Dr Jeffrey Weber – Perlmutter Cancer Center, New York, USA
Dr Axel Hauschild – University Hospital, Schleswig-Holstein, Germany
Dr Dummer Reinhard – University of Zurich, Zurich, Switzerland
How would you decide which treatment to use for advanced melanoma patients?
JW: The easy answer is that anyone who has BRAF wildtype disease would be a candidate for nivo adjuvant therapy. When you come to the BRAF mutant population, again, you’re going to have to do an apples and oranges comparison. You can do some sleight of hand statistical arguing to try to compare the two trials and make a decision what you should do with your BRAF mutant population and if you do this sleight of hand you would have to subtract the stage 4 patients and only look at the stage 3b/3c patients from the 238 trial. You would have to go to the COMBI-AD trial and then subtract the stage 3a patients who would have a significantly more favourable outcome and that was about 18-19% of the total. Then you would have to start cutting and slicing and making assumptions about the hazard ratio which in the COMBI-AD trial was against placebo whereas in 238 it was against an active control arm, active not only in relapse free but overall survival. If you do such a, probably as we would say, non-kosher statistical analysis you come up with a hazard ratio of nivolumab versus placebo that’s at least as good as what was seen in the COMBI-AD trial, maybe better, but again these are, as I said, hand-waving arguments. So at the end of the day, if you wanted to do that, you would have two great choices. It comes down to whether you believe there will be a tail on the curve for immunotherapy with relapse free survival in the adjuvant mode as you see in metastatic patients compared to a lesser tail on the curve for BRAF MEK drugs in the metastatic mode. It’s going to be a tough decision. I would think, I would speculate in the US at least, a lot of docs will like immunotherapy and will use nivolumab even in the mutated patients and a considerable number of patients will get BRAF MEK in the adjuvant setting.
Professor Hauschild, would you like to add something and then the commentator please?
AH: Yes, after this very eloquent and sophisticated response by Dr Weber I need to say the patient perspective might be different because one is an immunotherapy which needs to be given two weekly with infusions, the other one is an oral therapy. So that’s two differences. They have completely different toxicity profiles so there are patients who will be considered not to be good candidates for targeted therapies or not to be good candidates for immunotherapies. So that’s practical considerations. As for stage 4 disease it’s a bit of gut feeling. I don’t think that we will have any direct comparison because it was not a head to head comparison of nivolumab versus dabrafenib and trametinib. Therefore we can speculate whether one is superior to the other one but this would be unfair. So let’s say they are equivalent and then it’s a choice of the physician in discussion with the patient if you are choosing tyrosine kinase inhibitors or immunotherapies. In Europe I would say it’s not always the same as in the US. There is also an enthusiasm for immunotherapy but still there is a role for tyrosine kinase inhibitors. In the BRAF V600 mutated patients I would say there’s a good chance that these patients receive this first. The burning question for me is another one: once you give these immunotherapies or the targeted therapies as an adjuvant treatment will these patients have the opportunity to be re-treated once they progress to stage 4 disease? This is a burning question for the future and we learned at this ASCO conference three months ago that the rechallenge with tyrosine kinase inhibitors leads to a very good success, not in the same magnitude as the initial treatment but the rechallenge, particularly of those patients who didn’t progress on the adjuvant treatment, might be a good opportunity. We will be able to analyse this in the COMBI-AD clinical trial because there were almost 30% of patients who got a rechallenge of BRAF plus MEK in the subsequent salvage therapies which is really interesting. The analysis is not yet ready but it will be done.
I invite the commentators to give an opinion on this.
DR: Maybe I’ll start. The good news is that we have two positive clinical trials and the results of these trials are extremely encouraging. Both of the results will change our current practice. Today we are using interferons, some centres are using irradiation therapy, some people are using alternative medicines. Many treatment options and now we have two options that have been investigated very carefully. A direct comparison of these two studies is very challenging so we have different inclusion and exclusion criteria. In Professor Weber’s trial we have metastatic patients included; in Dr Hauschild’s trial we have stage 3a patients included. Here we have a placebo control, on the other side we have an active control arm and the BRAF MEK inhibitors can only be given in a subpopulation, so the patients with the mutation. So a direct comparison is really very difficult so just stay with the facts, no speculation. We have two treatment options and the future will show which is the more beneficial.