BSR_David

Dendreon: The FDA's Commissioner Doth Protest Too Much!

"Been There" doesn't have the facts straight. Let's look through them...

> Provenge failed to prove effectiveness several years ago, but did
> show an apparent activity in a subset of patients. Dendreon then
> did a second phase III trial in the subset as requested by the FDA.

The IMPACT trial (9902b) was originally designed by Dendreon to look at Gleason < 8 patients. This was not at the request of the FDA. IMPACT was subsequently amended to look at patients of any Gleason score. 9901 showed a survival advantage and was nominally statistically significant on the primary endpoint of survival. When adjusted for imbalances favoring the control arm, 9902a was also statistically significant for survival. Pooled data from the two trials, which were designed to be pooled, showed a statistically significant survival advantage on an adjusted and unadjusted basis. In each case, the survival advantage was also highly clinically significant.

> Recently Provenge failed to show efficacy in that subset, but
> apparently did show efficacy in a subset of the subset.

I have no idea what you are talking about here. There have been no substantially new data on Provenge since 2005. All data ppints mentioned above were intent-to-treat analyses and not subset analyses.

> The FDA should now require a third phase III trial to prove that
> Provenge actually works in the subset of the subset.

The "third" IMPACT trial was started years ago and enrolls all HRPC/AIPC men with minor pain. This is not a subset nor a subset of a subset.

> I would suggest that Dendreon find a biomarker for the subset of
> the subset of patients, because if they can not identify the subset
> of the subset of the patients that walk into a doctors office, then
> their patients will not be able to be identified and I suspect the
> responsive patient numbers will be under ~10% of the total patient > population and Provenge will not be approved.

Again, there is no need for a subset biomarker since the survival data were positive across all men regardless of Gleason score in a standard intent-to-treat analysis of the entire randomized population.

In the first two trials, Dendreon screened patients for PAP expression since Provenge is targeted to the PAP antigen. This was dropped in IMPACT and it remains to be seen if it will have any effect. Since only 5% of men were screen failures in 9901/9902a due to PAP expression, it is mathematically unlikely the lack of screening will make a difference.

> The patients may be unhappy, but there is a background of cancer
> patients who will actually survive without chemotherapy or
> immunotherapy, again a group who can not, as yet, be identified,
> prospectively.

Actually, they can be identified prospectively. It's called a nomogram and was published by Halabi et al a number of years ago. There have been several other concepts put forth to identify HRPC patients of high, medium, and low risk. Provenge would be best used on the latter two categories as a monotherapy. In high-risk patients, Provenge has been shown to confer a survival advantage, but that advantage might be magnified when used in conjunction with chemotherapy for younger men and/or those can stand the considerable side effects of Taxotere. A prospective combination trial needs to be run on combination therapy.

While comparisions between the 9901 and TAX-327 trials are difficult, it appears Provenge provides superior survival benefit to Taxotere at comparable projected costs and lower side effects across all patient subsets.

> So, at the moment, Provenge does not seem to be any better than
> no treatment or at least the standard treatment, which is not very
> good either.

This is simply not accurate. The data clearly contradict. You can also examine the positive advisory committee vote on the two questions of safety and efficacy. Finally, a careful analysis of the committee transcript shows a majority (9-8 or 10-7, depending on how you score) of panel members also thought the drug should be approved.

> The author owns no cancer vaccine stocks, but does agree that
> committee members with the stock ownership indicated should not
> be on the committee for this compound.

Part of the problem here is the concept of conflict of interest is limited to stock ownership. It took a decade to get the current large Taxotere adjuvant trials started. It was clear from Hussein and Schers' letters they were worried that the approval of Provenge would hurt enrollment of these trials, which they personally and financially benefit from either directly or through their institutions' participation in these trials.

> However, I also think the last advisory committee was incompetent
> to judge Provenge

The committee members included some ofthe country's leading immunology and immunotherapy experts. Special expertise in cardiac effects of immunology was added to address adequately questions of CNS safety. Only someone who is hung up on the chemo-centric practice of oncology would say the panel was incompetent.

I could also argue there should have been no oncologists on the panel at all, since the treatment of asymptomatic HRPC is almost exclusively the province of urologists. So if the lack of more urologists is leading you to make the statement above I agree.

Oncolgists are economically threatened by this drug. Its easy and essentially side-effect free administration and survival benefit means urologists will hang on to patients (and their revenues) longer.

Oncologists are only now comprehending the idea of a cancer drug that has patient benefit without shrinking tumors. I suggest you look up the 2006 NCI/FDA symposium on immunotherapy and brush up on the science before assuming oncologists are the only people qualified to judge cancer drugs.

> I am happy the FDA stuck to their
> principles.

This is a joke. In the last 18 months, the FDA turned down multiple oncology drugs that hit a primary surrogate endpoint but failed to show statistically-signific... survival benefits under the rationale that surrogate success without survival benefit is not success at all.

Contradicting this reasoning, they turned down Provenge because it was only nominally statistically significant on a primary endpoint TTP (an endpoint ODAC said in 2005 was not suitable for making an approval decision on in PCa) ignoring its highly and robustly statistical significance on survival.

Contradicting themselves again, they approved Avastin for breast cancer against the recommendation of their ODAC panel. Avastin was positive on the surrogate of PFS, but negative on survival.

I have no idea what "principles" you are referring to, but there aren't any in the oncology division by any objective analysis of their decisions in the Pazdur era.


None of this is proof the IMPACT trial will be successful. If it was, we wouldn't have to run the trial. It does prove, or at least cast serious doubt, on the idea you are familiar enough with the facts of this situation to comment authoritatively.