Updates in Targeted Therapies for B-Cell Malignancies - Episode 5
Ian W. Flinn, MD, PhD: I want to turn now and talk a little bit about some of the newer Bruton tyrosine kinase [BTK] inhibitors. Let’s first talk about acalabrutinib. We’ve seen the data from the ASCEND trial that look at acalabrutinib. Matt, you’ve seen this data. What do you think?
Matthew S. Davids, MD, MMSc: Acalabrutinib is sort of a next-generation BTK inhibitor. It’s more specific for BTK compared to ibrutinib, and has fewer of these off-target adverse effects on kinases like ITK [interleukin-2-inducible kinase] and TEK kinase, for example. In theory, this should be a better-tolerated agent, and I think the phase I/II data certainly did suggest that, although not in a comparative setting.
Ian W. Flinn, MD, PhD: Before we go on to that, is that your personal experience?
Matthew S. Davids, MD, MMSc: That has been my personal experience using the drug.
Ian W. Flinn, MD, PhD: Maybe they get a little bit of a headache. They had slightly different adverse effects early on, but otherwise are tolerating it pretty well.
Matthew S. Davids, MD, MMSc: Yes, I would say so. The ASCEND study is very interesting, because it’s our first randomized trial comparing 2 different novel agent-based regimens. It compared acalabrutinib as monotherapy to idelalisib, the PI3-kinase inhibitor, with rituximab, in the relapsed/refractory setting. Patients could also be on bendamustine/rituximab instead of the idelalisib/rituximab. It’s a little bit of a hodge-podge in the control part. Nonetheless, comparing the acalabrutinib with idelalisib/rituximab or with the bendamustine/rituximab, acalabrutinib was superior in terms of the progression-free survival and response rates. I think particularly striking in this trial was the tolerability of acalabrutinib.
Half the patients on the idelalisib-based regimen had to come off due to toxicities. With bendamustine/rituximab, we saw the usual infections and cytopenias that we might expect, particularly in the relapsed population, where we’re not using that much bendamustine and rituximab. The headache that you mentioned, which had been seen in close to 40% in some of the early-phase studies, was only seen in about 20% of the patients in this phase III data set, which I think is interesting. There were few cases of atrial fibrillation, very few major bleeding events, and a more robust phase III data set. This is reassuring that some of the signals that we were seeing in phase I/II are starting to pan out in phase III for acalabrutinib. We still don’t have head-to-head data yet for acalabrutinib versus ibrutinib, but hopefully that’s coming.
Ian W. Flinn, MD, PhD: It may be a little while before we get that data, but I think they are going to be key. John, you’ve used acalabrutinib a lot, right? What is your take on this and the data that Matt just discussed?
John Pagel, MD, PhD: I think acalabrutinib is definitely emerging as a very viable alternative for patients. It will certainly get more data in the next many months. The ASCEND trial message wasn’t so much that it was better than idelalisib, we anticipated that. The biggest message there was the tolerability of the acalabrutinib. It was very consistent with what we’ve seen before. It does appear to be a better-tolerated drug, but it’s a twice-a-day drug, and that’s important to recognize as well. I think we’ll have some data that we’ll get to see in the very near future regarding its comparison directly in a randomized trial with ibrutinib in high-risk relapsed CLL [chronic lymphocytic leukemia] patients.
That data are going to be from a noninferiority trial. We’re not expecting any differences in the primary endpoints, which are around efficacy. I think we’re all very much anticipating and wanting to see the results, from a tolerability standpoint, comparing ibrutinib and acalabrutinib. That will be the test. If that’s really true, it’s important for us to recognize if we can avoid atrial fibrillation, major hemorrhage, and hypertension when our patients are on 2 or 3 antihypertensive medications, which doesn’t happen often, but does happen. Those are important things for us to think about, and we’re all excited about that emerging data.
I think this is all exciting. We do have data of using acalabrutinib in the front line from the ACE-CL-001 trial that we did in about 100 patients. If you look at 4-year follow-up, almost all of the 100 patients are still on the drug at 4 years, doing well, and without progression. It tells you a lot about the tolerability of acalabrutinib. Rates of discontinuation in that upfront setting are very low, and even dose adjustments are not common. That’s another nice thing about acalabrutinib. If you want to do a dose adjustment, you just go from 2 pills a day to 1 pill a day. We also know that likely, over time, as you decrease disease burden and get things under control, we might not need so much drug to get maximal binding of the BTK binding pocket. Once-a-day dosing will probably emerge as a very efficacious approach moving forward, as well.
Ian W. Flinn, MD, PhD: Keeping with the front line, there’s this ELEVATE-TN trial using ACALA [acalabrutinib] alone or with obinutuzumab, versus obinutuzumab and chlorambucil. There’s a press release that says that it’s superior. Does that shock you?
John Pagel, MD, PhD: No, it doesn’t shock us. Hopefully, we can stop doing a lot of trials with chlorambucil, or at least not as single agent. It’s an important regimen for some patients, but clearly, we’re starting to see that there’s not even a role for that in our randomized trials. The upfront ELEVATE trial was a 3-arm study. They were acalabrutinib with obinutuzumab, acalabrutinib alone, or chlorambucil and obinutuzumab. There are a couple things that we’re going to learn there. The acalabrutinib is going to prove to be better than the chlorambucil arm; we know that. We’re also looking back at this idea of whether the obinutuzumab is going to be an advantage or not. It’s important to know because we shouldn’t be giving people an expensive drug, an IV [intravenous] infusion, if it’s not needed. This will be another important tool for us to use in treatment-naive patients. If it is better tolerated, it might be a preferred approach in many patients, getting back to the comorbidities of older CLL patients.
Ian W. Flinn, MD, PhD: Matt, there are data. It’s a single-arm study with Jennifer Woyach MD at The Ohio State [University Comprehensive Cancer Center] looking at acalabrutinib with obinutuzumab. There is some experience there. What is your take on that?
Matthew S. Davids, MD, MMSc: That study certainly showed the excellent efficacy of that acalabrutinib and obinutuzumab combination. We had seen an earlier data set a couple years ago, and then recently, Jen Woyach presented the data at ASCO [American Society of Clinical Oncology annual meeting]. It showed that over time, with what is now 3 years of follow-up, they’re seeing deeper responses than were reported initially. It was about a 15% CR [complete response] rate, initially. In this most recent presentation, close to one-third of patients achieved CR. Whether that’s relevant, I’m not sure, because this is still given as a continuous therapy. Do you need to get to CR? I’m not sure. Maybe that does predict for progression-free survival, but I think time will tell. The tolerability is overall good, but as John points out, there’s the inconvenience of getting the infusions. There are still infusion reactions to obinutuzumab, probably a little more in the way of cytopenias and infection. It’s really going to be important to see the results of the ELEVATE treatment-naive study to tease out that difference and whether we need the CD20 antibody there.
Transcript Edited for Clarity