Comparing BTK Inhibitors: Key Findings from Head-to-Head Trials

EP: 1.Mechanism and Frontline Use of BTK Inhibitors in CLL

EP: 2.Covalent BTK Inhibitors in Relapsed/Refractory CLL

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EP: 3.Comparing BTK Inhibitors: Key Findings from Head-to-Head Trials

EP: 4.Clinical Considerations for BTK Inhibitor Treatment Selection

EP: 5.Molecular Mechanisms of Resistance to Acalabrutinib in CLL

EP: 6.Treatment Options for Patients with CLL Progressing on Covalent BTK Inhibitors

Dr. Brian Hill: Maybe we will proceed to talk a little bit about some of the head-to-head trials here. So we're going to shift to the ELEVATE-RR trials. So Dr. Ghia, maybe you can share with us the design of the ELEVATE-RR study and what were the key findings?

Dr. Paul Ghia: Yes. The ELEVATE-RR as you may understand from the name is RR in the relapse refractory setting. It was a head-to-head comparison between acalabrutinib second generation BTK inhibitor and ibrutinib in the first BTK inhibitors. That was in the relapse refractory setting, but in a very specific subgroup meaning the patient with either deletion 17 P or deletion 11 Q. So difficult to treat patient with the idea that the readout of the study would've been earlier. But we know now that BTK inhibitors are very good, even the rux factor setting, even in patient with P 53 ablation and indeed the study read out after almost four years. Having said that, the primary endpoint of the study was a non-inferiority study. Actually, the PFS was a primary endpoint as non-inferiority. And indeed the study confirmed that ibrutinib and acalabrutinib have the same progression phase survival more relevant for us for the use daily use. The secondary endpoint, which were mainly safety, related to safety the frequency of atrial fibrillation, for example, that turn out to be inferior compared to less atrial fibrillation with acalabrutinib compared to ibrutinib. What the study showed though there were not endpoints, official endpoints, is that there is also a lower rate of hypertension with acalabrutinib, a lower rate of bleeding in general, minor bleeding in particular, the major bleeding remains the same. And overall acalabrutinib showed to be better tolerated also in terms of myalgia and arthralgia, for example. So all these nuisance adverse event that typically affect the patient under ibrutinib.

Dr. Brian Hill: Very good.

Dr. Paul Ghia: And so now the other important head to head study with BTK inhibitors was Alpine. So please tell us.

Dr. Brian Hill: Yes. So the Alpine study was similar in design to ELEVATE-RR although there's some key differences. This was a patient population of with relapse refractory CLL. And unlike ELEVATE-RR, they did not have to have 17 P or 11 Q deletion but did have many high risk features. It was a randomized study of open-labelled trial of ibrutinib versus zanubrutinib at standard doses. And again, the endpoint was non-inferiority. But in the final analysis, as was recently published in the New England Journal Medicine, the progression-free survival and response rates seemed to favor zanubrutinib over ibrutinib. Importantly in terms of toxicities as similar as was seen in ELEVATE-RR, there was significantly less atrial fibrillation with zanubrutinib compared to ibrutinib and lower rates of discontinuation. So overall, I think that this, along with the ELEVATE-RR trial give very good level one evidence for the comparable or better sort of efficacy relative to ibrutinib with improved safety for patients with CLL.