Constantine Si Lun Tam, MD, MBBS, FRACP, FRCPA, on Results of the Phase III ASPEN Trial


The trial compared zanubrutinib, a potent and selective BTK inhibitor, versus ibrutinib, a first generation BTK inhibitor, in patients with Waldenström macroglobulinemia.

Results from the randomized phase III ASPEN trial, presented at the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Meeting, indicated that zanubrutinib (Brukinsa) was associated with a higher complete response or very good partial response (CR+VGPR) rate and demonstrated clinically meaningful advances in safety and tolerability compared to ibrutinib (Imbruvica) in patients with Waldenströmmacroglobulinemia.

However, the results of this trial were not statistically significant, and further follow-up is needed to establish other endpoints such as progression-free survival and overall survival between the 2 arms.

In an interview with CancerNetwork®, Constantine Si Lun Tam, MD, MBBS, FRACP, FRCPA, of the Peter MacCallum Cancer Centre, discussed the study design of ASPEN and the results presented at ASCO.


So, the phase III Aspen study is a study in Waldenström macroglobulinemia, and it’s a head to head comparison of 2 BTK inhibitors: ibrutinib and zanubrutinib. So, zanubrutinib is a next generation BTK inhibitor that is more specific than ibrutinib. So, therefore, the potential for fewer side effects and it also has higher drug levels with the potential for better efficacy. Now ASPEN was actually set up as a superiority study to try and demonstrate that zanubrutinib achieves a higher very good partial remission and complete remission rate compared to ibrutinib. So therefore, a reduction of paraprotein by over 90%, which is what VGPR is.

Now, the study endpoint is the primary endpoint, which is the point that we reported at this ASCO meeting, the independent response committee decided that the trial did not meet these endpoint being of superiority. So, the VGPR rate was 28% for the zanubrutinib arm, and 19% for the ibrutinib arm, so a difference of about 10%; but the P value was 0.09. So, it didn't quite meet the required P value of less than 0.05.

We then did a pass because of the responses do mature with time we did do a secondary follow up of these patients with an extra 5 months of follow up. And at that time, the VGPR in the zanubrutinib arm has matured to 30% as called by the investigators, and at that time, there was a positive P value 0.03, but, you know, the official primary endpoint of the study was negative in that zanubrutinib, it did not demonstrate a superior VGPR rate as judged by the IRC.

The study did compare the toxicity rates which... And the toxicity rates are significantly different between the 2 arms. So, ibrutinib was associated with a higher rate of discontinuation and the emerging high number of patients who died of adverse events, as well as higher rates of dose interruptions… and ibrutinib was associated with an increased risk of BTK associated toxicities including atrial fibrillation, bleeding, diarrhea, peripheral edema, and hypertension. Zanubrutinib recently was associated with an increased risk of neutropenia, although not associated with infection, so it's quite different to see the 2 BTK inhibitors of quite different toxicity profiles. And in particular, the atrial fibrillation rate was about 6 times higher five for ibrutinib at 18% compared to 3% for zanubrutinib.

So, our conclusion was that the study showed that the study did not meet its primary endpoint. We found that there were some indicators that zanubrutinib were more effective by other analysis other than the primary endpoint. But there was most definitely a clinically significant difference in the toxicity rates between the two arms.

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