We are talking here about immunotherapy in a paediatric cancer, in neuroblastoma. We have a big high-risk front-line trial, High Risk number 1, that addressed previously two immunotherapy questions on how immunotherapy should be given most adequately.

In Europe we developed dinutuxuimab beta and in the US there is another molecule, dinutuximab, but they are functionally and molecularly different molecules although name wise quite alike. In the earlier results the 2-year event free survival rates of both products in the hands of each of the cooperative groups in the US and also in Europe looked very much alike in terms of survival rates reaching about 60%. So we were thrilled by the outcomes in high-risk disease. It’s worth it here to say that in the US it was used in a combination with IL-2 plus GMCSF and in Europe plus IL-2 because GMCSF was not available. We also used IL-2 subcutaneously to reduce the toxicity profile.

So, as things evolved over time and these were two outcomes that we reported previously at ASCO as an outcome of two immunotherapy randomisations, that IL-2 does not impact the outcome. This can be safely left behind. So this is the important message that we want to bring because our next step was really once we had ruled out IL-2 for the toxicity burden to further investigate if side effects of the antibody that has a couple of side effects that are important to the children, most importantly pain but also allergic reaction as one of the predominant ones, that this again could be significantly reduced by prolonging the infusion time from previously five days to a total of ten days but the total dose of the antibody given per cycle with 100mg/m2 total cycle dose stayed the same in both application modes. So we have an 8-hour infusion in the short-term schedule and we have a 24-hour infusion over ten days in the long-term schedule.

What are the clinical implications of these findings?

The most important clinical impact that we could demonstrate here, even if we left out the use of IL-2, so we lowered the toxicity profile, looking at the total cohort that we have in the trial, that we had a significant improvement of 10% by using the long-term infusion scheme. So that was possible that we took the populations from both randomisations in the high-risk arm and made it also very clear for interfering risk factors because there were two high-dose regimens in question previously. So we focussed on busulfan melphalan treated patients. Notably, one also has to remember whoever was ready to undergo high-dose treatment would have cleared the bone marrow and only have three skeletal [??] positive spots.

So, having said all this, we were coming out with a cleared population that we used for this comparison of 345 and 360 patients out of these previous randomisations. This is where we see this very clear advantage in event free survival which is in the overall group 10% and in the stage 4 patients, solely focused on, 11%. That means also if you translate it into the cumulative incidence of relapse rates, also to translate an advantage of more than 10% of reducing effectively the relapses in this very population.

So we thought that this is a major finding that can be explained by a number of actions in the background. We do believe that immunotherapy works differently and the prolonged scheme gives a chance to achieve a higher AUC and a higher factor activation over the longer time-span, finally resulting in these markedly improved significant results.

Is there anything else you would like to add?

For the future, what I would like to add is the point of the ten days of treatment, that it sometimes comes into discussion. It’s very important to note that it’s for the first cycle important to have the patient in the hospital to understand the individual patient’s tolerance. But the profile of toxicity reaction goes down cycle by cycle and after cycle 1 there are more and more patients that can be treated in home care with pump infusion systems. So it’s not a day by day cost in the hospital but they also can be safely released in a home care setting. I think that’s a very important take-home message.

Obviously we are only happy if all the patients survive. So this is now subject to early trials and investigations of newer immune modulators that hopefully would increase the efficacy without increasing toxicity.