Zanubrutinib in Patients with CLL and Intolerance to Prior BTKIs: Updated Phase 2 Study Data
Pooja Advani, MBBS, MD, discusses that switching from ibrutinib to second-generation BTK inhibitors like acalabrutinib leads to fewer off-target side effects like atrial fibrillation while maintaining high disease control.
Asher A. Chanan-Khan, MD, MBBS: There was a very interesting paper earlier in the year by Dr Sharma, who reported in Lancet Hematology about the role of zanubrutinib in patients who are intolerant to prior BTKi [Bruton tyrosine kinase inhibitors]. This was about 60 patients who were intolerant to either ibrutinib or acalabrutinib, and the primary end point of this particular study…was recurrence and change in severity of the adverse effects that are noted with these 2 particular agents. The question is: Within the second generation, is there a certain distinction that can be made for clinicians to pick one or the other if they have to? The data showed the recurrence of the adverse effects with ibrutinib was about 30%. [Also,] 70% of the patients actually did not have recurrence when they were switched over to ibrutinib from zanubrutinib, which is pretty decent vs if you were already on the second generation. The recurrence was actually better in 17% with acalabrutinib, in those patients who showed a recurrence of the adverse effect. The severity was definitely less, it wasn’t more, and the study was small. But for such a question, I think it’s a reasonable gauge for us to get; 96% of the patients had 1 or more adverse events on that. They did have adverse effects but they were not the risk. The question was if they were so intolerable, as you mentioned, that they had to change therapy or stop therapy, could they go on zanubrutinib…if they had either [tried] ibrutinib or acalabrutinib? And the answer to that was yes. Atrial fibrillation [AFib] occurred in about 4% of the cases when [patients] were switched to zanubrutinib, and again it was a short follow-up. But the disease control, fortunately from the patients’ perspective and clinicians’ perspective, was still over 90% again. So Pooja, [do you have] any comments on this retreatment with the second generation, the toxicity profile, and recurrence of that? [Is there] anything that you would recommend from a mechanistic perspective, whether it’s the scope of off-target effects becoming a different one, and so forth?
Pooja Advani, MD, MBBS: I think it’s important to recognize that AFib is believed to be an off-target adverse effect. And I think I mentioned a little bit earlier that acalabrutinib and zanubrutinib mostly inhibit HER4 and very slightly TEC, which stands for tyrosine protein kinase. So it is not without reason that they have fewer adverse effects, particularly as you switch from ibrutinib to the second generation. Ibrutinib tends to inhibit a lot more off-target kinase, such as HER4 and, [has] a higher degree of TEC protein kinase inhibition. So I think it translates clinically really well.
