Transcript: Michael Wang, MD: I led an international trial that led to FDA approval on ibrutinib. That was published in the New England Journal of Medicine. I led another international trial that led to the FDA approval of acalabrutinib. I have been on and off...zanubrutinib from the trial concept, preclinical data. I’ve been communicating and contributing my half. I’m often being asked which BTK [Bruton tyrosine kinase] inhibitor is the best. It’s very hard to pinpoint which 1 is best because I feel it’s comparing apples with pears.

First of all, the 3 of them are all irreversible covalent BTK inhibitors—all very effective in treating relapsed mantle cell lymphoma. With ibrutinib, response rate was 68%, but that’s after 3 prior lines of a therapy. Acalabrutinib resulted in a response rate of around 81%, and that’s in the 2 prior lines of therapy. Zanubrutinib had a response about 84%. If you look at the number, you will feel that maybe zanubrutinib is most effective. In fact, that would not be correct to conclude that because the study population is different. Ibrutinib treated 3 prior lines, which is a much sicker population and with the same medicine it would yield a lower response rate.

In my opinion, their efficacies are very similar. For example, there’s a recent Waldenström macroglobulinemia phase III clinical trial comparing zanubrutinib with ibrutinib head-to-head. There is no difference in efficacies. I always tell people I think the real difference is in the toxicity profile—it’s not in the efficacy profile. For example, ibrutinib has been known to induce atrial fibrillation, infections, bleeding, and also other adverse effects such as arthralgia and even some rashes, LFTs [liver function tests]. Acalabrutinib, the second-generation is a little better in terms of adverse-effect profile with less rash, and zanubrutinib has even fewer adverse effects reported.

I want to remind everybody that I like the 3 drugs for their individual properties, but we have treated nearly 200,000 patients with ibrutinib with 6 years of follow-up data since 2013. Therefore, the longer you treat the patient, and the more patients you treat, you will have more adverse effects. Acalabrutinib was approved 2 years ago in 2017. It treated much fewer patients than ibrutinib. The follow-up time is only about 2 years instead of 6 years. Therefore, it may appear that acalabrutinib is less toxic, with fewer adverse effects.

Acalabrutinib was approved 2 years ago, so we treated much fewer patients. This was only 2 years of follow-up instead of 6 years of follow-up. Compared with ibrutinib, it may appear it’s less toxic. The newly approved zanubrutinib with the least cases among the 3, with the shortest follow-up times; it may appear a little less toxic. But that does not mean that the 3 drugs are totally the same in efficacy and in toxicity. While we’re waiting for more patients to be treated, while we are waiting for more follow-up time to accumulate the adverse effects, we need to know that the 3 drugs have very different properties in toxicity.

Oftentimes, if you look at the molecular structure of the 3 drugs, they are very similar with only small changes in chemical structure in the molecular design. But we also know a tiny change in the molecular structure could result in significant different biological properties. Although…I do think there are intrinsic properties that are different among the 3 drugs.

I would like to see some things for the newer BTK inhibitors. At least in the test tube, zanubrutinib is better than acalabrutinib. Both of them are better than ibrutinib in terms of enzyme specificity. On the preclinical study, it looks like zanubrutinib is the most selective. The acalabrutinib is second, and ibrutinib is less specific. Therefore, it’s affecting off targeted kinases causing adverse effects. This is theoretical. We need time to prove that this is true in the clinical experience.

At least I would like to see the second-generation BTK inhibitors resulting in less atrial fibrillation, fewer severe infections such as fungal pneumonia, fewer bleeding events such as intracranial bleeding, and fewer cardiac arrhythmia problems. Theoretically they should. But we cannot conclude that until more cases are treated and more time is given for follow-up to test this clinical phenomenon. I hope that the 3 BTK inhibitors will be different, so we can select which is best for which patient. I would hope for that, but we need time to make the conclusions.

Transcript Edited for Clarity