Gensi,
If the FDA wants to play hardball they'll have to remove the indication. I'm sure they'll face an uproar if they do.
FDA transcript:
Genentech, Inc submitted two efficacy supplements to the Biologics License Application (BLA) for Avastin (bevacizumab), STN BL 125085/191 (AVADO trial), and STN BL 125084/192 (RIBBON1 trial) to support label expansion for Avastin for first-line treatment of metastatic breast cancer (MBC) in combination with docetaxel, anthracycline, or capecitabine and to support conversion from accelerated approval to regular approval for first-line treatment of metastatic breast cancer.
Avastin in combination with paclitaxel received accelerated approval for first-line treatment of patients with MBC on February 22, 2008 based on the results of the E2100 study, a randomized, multicenter, open-labeled trial of bevacizumab with paclitaxel or paclitaxel alone that enrolled patients with HER-2 neu negative breast cancer who received no previous chemotherapy for metastatic disease. The addition of bevacizumab to paclitaxel resulted in a 52% increase in progression-free survival (HR 0.48, 95% CI 0.39, 0.61; p< 0.0001) with an observed 5.5-month difference in median PFS, based on an independent radiographic review. There was no significant difference in overall survival, a secondary endpoint, between the two treatment arms. The tumor response rate was higher with bevacizumab plus paclitaxel as compared to paclitaxel alone (48.9% versus 22.2%).
As a condition of the accelerated approval, Genentech was required to submit data from two ongoing, placebo-controlled trials (AVADO and RIBBON1) to provide verification of the treatment effect on PFS and to provide additional information on the effects on overall survival.
AVADO (STN BL 125085/19) was a double-blind, placebo-controlled, three-arm trial of docetaxel plus placebo, docetaxel plus bevacizumab 7.5mg/kg, and docetaxel plus bevacizumab 15 mg/kg. A total of 736 patients with HER-2 neu negative tumors who had not received prior chemotherapy for metastatic breast cancer were enrolled. The addition of bevacizumab 7.5 mg/kg to docetaxel resulted in 30% increase in progression free survival [HR 0.70 (95% CI 0.55, 0.90)] with an observed 0.8-month difference in median PFS while the addition of bevacizumab 15 gm/kg to docetaxel resulted in 39% increase in progression-free survival [HR 0.62 (95% CI 0.48, 0.79)] with an observed 0.88-month difference in median PFS. Objective responses were observed in 44% of patients in the placebo arm, 55% in the bevacizumab 7.5 mg/kg arm (p-value 0.0295) and 63% in the bevacizumab 15 mg/kg arm (p -value 0.0001). Mature survival data showed a HR of 1.103 (95% CI 0.84, 1.45) favoring the placebo arm over the 7.5mg/kg bevacizumab arm. The HR for overall survival was 1.003 (95% CI 0.76, 1.32) for the 15 mg/kg bevacizumab arm compared to the placebo arm
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Safety data showed an increase of grade 3-5 adverse events, serious adverse events and study drug discontinuation with the addition of bevacizumab to docetaxel. More patients in the bevacizumab-containing arms required interruption/dose reduction or discontinuation of docetaxel due to an adverse event.
RIBBON 1 (STN BL 125084/192) was a double-blind, randomized, parallel group study conducted in women with metastatic or locally recurrent HER 2- neu negative adenocarcinoma of the breast, who had not received prior chemotherapy for their advanced or metastatic cancer. A total of 1237 patients were randomized (2:1) to receive anthracycline- or taxane-based chemotherapy (n=622) or capecitabine (n=615) in combination with bevacizumab or placebo. The taxane/anthracycline cohort and capecitabine cohort were analyzed as separately with the alpha split equally (1-sided a 0.025) for comparisons of PFS within each subgroup.
The addition of bevacizumab to taxane/anthracycline-based chemotherapy resulted in 36% increase in progression free survival [HR 0.64 (95% CI 0.52, 0.80)], with an observed 1.2-month difference in median PFS. Objective response rate was higher in the bevacizumab containing arm, with an absolute increase of 13.5 % (95% CI 4.6, 22.3%) with the addition of bevacizumab to anthracycline/taxane-based chemotherapy. Mature survival analysis yielded a HR of 1.11 (95% CI 0.86, 1.43) favoring the placebo arm.
The addition of bevacizumab to capecitabine resulted in 31% increase in progression free survival [HR 0.69 (95% CI 0.56, 0.84)], with an observed difference of 2.9 months in median PFS. Objective response rate was higher in the bevacizumab containing arm, with an absolute increase of 11.8 % (95% CI 3.4, 20.2 %) observed with the addition of bevacizumab to capecitabine. A comparison of the mature survival data for the capecitabine cohort showed a HR of 0.88 (95% CI 0.69, 1.13) favoring the bevacizumab containing arm.
Overall, the incidence of grade 3-5 AEs and serious AEs were almost twice as high in the bevacizumab arms compared to placebo arms in both cohorts. In the taxane/anthracycline cohort, taxane subgroup, there was slightly more deaths in the bevacizumab containing arm than placebo arm (49.8 % versus 43.1 %). The vast majority of the deaths were attributed to breast cancer. Adverse events known to be caused by bevacizumab were, as expected, increased in the bevacizumab containing arms in both cohorts. The most common AEs associated with bevacizumab were hypertension, bleeding/hemorrhage and febrile neutropenia. The incidence of AEs is not significantly different than currently described in the Avastin® package insert.
The key issue for discussion is the balance of benefit versus risks. AVADO and RIBBON 1 are well conducted, double-blinded trials. The magnitude of the improvement in PFS observed in these two studies failed to confirm the magnitude of PFS improvement observed in the E2100 trial, the basis for the accelerated approval. The magnitude of treatment effect is clinically important because it is really a measure of delaying symptoms from tumor progression, which has to be weighed against drug toxicity that is present for the duration of treatment. The addition of bevacizumab to chemotherapy resulted in an increased rate of serious adverse events, of grade 3-5 adverse events and of adverse events attributable to bevacizumab in both studies. Overall survival data showed hazard ratios favoring the placebo arms in both the AVADO study and the taxane/anthracycline cohort of the RIBBON1 study.
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