Acalabrutinib in CLL: Insights from the ELEVATE TN and ASCEND Trials

Anthony R. Mato, MD, MSCE: Let's delve into the next-generation BTK (Bruton tyrosine kinase) inhibitors because this is probably one of the hottest topics in the field. We'll call them second-generation covalent inhibitors. I don't know what the right term is anymore. Callie, I want to start with you, and I want to talk about the Elevate TN [study] (NCT02475681) because this is a trial that just keeps giving us more and more knowledge. I think the updates are actually more exciting than the original presentation. Can you summarize what's been updated [with] a couple lines about the design and and what you're learning from that dataset?

Catherine C. Coombs, MD: Matt had just alluded to this study. I totally agree with your assessment that the updates are getting more and more exciting every year. Elevate TN was a 3-arm trial. The randomization was to acalabrutinib with obinutuzumab, acalabrutinib as a monotherapy, and the standard arm was chlorambucil and obinutuzumab. We got the 5-year update at the most recent congresses, and what that shows is that acalabrutinib with obinutuzumab continues to have an edge with respect to the other 2 arms. The primary analysis of course showed that both acalabrutinib containing regimens were superior to chlorambucil obinutuzumab, but we're seeing the acalabrutinib plus obinutuzmab arm really have the most favorable rates of progression-free survival (PFS). At 5 years, that ends up being 84% for acalabrutinib plus obinutuzumab compared to 72% for acalabrutinib by itself. Chlorambucil is somewhere in the 20% range, so quite a bit more dismal.

The other really exciting thing from the 5-year update is that there's starting to look like a survival advantage to the acalabrutinib plus obinutuzumab regimen, and I think that's really changing my mind on whether to offer obinutuzumab to patients. Early on when I thought it was just a PFS advantage, I had concerns about the potential added toxicity of obinutuzumab. However, what we're seeing now with this further follow-up is that the acalabrutinib plus obinutuzumab patients have the highest rate of OS at 5 years, specifically 90% compared to 82% for the chlorambucil plus obinutuzumab patients. Though there may be added toxicities with obinutuzumab compared to just doing acalabrutinib by itself, this may be paying off in dividends with respect to survival, which may become more pronounced with further years of follow-up. We will have to see.

Anthony R. Mato, MD, MSCE: I want to stay on the topic of acalabrutinib. I think this drug gets the credit of comparing itself to more than 1 targeted therapy, which hasn't happened with the other molecules. I want to talk about the ASCEND trial (NCT02970318), Brian. This trial was recently updated. I think it's the 4-year update and maybe the final analysis as well, where acalabrutinib was compared to idelalisib/rituximab and bendamustine/rituximab in the relapsed/refractory setting. You want to comment on that comparison and then give us perspective on where the PI3K inhibitors fit into the relapsed/refractory setting?

Brian T. Hill, MD, PhD: Sure. As you point out, sometimes the CLL studies have been criticized for not [having] robust comparators. Chlorambucil was beat up on for many years [in] trials as a frontline standard arm for older patient. The ASCEND trial was in the relapse setting, and it compared treatment with acalabrutinib vs what would be considered more active therapies: idelalisib with rituximab, which is an active PI3K inhibitor that we know has some toxicities. But there's also bendamustine/rituximab, which still is used, particularly in Europe and in the community for patients [with] relapsed CLL. What was remarkable was just how much better the BTK inhibitor was than both idelalisib or bendamustine/rituximab. At 42 months, the PFS rate was 62% vs 19%, with comparator arms. Not even close in terms of PFS, and there was also an OS trend in favor of the acalabrutinib arm. I think this type of data is important to really show the utility in the relapse setting of novel agents like BTK inhibitors, [such as] acalabrutinib.

Anthony R. Mato, MD, MSCE: One other comment about acalabrutinib. Every drug has limitations. Michael already highlighted the headache issue, but the other limitation I can think of is the drug-drug interactions with PPI (proton pump inhibitors), and there were data presented at [the 2022] ASH (American Society of Hematology) [Annual] Meeting [& Exposition], where the ELEVATE+ was presented, and this is a new formulation of acalabrutinib which doesn't have to deal with the drug-drug interactions. Does anyone have any comment or update as to when we might actually see that in practice? I'm not sure, but does anyone have a timeline? Everyone's shaking their head no. We don't know, but we think it will be important when it finally does become available to us.

Transcript has been edited for clarity.