Ovarian cancer (advanced): bevacizumab 7.5 mg/kg in combination with paclitaxel and carboplatin for first-line treatment

Summary

One large (n=1528), open-label, randomised controlled trial (RCT; ICON7) that assessed the efficacy and safety of bevacizumab 7.5 mg/kg for treating ovarian cancer was identified; quality of life outcomes from this study were also reported separately (Stark et al. 2013). ICON7 found that interim analysis of overall survival data showed no benefit for adding bevacizumab to standard chemotherapy compared with standard chemotherapy alone, except in a subgroup deemed at high risk for progression. In this subgroup median results for progression-free survival after a median follow-up of 19 months were 10.5 months with standard chemotherapy and 15.9 months with standard chemotherapy plus bevacizumab. Adding bevacizumab to standard chemotherapy resulted in a small but clinically relevant reduction in quality of life.

Regulatory status: Off-label for treating advanced ovarian cancer at the 7.5 mg/kg dose.

Key points

Bevacizumab (Avastin, Roche) at a recommended dose of 15 mg/kg, in combination with paclitaxel and carboplatin, is licensed for the front-line treatment of adults with advanced (International Federation of Gynaecology and Obstetrics [FIGO] stages IIIB, IIIC and IV) epithelial ovarian, fallopian tube or primary peritoneal cancer. NICE assessed bevacizumab in combination with paclitaxel and carboplatin for first-line treatment of advanced ovarian cancer (NICE technology appraisal guidance 284) at the licensed dose of 15 mg/kg and did not recommend it.

Bevacizumab at a dose of 7.5 mg/kg is not the recommended licensed dose for first-line treatment of advanced ovarian cancer and so its use is off-label.

This evidence summary is based on 1 open-label, multicentre RCT which studied the efficacy of bevacizumab 7.5 mg/kg in addition to standard chemotherapy for treating ovarian cancer in 1528 women (ICON7, Perren et al. 2011); quality of life outcomes from this study were also reported separately (Stark et al. 2013)

Women were randomised to receive standard chemotherapy (paclitaxel and carboplatin given every 3 weeks for 6 cycles) or the same regimen plus bevacizumab 7.5 mg/kg given every 3 weeks for 5 or 6 cycles and then bevacizumab continued on its own for 12 additional cycles or until progression of disease.

After a median follow-up of 19 months, median progression-free survival was 19 months in the bevacizumab group compared with 17.3 months in the standard chemotherapy group. The ICON7 authors also reported results from a pre-planned subgroup of 465 women with advanced ovarian cancer whom they termed at 'high risk for progression' (women had either FIGO stage III disease and >1.0 cm of residual disease after debulking surgery or FIGO stage IV disease). For the subgroup at 'high risk for progression', median progression-free survival was15.9 months in the bevacizumab group compared with 10.5 months in the standard chemotherapy group.

An updated analysis of progression-free survival was performed after a median follow-up of 28 months. This found that median progression-free survival was 19.8 months in the bevacizumab group compared with 17.4 months in the standard chemotherapy group. For the subgroup at 'high risk for progression', median progression-free survival was16.0 months in the bevacizumab group compared with 10.5 months in the standard chemotherapy group.

Further results for overall survival are still awaited, but no statistically significant difference was found after a median of either 19 or 28 months' follow-up. However, in the subgroup at 'high risk for progression', after a median follow-up of 28 months, interim analysis showed that median overall survival was 36.6 months with bevacizumab compared with 28.8 months with standard chemotherapy alone. These results are preliminary and should be interpreted with caution. The trial was in women with all stages of ovarian cancer (FIGO stage I to IV), including a proportion of women with FIGO stage I and II (18%) who are not representative of the advanced ovarian cancer population.

The manufacturers of bevacizumab (Avastin, Roche) advise that unless the final intention-to-treat overall survival data from ICON7 shows a significant overall survival benefit for the 7.5 mg/kg dose then it is unlikely that a licence will be applied for (Roche: personal communication, September 2013).

Stark et al. (2013) found that in women whose disease had not yet progressed, mean global quality of life at 54 weeks was statistically significantly lower in the bevacizumab group compared with the standard chemotherapy group (69.7 points compared with 76.1 points respectively). This statistically significant (p<0.0001) difference of 6.4 points was small but considered clinically relevant. A higher proportion had a clinically significant improvement in health-related quality of life of at least 10 points in the standard chemotherapy group (66%) compared with the bevacizumab group (56%) between baseline and 54 weeks. This was measured using the European Organisation for the Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire.

The ICON7 trial reported recognised adverse events of bevacizumab including mucocutaneous bleeding, bleeding within the central nervous system (CNS) grade 3 or more, gastrointestinal perforation grade 3 or more, thrombotic events, complications of wound healing and hypertension. These adverse events occurred more frequently in the bevacizumab group compared with the standard chemotherapy group.

The manufacturer of bevacizumab (Avastin, Roche) warned about the risk of necrotising fasciitis associated with bevacizumab in May 2013 in information sent to healthcare professionals about the safety of medicines.

The summary of product characteristics lists adverse reactions that may be associated with bevacizumab treatment. These include gastrointestinal perforations, fistulae, wound healing complications, hypertension, posterior reversible encephalopathy syndrome, proteinuria, arterial and venous thromboembolism, haemorrhage, pulmonary haemorrhage or haemoptysis, congestive heart failure, neutropenia and infections, hypersensitivity or infusion reactions, osteonecrosis of the jaw, eye disorders, and ovarian failure.