Molecular Mechanisms of Resistance to Acalabrutinib in CLL

Dr. Brian Hill: So that kind of brings us to probably the next frontier, if you will, of BTK inhibition, which is, as you mentioned at the beginning, the CLL cells are highly dependent on tonic signaling through the B-cell receptors apparatus. And if you apply selective pressure with a covalent BTK inhibitor eventually resistance can occur. So maybe we could talk a little bit about what are those molecular mechanisms of resistance with ibrutinib? And then maybe also a little bit about some of the merging data with the newer agents.

Dr. Paul Ghia: So it is true that one of the consequences of the continuous treatment with BTK inhibitors is indeed that we are somehow pressing the clone and therefore the clone will try to escape the pharmacological pressure and therefore will develop mutation in the BTK molecules and maybe even downstream in the PRC gamma two molecule that will allow to avoid in the inhibition by the different BTK inhibitors. And indeed that's consequence, so the patient will relapse at the end. So this has been shown with ibrutinib, the ERIC, the European Research Initiative on CLL just published another real world evidence, real world study showing that probably two third of the patient carry mutation in BTK and also in PS gamma two. Though at the lower frequency, still one third of cases don't have this mutation. So we have to do more research to indeed understand better the mechanism of resistance to BTK inhibitors. But having said that, we presented here at ICML a poster, actually Jennifer Voya presented, I was one of the co-author we where we compare the pattern of mutation in BTK between acalabrutinib and ibrutinib, again, taking advantage of the study that we mentioned earlier. So ELEVATE-RR and the interesting point is that the mutation appear very similar in terms of quality, meaning that the type of mutation are virtually the same. Particularly the most frequent is always the C48 1S mutation that has been the first one to be described. What changes is the frequency of the different mutations in BTK and we need to see if that has an impact in terms of clinical relevance. But that's probably the major conclusion of the paper, that really, the type of mutation that we see appear to be very similar. So suggesting that if someone is resistant to Ibrutinib, is also resistant to acalabrutinib and vice versa. That is something that we know in the clinic. So nobody would dare to use a second inhibitor, BTK inhibitor with - second generation BTK inhibitor with inpatient relapsing on ibrutinib.

Dr. Brian Hill: Sure.