ASH 2022 | Comparing the safety & efficacy of reversible and irreversible BTK inhibitors in CLL

The story with irreversible BTK, which have had for a while, so a big story of this congress is that zanubrutinib has a superior progression-free survival compared to ibrutinib in the ALPINE study, and that’s a late breaking abstract. Whereas ibrutinib and acalabrutinib has equivalent results so far.

So there’s some suggestion that maybe not other irreversible covalent blockers are the same. Now the new kid on the block, of course is pirtobrutinib and nemtabrutinib, and these drugs also look really good. And they’re active against the 481 mutation that stops the irreversible blockers from working.

So I suspect what we’re going to see, is at the moment, the natural place for those drugs will be after the covalent blockers. But because pirtobrutinib is so well tolerated in clinical trials, it’s now being moved earlier and earlier in the first- and second-line therapy. So those clinical trials will tell us if pirtobrutinib can replace the irreversible blockers.

I think the other big story in this congress, which is an emerging story, is a story of mutations. So we now know that apart from the 481 BTK mutations, that there are some really important and interesting mutations, including the gatekeeper 474 mutation. And a new mutation, the L528W, which has been described in zanubrutinib, and described in ibrutinib, and probably occurs for other products as well, but have not been really fully tested for.

And I think that what we’re going to see in the next three to five years, we are understanding that the different products produce a different range of mutations. And in turn, different products are active against a different range of mutations. And we might end up in a chronic myeloid leukemia, CML world, where we are picking and sequencing our products depending on what mutations we find.