I presented the ASPEN study which was presented at ASCO 2020. This is a phase III study comparing two BTK inhibitors, zanubrutinib versus ibrutinib in patients with Waldenström’s macroglobulinemia. This is really a notable study in that this is the first study in any disease of a head to head comparison between two BTK inhibitors.

So, in more detail, the study essentially randomised 201 patients with MYD88 mutant Waldenström’s on a one to one basis to treatment with either ibrutinib or zanubrutinib, which is a next generation BTK inhibitor potentially with fewer side effects because of specificity and potentially with greater efficacy because of higher drug levels. The study enrolled 201 patients, 99 on the ibrutinib arm, 102 on the zanubrutinib arm, and essentially we reported the primary endpoint which was an efficacy endpoint. The primary endpoint was the proportion of patients in either CR or very good partial remission, so a 90% reduction in paraprotein IgM, comparing ibrutinib against zanubrutinib. Because very few patients get into a complete remission on BTK inhibitors effectively this is a head to head comparison of VGPR rates.

At the time of the primary endpoint analysis the VGPR rate was 28.4% for patients on zanubrutinib and 19.2% for patients on ibrutinib. So roughly a 10% greater number of patients on zanubrutinib got into VGPR but this was not a significant p-value of 0.9. So the study actually did not achieve its primary endpoint which is to meet a significant p-value by VGPR rate comparison at the primary endpoint.

However, when we did further follow-up for an extra five months and we looked again the VGPR rate for zanubrutinib is now 34.4% and this is an assessment by investigators and not by the central committee which is what the primary endpoint initially was. This is now a positive p-value of 0.03.

So the study didn’t meet its primary endpoint of improved efficacy at the time of analysis but there were secondary indicators that zanubrutinib may be more effective. Probably the most interesting finding was that zanubrutinib was undoubtedly more tolerable than ibrutinib. So the rates of adverse events leading to death, treatment discontinuation, dose hold or dose reduction, they were all lower for zanubrutinib. If you look at the specific side effects which are common in BTK inhibitors, things like diarrhoea, contusion, muscle spasms, peripheral oedema, atrial fibrillation and pneumonia were all less common in the zanubrutinib arm. The only adverse event that’s more common with zanubrutinib being neutropenia and even then the rates of febrile neutropenia on infection did not differ. So it was really a laboratory finding without a clinical consequence.

I just want to touch base on the most important side effects which were atrial fibrillation and hypertension which on the ibrutinib arm atrial fibrillation was 18.4% compared to 3% on the zanubrutinib arm, so a sixfold difference in AF rates. Also hypertension, in terms of grade 3 or higher hypertension, it was 15.3% on the ibrutinib arm and 7.9% on the zanubrutinib arm, so essentially half as common in terms of severe hypertension. If you followed the events over time you would see that almost all the atrial fibrillation or hypertension in the zanubrutinib arm happened in the first twelve months and there was no accumulation of events whereas for ibrutinib there appears to be an ongoing risk beyond twelve months up to about the two year mark for those events.

So the conclusion of the study was that it didn’t meet its primary endpoint although there were other indicators that zanubrutinib may be more effective. But we felt that there was a definite difference in terms of adverse event profiles. In particular, cardiovascular events are far less common on zanubrutinib compared to ibrutinib which is significant because this is the first time that we have shown in a head to head comparison that the next generation BTK inhibitors may behave differently from ibrutinib.

What does this mean for future treatment choices?

What that means is that we now have an extra drug that we can use. It’s twice a day as opposed to ibrutinib which is once a day so it’s slightly less convenient in terms of that. But the side effect profiles are particularly good so I would say that if you have a patient who can’t tolerate ibrutinib or a patient who has very high cardiovascular risk then zanubrutinib is a better choice.