 months or until progression.

The NCCN guidelines listed upfront bevacizumab with chemotherapy followed by maintenance therapy as a Category 3 recommendation as there were major disagreements within the NCCN Panel. Less than 50% of panel members agreed with the recommendation. It was felt that data from GOG 0218 and ICON 7 had not shown a statistically significant increase in OS and/or improved QoL.

4 out of 8 SCAN Workgroup members concurred with the ESMO guidelines as it defined the role of bevacizumab comprehensively. However, while bevacizumab is licensed at a dose of 15mg/kg in the European Union, SCAN Workgroup members unanimously agreed that a dose of 7.5mg/kg based on the ICON 7 regimen is preferable due to the lower toxicities and cost involved. 3 members expressed disagreement with regard to the NCCN guidelines, endorsing the widely differing opinions regarding the use of bevacizumab. 1 member agreed with the recommendation by the SIGN guidelines against upfront bevacizumab as cost-effectiveness analyses have shown that the treatments cost does not justify its health benefits.

The workgroup acknowledges that there is currently no local data on upfront bevacizumab. The diverse views of the SCAN Workgroup are reflected in the NCCN guidelines. The workgroup has voted in favour of the ESMO guidelines (Supplementary Table 1) but recommends the careful selection of patients when considering the use of upfront bevacizumab. Only patients with poor prognostic features as defined in ICON 7 should be considered for upfront bevacizumab. The preferred dose of bevacizumab is 7.5mg/kg as defined by the ICON 7 regimen.