EMA Recommends a Variation to the Terms of the Marketing Authorisation for Bevacizumab

New indication concerns the treatment of patients with platinum-resistant recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer

On 26 June 2014, the European Medicines Agency (EMA) Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion recommending a variation to the terms of the marketing authorisation for the medicinal product bevacizumab (Avastin). The marketing authorisation holder for this medicinal product is Roche Registration Ltd. They may request a re-examination of the CHMP opinion, provided that they notify the European Medicines Agency in writing of their intention within 15 days of receipt of the opinion.

The CHMP adopted a new indication as follows:

Bevacizumab in combination with paclitaxel, topotecan, or pegylated liposomal doxorubicin is indicated for the treatment of adult patients with platinum-resistant recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who received no more than two prior chemotherapy regimens and who have not received prior therapy with bevacizumab or other VEGF inhibitors or VEGF receptor–targeted agents.

Detailed conditions for the use of this product will be described in the updated summary of product characteristics, which will be published in the revised European public assessment report, and will be available in all official European Union languages after the variation to the marketing authorisation has been granted by the European Commission.

The positive opinion is based on a pivotal phase III study

When treating recurrent ovarian cancer, the time between receiving the last dose of platinum-based chemotherapy and disease recurrence is used to help determine the choice of chemotherapy used in the next line of treatment. Patients have platinum-resistant disease if their disease progress between one and six months following completion of platinum-based chemotherapy, and platinum-sensitive disease if it progress more than six months after. A quarter of those who relapse after initial treatment - nearly 60,000 women a year globally - will have platinum-resistant cancer. Median overall survival of patients with platinum-resistant ovarian cancer is approximately 12 months and novel strategies are needed.

Ovarian cancer is associated with high concentrations of vascular endothelial growth factor (VEGF). Studies have shown a correlation between a high concentration of VEGF and ascites development, disease progression, and a poorer prognosis in women with ovarian cancer. Bevacizumab is designed to specifically target VEGF and is currently the only targeted therapy approved by the EMA for ovarian cancer. Bevacizumab is EU approved as a front-line treatment of advanced ovarian cancer, and as a treatment for recurrent, platinum-sensitive ovarian cancer.

The new EU filing was based on results of the phase III AURELIA study which involved 361 women with recurrent, platinum-resistant ovarian cancer who received either chemotherapy (weekly paclitaxel, topotecan or pegylated liposomal doxorubicin) or bevacizumab added to chemotherapy.

Results showed that at a median follow-up of 13 months for women who had received chemotherapy alone and 13.9 months for those who had received the combination, the addition of bevacizmab to chemotherapy gave a clinically meaningful benefit, nearly doubling the median progression-free survival from 3.4 months to 6.7 months (HR = 0.38, p < 0.0001).

Patients who received bevacizumab in combination with chemotherapy had a median overall survival of 16.6 months compared to 13.3 months for patients treated with chemotherapy alone (HR = 0.87, p = 0.27).

In addition, patients who received bevacizumab in combination with chemotherapy had a significantly higher rate of objective response rate, compared to patients who received chemotherapy alone (28.2% vs. 12.5%, p = 0.0007).

The results of prespecified Quality of Life analyses indicated that the benefits of bevacizumab in AURELIA extended beyond the prolongation of progression-free survival to include greater improvements in ovarian cancer associated abdominal/gastrointestinal symptoms.

No new safety findings were observed in the AURELIA study and adverse events were consistent with those seen in previous trials of bevacizumab across tumour types for approved indications.

AURELIA is the fourth phase III study of bevacizumab in ovarian cancer (following GOG 0218, ICON7 and OCEANS) to show that adding bevacizumab to chemotherapy significantly increased progression-free survival.
AURELIA was set up in cooperation with the Group d'Investigateurs Nationaux pour l'Etude des Cancers Ovariens (GINECO) and was conducted by the international network of the Gynecologic Cancer Intergroup (GCIG) and the pan-European Network of Gynaecological Oncological Trial Groups (ENGOT). The primary endpoint of the study was progression-free survival. The secondary endpoints of the study included overall survival, objective response rate, Quality of Life, safety and tolerability.

The full indication(s) for bevacizumab will be as follows:

Bevacizumab in combination with fluoropyrimidine-based chemotherapy is indicated for treatment of adult patients with metastatic carcinoma of the colon or rectum.

Bevacizumab in combination with paclitaxel is indicated for first-line treatment of adult patients with metastatic breast cancer.

Bevacizumab in combination with capecitabine is indicated for first-line treatment of adult patients with metastatic breast cancer in whom treatment with other chemotherapy
options including taxanes or anthracyclines is not considered appropriate. Patients who have received taxane and anthracycline-containing regimens in the adjuvant setting within the last 12 months should be excluded from treatment with bevacizumab in combination with capecitabine.

Bevacizumab, in addition to platinum-based chemotherapy, is indicated for first-line treatment of adult patients with unresectable advanced, metastatic or recurrent non-small cell lung cancer other than predominantly squamous cell histology.

Bevacizumab in combination with interferon alfa-2a is indicated for first line treatment of adult patients with advanced and/or metastatic renal cell cancer.

Bevacizumab, in combination with carboplatin and paclitaxel is indicated for the front-line treatment of adult patients with advanced (International Federation of Gynecology and Obstetrics (FIGO) stages III B, III C and IV) epithelial ovarian, fallopian tube, or primary peritoneal cancer.

Bevacizumab, in combination with carboplatin and gemcitabine, is indicated for treatment of adult patients with first recurrence of platinum-sensitive epithelial ovarian, fallopian tube or primary peritoneal cancer who have not received prior therapy with bevacizumab or other VEGF inhibitors or VEGF receptor–targeted agents.

Bevacizumab in combination with paclitaxel, topotecan, or pegylated liposomal doxorubicin is indicated for the treatment of adult patients with platinum-resistant recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who received no more than two prior chemotherapy regimens and who have not received prior therapy with bevacizumab or other VEGF inhibitors or VEGF receptor–targeted agents.