Replies to post #710 on Dendreon Corp fka DNDNQ

[poorgradstudent]

>If they did not reveal the stat sig covariate, the analysis was not accurate. And if that wasn't, their reputation would be on the line.<

Higano makes it clear that the 5 that she is examining were found in 9901. The transcript is quite clear... they simply used 9901's findings to define their realm of covariates for 9902a. And importantly, there is no deliberate or misleading omission of 9902a-specific stat sig prognostics because there is no presentation or representation that the 5 listed were from an exhaustive analysis of 9902a itself. It is simply reported that they took the 5 from small's presentation and adjusted 9902a's p value accordingly.


Transcript:

"In the earlier 9901 study an analysis was done adjusting for differences in prognostic factors. Dr. Small already presented this analysis in detail at ASCO, but to review these five prognostic variables remain significant after treatment effect and were used in a COX Proportional Hazards Regression model. After adjusting for prognostic variables, survival in the APC8015 arm becomes significant with a hazard ratio of 1.9 and a P-value of 0.023."

[io_io]

"If they did not reveal the stat sig covariate, the analysis was not accurate. And if that wasn't, their reputation would be on the line."


Meaning ? I wouldn't agree with the normal meaning of your first sentence either. But I doubt that's what you are trying to say.

[rancherho]

The discussion of 9901 and 9902a seems somewhat historical and reactive (my 8 introductory words)

ocyanblue:
1. It seems like PGS likes to beat the issue of covariates to a meaningless pulp.

2. What would really be interesting is to use those same covariates to bullet proof the CD54 (ICAM-1) upregulation vs. survival data that Dr. Provost presented to the CBER Advisory Committee on 2/9/06.

3. There are many good studies linking: (a) CD54, aka ICAM-1, the Provenge potency marker, and (b) dendritic APC trafficking to secondary lymphoid tissue- more likely with the infusion of Provenge rather than injection and injection site recruitment of dendritic cells- to the increased priming of long term central memory T cells. High levels of central memory T cells targeting PAP and related antigens through epitope spreading would be extremely important in suppressing slow growing, widely disseminated tumor cells in AIPC, and would be consistent with Provenge's 36 month survival results. In addition, the Fishers Exact P values in the 9901 trial presented by Dr. Hershberg to the Cancer Vaccine Consortium Working Group on 11/10/05 (with key FDA CBER docs reportedly present during that meeting)showed that the p values for survival got worse and were not statistically significant for those who received chemo, even after Provenge, possibly due to chemo's destruction of memory T cells as documented in studies of other vaccines. New microarray diagnostics developed at the NCI that can measure memory T cell levels are now available, which could be very useful in connecting the in vivo effector bullets with the smoking gun of ex vivo Provenge processing.

4. As you have noted in the past, the 2/9/06 CD54 upregulation data incorporated in Dr Provost's presentation must have been a work in progress since it was incomplete with respect to 9901 and 9902a ITT and crossover data as well as P-11 enrollee data. Also, describing data as above and below median, as it did, is done more with a meat cleaver than with scientific precision. The 40% survival at 36 months for those with above median CD54 upregulation is obviously balanced by a lower figure below median to yield the overall 34% 36 month survival rate.It would seem that a plot of all CD54 upregulation data vs. survival corrected in some maner for Cox covariates found to be statistically significant for survival would be a more precise and useful tool for both DNDN and prescribing docs. It could also head off the almost predictable sniping that those with high upregulation just happened to be the healthiest patients.

5. DNDN's PR has apparently mentioned to other posters that DNDN is already working on an enhanced version of Provenge. Since Dr. Provost mentioned that there was a CD54 uptrend on subsequent doses, this could be as straightforward as giving additional Provenge doses until an individual patient reached his maximum achievable up regulation and the level of memory T cells was maintained thereafter. There are also several ex vivo and in vivo methods discussed in the literature of potentially increasing ICAM-1. One of the in vivo adjuvants used with relative success in past clinical trials was the TRICOM adjuvant developed by the NCI and used with the Therion pc vaccine, although it could not rescue the underlying vaccine.

6. There are other factors such as the degree of epitope spreading / antigen cascade and the in vivo regulatory T cell environment into which Provenge is infused that may become increasingly important in the future for optimizing its use. For now, it's likely that CD54 / ICAM-1 may take center stage and its role in connecting the dots on Provenge's cause and effect will go a long way in proving its case. My guess is that many years from now, with the prodding of cancer, autoimmune diseases and avian viruses and the like, many of these somewhat esoteric immunity system concepts will be commonplace and taught in good HS biology classes with future generations wondering what was so revolutionary about developing the first therapeutic cancer vaccine.

Good luck to you and to all DNDN longs.