Results of subgroup analysis of the HELIOS trial

Dr Paula Cramer – University of Cologne, Cologne, Germany

Would you like to tell us a bit about your research and the HELIOS trial?

So let me begin with a summary of the trial which was already presented at ASCO and EHA last summer. This trial was designed to evaluate the addition of ibrutinib to bendamustine rituximab and in total there were 578 patients included and randomised to receive six cycles of bendamustine rituximab combined with either ibrutinib or placebo in a double blind fashion. The [?? 0:38] was continued until progression and patients from the placebo arm were allowed to cross over after confirmation of their progression by an independent review committee.

The findings of the trial were excellent, actually the primary endpoint was the progression free survival and already in the interim analysis it was found to be very much prolonged with the addition of ibrutinib. So the patients receiving BR plus placebo had a median progression free survival of only 13 months whereas patients receiving ibrutinib added to the BR did not yet reach the median progression free survival and that’s an 80% reduction of the risk of progression, progression or death. Regarding safety there will be another presentation at this meeting. My presentation was focussed on the subgroup analysis. There were several risk factors, actually this was a high risk population, 80% of the patients had an unmutated IGVH status and quite a high number of patients had bulky disease, more than 50%. Also most of the patients, two-thirds, had time between last treatment and inclusion to the trial lower or shorter than three years. So this is pretty much a difficult to treat population of patients which are refractory.

We looked at these different risk factors and we saw that in all the different subgroups the addition of ibrutinib was positively impacting on progression free survival. Furthermore, we even found that with ibrutinib added to the BR regimen that the adverse prognostic impact of IGVH unmutated status and also deletion 11q was abrogated, so there was no difference anymore.

You mentioned the safety profile and another presentation, can you talk a bit about that?

The safety profile that was observed in that trial is pretty much what we would have expected. It’s the adverse events we know occur with bendamustine chemo-immunotherapy plus what we already know with ibrutinib. So there was no cumulative toxicity because of the addition of ibrutinib. The main adverse events which were more common with the ibrutinib added were diarrhoea, which was mainly low grade, and also some minor bleeding events; very few severe bleedings and some cases of atrial fibrillation.

What’s the take home message from your research?

The difficulty of that trial is if we would have designed it today we would have added a third arm with single agent ibrutinib. So we cannot answer the question if we really need the bendamustine rituximab. We now know that ibrutinib adds something to chemo-immunotherapy but we don’t know if it’s the same vice versa so we don’t know if chemo-immunotherapy adds something to ibrutinib single agent. There is a higher response rate, there’s much more complete remissions and there is MRD negativity already in a very early stage after treatment. So I think that the timing of response might also be important but at this time point we cannot prove it.