First we had the usual small talk…How ‘bout those O’s?  How ‘bout those National’s?  Boy, do they ever suck!  Did you see any Ravens games this year?  Blah, blah, blah.

Before we got into the nitty gritty Dr. Levitsky said that while he’s done consulting work for Dendreon and he was one of the inventors of GVAX, HE DOES NOT OWN ANY SHARES IN EITHER COMPANY!!!

I then asked him if it was ok for me to record our conversation.  He said that that would definitely be ok…  “R” = Rufus and “L” = Levitsky:

R.   O.K, I guess it’s working now. O.K I sure as Hell hope it is working.   Um anyway, I got some questions to try and get myself a framework. Would you mind if I go through some of these?

L.    No, I will do my best

R.    I will probably go off on some tangent here, but uh, uh, so a basic question I ask first is what does   this mean to guys like you in the field of tumor immunology?

L.    I feel you can answer that question a whole number of different ways.  I guess the first thing I would like to say before I answer any or your questions,  just for the record is, I haven’t seen their  data and none of us will until this urology meeting that they are going to present at.  But,  I have seen the same press release that you have seen and  Mitch Gold has certainly used adjectives that  would infer that their trial is positive and has met its  predetermined goals and it will be  very interesting to see the specifics of it and how it compares to historical controls,  how it compares to the results of  tests  and even how it even compares to the negative GVAX  Study,  recognizing that it is looking across trials. 

But in terms of your question, how this impacts on the field of tumor immunology, I feel it will very much depend on the nature of the data they present, assuming for the sake of discussion, that this is  an unequivocal and unambiguous  win, then I think it will have a very significant impact.  Number one,  I think that unless there are aspects to this that have not been made public, I think the FDA  would in this instance  need to move it forward in the approval process and I think that  how it ultimately gets integrated into clinical practice will be a fascinating thing to watch.  In terms of when it is used and how it is integrated and sequenced with the cytotoxics comes to be a pattern in which it is used.   In terms of the field more broadly, I think there are a lot of naysayers out there, and to be fair, there has been a lot of reason for naysaying and it has been difficult for any of the cancer vaccine platforms to cross this milestone. And to have one do it is sort of like breaking the sound barrier. When it happens than everyone says, “Well I guess it can happen”.   I think it really opens a path for other opportunities for other approaches.  It is interesting, I would also comment, not only if this is approved, not only would this be the first cancer vaccine in the U.S to be approved, it so happens, it is a patient specific product  as opposed to an off the shelf product.  That also runs counter to a sort of conventional wisdom in this world that at some time has levied against these kinds of individualized therapies.  So, I think that from a number of perspectives it is really quite interesting.

R.    You touched on the old RECIST  versus survival debate and the research of Dr. Schlom  at the National Cancer Center.  He has had a running debate going on with Steve Rosenberg …

L.    I think a lot of people have.

R.  You talk about conventional wisdom.  Do you feel that the FDA and the conventional wisdom has been stuck on this as a result of this tumor size reduction paradigm and sort of missed the boat, going the survival route.  It seems like the war on cancer has been stuck by looking at basically a cytotoxic route and not really impact of survival in a lot of  solid tumors and they have  kind of slowed down the process now, is my perception.  How do you feel about that?

L.    Well I think it is important to acknowledge, and all parties to acknowledge, this if they are confronted with it.  It is important to acknowledge that tumor response is a surrogate endpoint.  It is a surrogate endpoint for perhaps 2 other endpoints that might be more meaningful.  One is overall survival which is the gold standard and the other perhaps is the quality of life.  No one can argue that those two things have sort of the paramount  importance where as to an objective 50% or greater reduction  in the mean diameter of all measurable tumor masses is an interesting yard stick, but it is only a yard stick.             

