Constantine Si Lun Tam, MD, MBBS, FRACP, FRCPA, on the Phase 3 ASPEN Trial

Results from the randomized phase 3 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 Waldenström macroglobulinemia.

In an interview with CancerNetwork®, Constantine Si Lun Tam, MD, MBBS, FRACP, FRCPA, of the Peter MacCallum Cancer Centre, discussed the phase 3 study and what the future holds for this patient population.

CancerNetwork®: First off, can you just explain the study design for the phase 3 ASPEN study?

Tam: 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.

So, for patients who may be unclear as to the study findings, could you explain the key highlights of the study?

So, I think the key highlight for the patient is that we've got 2 drugs which are similar. One is zanubrutinib, it’s a more selective, in other words more targeted, version of ibrutinib, potentially with better side effects and will be competitive to drugs head to head. Indeed, we do see a difference in side effects, with zanubrutinib having less side effects and better tolerance than ibrutinib, which is great because it gives us extra options for treatment of Waldenströms.

Are there any next steps for this study?

So, obviously we need to do prolonged follow up to see if the progression-free survival, the duration people remain in remission, and the overall survival differ between the 2 arms.