Hematologic Oncology Update, Issue 3, 2016 (Video Program) - Video 14Activity and tolerability of the Bruton tyrosine kinase inhibitors ibrutinib and acalabrutinib (ACP-196) in CLL
2:26 minutes.
TRANSCRIPTION:
DR NASTOUPIL: One of the primary questions with ibrutinib is, we know that there are some off-target effects, that it’s not purely selective for inhibiting BTK. And what is the impact of those off-target effects? We know it probably adds to some of the toxicity, including the Tec and the platelet aggregation, potentially EGFR and rash and diarrhea. So I think one of the interests in pursuing more selective agents such as acalabrutinib is, what is the impact on efficacy, if you can dial down some of the toxicity? And that’s a primary question with this agent. They tested it in patients with relapsed CLL. And we know that ibrutinib fares quite well in relapsed CLL in terms of very high response rates. And they essentially showed that the overall response rate was quite high, 95%. They had about 30% of patients who had 17p, and 100% of those patients responded. Now, most of the responses are going to be a partial response or partial response with persistent leukocytosis. But in patients with relapsed CLL, is that a failure? I don’t think so in my mind, if you can have adequate disease control for long periods of time. What they demonstrated, as opposed to some of the other previous BTK inhibitors, that the selectivity did not impact the efficacy. And I think that was really one of the primary questions. If you dial down some of these off-target effects, are you going to lose the efficacy? And at least in CLL, that does not appear to be the case. DR LOVE: What’s known in terms of bleeding and acalabrutinib? And is the thinking that maybe it would be maybe equally effective, but, say, less toxic or less bleeding? DR NASTOUPIL: Yes. That’s a great question that we’re learning more about as time goes on. But essentially acalabrutinib does not impact Tec. And we think that that is the reason why ibrutinib impacts platelet aggregation. So we do know from the New England Journal paper that there were no major bleeding events. What we don’t know is, over time, will that story change? We do know that acalabrutinib appears to be more potent. And so maybe you can intensify the dosing, because you’re seeing less in the way of side effects. And is that why they had very high response rates in the 17p? Is that going to impact the risk of transformation? We don’t know the answer to those questions. But I think that is clearly an interesting observation, that if you don’t hit those off-target, particularly Tec inhibitors, you might see less in the way of toxicity, particularly with bleeding. |