R.    Uh ha

L.    And, I understand why it was put out there and made intuitive sense that if your therapy couldn’t do that, than how would it achieve any of the other outcomes?   And the reciprocal is also true, or was also believed to be true.   If it did achieve some of those objectives, there was the likelihood that it would also prolong survival and improve quality of life.  And I also believe that for a large number of cancer types this has proven not to be the case.  And you know it is unfortunate because this is not only an argument that contrast classical chemotherapy to other forms of therapy such as immunotherapy,  it is true for even cytotoxic chemotherapy , that the surrogacy of a measurable disease response has now been brought into question.  This relates to overall survival.   And one of the implications of that is, if the paradigm is  you start with advanced disease,  you look to see if a new drug, or a combination of drugs that you are testing, results in the regression of the tumor, and ultimately if it does, do you consider moving into earlier stages of disease?  You have probably thrown out a lot of potentially useful drugs with that kind of a paradigm. 

R.    Yah, it seems sort of backasswards if you are talking about a cancer vaccine that would intuitively work better the earlier you get it.

L.    It is backwards and the history of that does come from cytotoxics which is that they are toxic just as the name implies

R.    Right

L.    And it was felt to be ethically only justifiable to test it in a setting where it was clear that things were pretty desperate and you needed something.  The challenge with doing studies in the states of minimal residual diseases is that for many cancers, a fraction of the patients are already cured by just what the surgeon did.

R.    Oh

L.    And you don’t know who they are.  So the question is; can you in good conscience expose otherwise healthy cured individuals to the risk of toxicities of an investigational drug.  And that was the logic which lead to what was referred to as the “ass backward approach”, but I think if you show in a small number of subjects that a new therapy is safe, than I think that the logical thing to do is move it into the early phases of the disease.  Now, let me just comment in fairness to the critics of the approach, one of the challenges, it takes a very, very long time to show an affect with that kind of protocol design.  Many companies don’t have financial runways that will allow them to get approval before they run out of funds.  That is one challenge.  The other challenge is that with overall survival as an endpoint,  obviously once somebody has appeared to have failed whatever experimental therapy you are testing, they have the desire and of course the right to pursue something else.  Right?

R.   Right

L.    So, it becomes tricky to evaluate survival after investigational drug X, if after they failed or seems to have failed drug X, they go get drug Y

R.    Well, I want to get to “seems to have failed drug X” issue.

L.   Uh ha,

R.    Former ODAC chair, Philip Schein, one of the leaders in combination of drugs, chemotherapy along with Vincent  DeVita.  He made the point that, in a couple papers of his, that the hurdles that the FDA puts forth for drugs that are meant to be for fatal disease, it seems to be ridiculous  to make a standard of .05 for P value.  A standard that was developed by a biostatistician in 1930, Dr. Fisher, People would be able to capitalize on that if you made it .06 or .07. Why make it , if you look at the Dendreon case with Provenge, the initial phase 3 number 1 goal was time to tumor progression and they came in with .052.  It seems that under Dr. Pazdur, the hurdle has been raised and the statistical dogma has become exactly that , dogmatic, Dr. Flemming has seemed to back him up on that.   Do you think that has been slowing the progress on things like immunotherapies and even other chemotherapies? 

L.    Yes, these are all good questions.  And I think that issues of the drug approval process and how the rules are set is an extraordinary challenge, and I have strong opinions about this as a scientist and as a physician that cares for patients.  I will comment on my own beliefs in just a moment.  It is important to recognize that whoever sets this policy has to do so with the recognition that is really the interface between science, medicine and the business world.  And that wherever the bar is set it cannot be arbitrary.  It can’t be, “we will do it one way because that is how we feel today and we will do it another way because that is how we feel tomorrow”.  It has to be reasonably unambiguous so that the investment community and other people that choose to place their bets, in the business sense of the word, know exactly what they can anticipate.  I’m conceding that there are challenges to doing it.  Having made that concession, I feel the way it has been done is not in the best interest of patients.  I also think that just as science and our knowledge of biology evolves, we should also take fresh looks at the way we test and ultimately approve drugs for cancer.  I am saying 2 contradictory things, you have to have consistency and you also have to evolve.