Podcast: ESMO 2011 Interview with Professor Jan Vermorken analyzing the results of the phase III SPECTRUM trial

EJCMO.tv:  Prof. Jan Vermorken is currently Professor of Oncology at the University of Antwerp.  Prof. Vermorken, hello and welcome to EJCMO.tv from ESMO.

Professor Vermorken:  It is a pleasure to talk to you.

EJCMO.tv:  You gave a number of important talks at ESMO this year. One that really stands out is a late breaking abstract that analyze the results of the phase III SPECTRUM trial.  Can you tell us a little bit more about this trial?

Professor Vermorken:  The SPECTRUM trial is a trial in patients with what we call recurrent and/or metastatic head and neck cancer.  That means that the patients have been treated in the past for their head and neck cancer and then have shown a relapse later on.  These patients were treated by chemotherapy or chemotherapy plus a monoclonal antibody (mAb) against epidermal growth factor receptor (EGFR) and that compound is calledpanitumumab.

I presented that study for the first time at ESMO last year and that study which comprised of a total of 657 patients had as a primary endpoint, an improvement in overall survival.  This was a global study so it was performed worldwide and about one third of the patients were treated in Western Europe, about one third were in Eastern Europe and the remaining in North and South America and the Asia Pacific. That study unfortunately, although there was clearly an indication that there was some improvement, did not show that the overall survival was significantly different.  Nevertheless, the patients who received the combined treatment had a median survival of 11.1 months and those who had chemotherapy alone had a mean survival of 9 months.  It also showed that the response to treatment was significantly higher in the patients who had a combined treatment and the disease control was also significantly better in the combined treatment.  The progression-free survival, which means the survival for the patients without a progression event was significantly better.  There were clearly indications that adding panitumumab to chemotherapy improved the outcome.  What I presented here at the congress was something completely new and we try to find whether the addition of panitumumab to chemotherapy leads to any other results when we look at the patients who had tumors that were human papillomavirus (HPV) positive or negative.  We were fortunate enough that we had a large proportion of patients from whom we got tumor tissue material to investigate.  In total, we had about 67% of all the patients that entered into trial.  We had tissue material and it proved to be analyzable and valuable in 411 patients. What our study showed was that the addition of panitumumab significantly improved survival only in the patients with HPV-negative tumors.  It has not shown clear benefits in the HPV-positive tumors.  It was a surprise to us because as mentioned, we did not find a significant difference in survival in the overall analysis. Now, we suddenly found a significant difference in survival that in the HPV negative set of patients.  We also stated that this is something that also needs to be looked into in other trials that have been performed in the same sort of patients. If that is being confirmed, then we should do trials in patients with relapsed head and neck cancer in the future where we separate the patients who have HPV-negative and HPV-positive tumors.

EJCMO.tv:  Which head and neck cancer sites were covered in the trial?

Professor Vermorken:  All four disease sites were involved.  If I look at the total number of patients in the SPECTRUM study of the 657 patients, we had oropharynx cancer in 26%, larynx cancer in 31%, oral cavity cancer in 27% and hypopharynx cancer in 16%.  In the patients that we looked at and presented two days ago, these figures were respectively 29%, 29%, 31% and 11%.  This means that the patients we analyzed for HPV were very much comparable to the whole patient population in terms of disease origin distribution.

EJCMO.tv:  Were the results consistent across all the sites?

Professor Vermorken:  I cannot say that with certainty.  On the other hand, what is very clear is that when we did a Cox regression analysis, which takes into account different prognostic factors, we could not find that there was a difference with respect to the different disease origins.

EJCMO.tv:  Which receptor does panitumumab target?

Professor Vermorken:  The receptor that is being targeted by panitumumab is the EGFR.  EGFR is being expressed in squamous cell carcinoma (SCC) of the head and neck in nearly all patients.  However, the level of expression is correlated to the outcome in a sense that those who express it very highly in general, are doing worse than those who have less expression.

EJCMO.tv:  Pre-clinical results seem to show that antibodies work very synergistically with chemotherapy.  Can you please explain this further for our listeners?

Professor Vermorken:  It means that what we have seen in pre-clinical work especially in the nude mouse models is quite interesting.  We have seen that if we give chemotherapy or radiotherapy to these animals and if we add antibodies against EGFR, the effects are significantly better.  It is very interesting because it means that what we have seen in the clinic in fact is very much in line with what we have seen in pre-clinical work.  It is not only surprising because we do not see that always, but it seems that the pre-clinical work here was quite predictive of what we saw in the clinic.  May I remind you that a trial which was published in the New England Journal in 2006 by Dr. Bulmer et al showed that if radiation is combined with cetuximab, which is also an anti-EGFR mAb, it had better local regional control and a better survival than the patients that were treated with radiation alone.  Together with a lot of collaborators, I have published a paper in 2008 that showed that in recurrent metastatic disease, the addition of cetuximab to chemotherapy also significantly improved survival.  This is something we have not seen before in 30 years.  That was quite a very important message and I can only hope that this is the beginning of something very beautiful that we are getting more drugs and compounds available to combine with chemotherapy or even combine different biological agents and hope that we can further improve the outcome for the patients.

EJCMO.tv:  This year at ESMO, there have been a few expert debates, some of which that you  chaired looked at the possibility of managing patients with HPV-positive tumors differently from those with HPV-negative tumors.  Did the results of the spectrum trial help better answer this question perhaps?

Professor Vermorken:  I do not think so at the moment because what you are referring to is untreated patients with locally advanced disease and then we talked about the four groups like oropharynx, larynx, oral cavity and hypopharynx.  What we have seen especially in oropharynx cancer is that the oropharynx cancer can over time, if I can compare this with let us say 15 years ago, worldwide, there is an increase in the incidence of viral associated oropharynx cancer.  So, HPV seems to be epidemic when it concerns oropharynx cancer.  The number of oropharynx cancers that are induced by smoking and alcohol is going to decrease because less people in the western world are smoking and we see an increase in the number of oropharynx cancers that are viral induced or HPV related.  Now what we know is that the viral associated orpharynx cancers have a better prognosis than the tobacco induced ones.  In fact, if you look at the five-year survival of these HPV positive tumors, especially in the non-smokers, they are doing very well.  The discussion then came up.  Should we then treat these patients with the same aggressive treatments as the patients that have tobacco induced tumors?  Although we all know that these patients are all doing better, we do not know if this is because of the treatment we gave them.  If we then have a debate treating them differently, then we first have to show that they will do as good as they do now with less intensive treatments.  Therefore, the conclusion of the debate was that the majority ultimately by the end of the debate, agreed that at the present time, we should not treat them differently but we should do trials separately in patients with HPV positive tumors and in those with HPV negative tumors.

EJCMO.tv:  What is next to clinical research in SCC of the head and neck?

Professor Vermorken:  That is not a very easy question.  I think what is next is we have the intention now to have a more personalized approach.  That means that we can distinguish different group of patients with different risks with respect to outcome.  What we are planning is to do separate trials in these different cohorts.  Patients with the highest risks may need more treatment and even perhaps more aggressive treatment.  Those who have lower risks may be given less aggressive treatments, a clear example of which I have given are those with HPV positive tumors.  This will take quite a lot of years to do all these trials in these different cohorts of patients.  I think what is very important then for research is that we define what we would call biomarkers that further distinguish different groups of patients that may need different forms of treatment.

EJCMO.tv:  Dr. Vermorken, thank you so much for joining us today.