Pharma Strategy Blog

Today I will be out of the office at client meetings, but many of you will be wondering what will happen at the FDA ODAC briefing meeting, which will be discussing the bevacizumab (Avastin) data in breast cancer this morning. You can take a look at the briefing documents here.

Background

Avastin was approved to much fanfare because it was basically shown to shrink tumours quite dramatically and the early magnitude of the PFS data suggested benefit in favour of adding Avastin to chemotherapy.  According to the FDA, full approval would be thus debated once the final survival data were available:

“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.”

According to the FDA documents:

“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%).”

Breast cancer was one of the early tumour types that Genentech tested the drug in but despite promising phase II data, the phase III study was negative and thus they decided to go back to the drawing board with the statisticians and investigate the drugs safety and efficacy in another large scale phase III trial.  Meanwhile, colon cancer overtook breast cancer and became the first approved indication for Avastin instead.

Fast forward to 2010.

The data from AVADO and RIBBON1 is now available in the FDA briefing documents. Here is a quick synopsis from each.  I confess that I found the FDA summary of the data a little confusing, but the tables tell the picture more easily and have included the efficacy data tables from the briefing documents, where appropriate.

AVADO

This study comprised a double-blind, placebo-controlled, three-arm trial of:

• docetaxel plus placebo
• docetaxel plus bevacizumab 7.5mg/kg
• docetaxel plus bevacizumab 15 mg/kg

with all therapies given on a standard three-weekly schedule.

A total of 736 patients with HER-2 neu negative tumors who had not received prior chemotherapy for metastatic breast cancer were enrolled.

Overall the data was summarised as follows:

Source: FDA (pdf link)

The OS Kaplan-Meier curve for the AVADO study looks like this – you can see that they cross over just coming up to two years:

Source: FDA (pdf link)

The FDA went on to describe the tolerability data as thus:

“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.”

RIBBON1

This was a double-blind, randomized, parallel group study conducted in people with metastatic or locally recurrent HER2-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 either bevacizumab or placebo.

The efficacy data looks like this:

Source: FDA (pdf link)

The FDA also summarised the side effect profile:

“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.”

Essentially though, the incidence of AEs is not significantly different than currently described in the prescribing information.

Overall Conclusions:

In the summing up to the ODAC committee, the FDA briefing document declares:

“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 short answer is that the overall survival data suggested hazard ratios favoring the placebo arms in the AVADO study and the taxane/anthracycline cohort of the RIBBON1 study.  This is important, because it raises the issue of risk:benefit because the women are being exposed to significant toxic side effects with no impact on overall survival.

What next?

Looking at the data from the two trials objectively, it is hard to justify treating women with newly diagnosed breast cancer with Avastin, when they would appear to live longer and have less side effects with chemotherapy alone.  The PFS effect seen in E2100 has not been confirmed at all.

Ultimately, I think Roche/Genentech would have a much better case to argue to the FDA and public if they had a biomarker to determine which patients are likely to do better on bevacizumab therapy, just as erlotinib works better in lung cancer patients who are EGFR mutation positive.

I wonder what ODAC will decide?

My educated guess is that one of two scenarios might happen:

1. Approval remains, but modify the PI language similarly to Iressa to indicate that there is no overall survival advantage associated with adding Avastin to chemotherapy in breast cancer.
2. Withdrawal of breast cancer indication for Avastin.

Technically, logic would suggest the latter option is more likely given the rules governing accelerated approval, but these panels are a notorious minefield sometimes, very hard to predict and the FDA doesn’t always follow their advice, as the original approval for Avastin in breast cancer demonstrated!

What do you think?

{UPDATE: My educated guess was correct – ODAC voted 12-1 to withdraw Avastin from the market.  The big question now is what will the FDA decide?}

{UPDATE 2: FDA decided to hold a public hearing, now scheduled for Weds June 29th, 2011}