ASH 2022 | Comparison of the different BTK inhibitors available & under investigation in frontline and R/R CLL

So we’re clearly seeing a lot of development in the BTK space over recent years. Initially we had ibrutinib available, that was licensed and approved for use in relapsed CLL, and then subsequently frontline CLL. More recently we’ve had the advent of acalabrutinib, again, both licensed in frontline and in relapse. Only very recently the Biogen BTK inhibitor, the second-generation BTK inhibitor zanubrutinib has also been approved in relapsed and frontline CLL.

So really, an embarrassment of riches in many respects in that we’ve been really fortunate to see the development of these drugs. And so naturally when there are different options, you’d want to compare which molecules are the safest and also which are the most effective. We’ve seen randomized clinical studies. So, we’ve seen a trial called the ELEVATE-RR, where patients with high-risk relapsed CLL were randomized between acalabrutinib and ibrutinib. Acalabrutinib is equally effective and better tolerated, particularly in terms of events such as cardiac toxicity, but also actually really across a number of different toxicities. Such as arthralgia, myalgia, diarrhea, et cetera. So, we know that acalabrutinib is as effective.

We’ve also seen an interim analysis of a study called the ALPINE trial where zanubrutinib has been compared to Ibrutinib. We’ve seen an early signal that there’s potentially improved progression-free survival with the zanubrutinib-treated patients. The toxicity profile also looks better with zanubrutinib. Now this study, in terms of its follow-up and maturity, is not as mature as that ELEVATE-RR study that I mentioned. Also, it’s in a broader relapsed population. So, comparing across those two studies will be difficult. But what I think we can broadly say is that the second-generation BTK inhibitors do look quite a bit safer in terms of the toxicity profile. There’s an open question at the moment about improved efficacy, although we have seen a press release suggesting that the final readout of the ALPINE study will show that there’s improved progression-free survival compared to ibrutinib.

So in the frontline setting when using a BTK inhibitor, we’ve got randomized data suggesting zanubrutinib is better than bendamustine-rituximab and acalabrutinib, with or without a CD20 antibody obinutuzumab is better than chlorambucil-obinutuzumab. So I would at the moment pick a second-generation BTK inhibitor in the majority of patients. Either in frontline or in relapsed BTK-naive patients.

And then of course we’ve got the non-covalent BTK inhibitors in development pirtobrutinib, the most advanced of those and looks very effective in those who’ve received a prior covalent BTK inhibitor. And so that may well become an option in that space. And of course, the ability to surpass a covalent BTK inhibitor will depend on both randomized clinical trials and also I think probably important sequencing data. Proving that you can sort of switch the BTK inhibitors in terms of their order based on their mechanism of action. Of course, lots of work needs to be done to show that in the future, but at the moment, second-generation BTK inhibitors, in my view, represent the standard of care in either frontline or relapse. And then non-covalent BTK inhibitors pirtobrutinib an extremely effective option following those.