Where U2 Will Fit in CLL Treatment Landscape?

At the American Society of Hematology (ASH) virtual meeting, a number of important chronic lymphocytic leukemia (CLL) trial updates were presented. MedPage Today brought together three expert leaders in their field: Moderator Susan O’Brien, MD, of Chao Family Comprehensive Cancer Center, University of California Irvine Health, is joined by Jennifer R. Brown, MD, director of the CLL Center at Boston’s Dana-Farber Cancer Institute, and Anthony Mato, MD, director of the CLL Program at Memorial Sloan Kettering Cancer Center in New York City, for a virtual roundtable discussion on the new and potentially practice-changing data from the meeting.

In this second of four exclusive MedPage Today episodes, the discussion centers on the phase III Unity-CLL Study.

Episode 1: The CAPTIVATE trial

Following is a transcript of their remarks:

Susan O’Brien, MD: Hi, everyone, and welcome to this roundtable where we’re going to discuss CLL presentations at ASH 2020 this year. I’m Dr. Susan O’Brien from the Chao Family Comprehensive Cancer Center at the University of California in Irvine, and I’m joined by two esteemed colleagues, Dr. Jennifer Brown from Dana-Farber and Dr. Anthony Mato from Memorial Sloan Kettering.

An interesting presentation at ASH this year that many people were looking forward to was the trial looking at the combination of what’s called U2, which is a novel anti-CD20 antibody, ublituximab, combined with a novel PI3K delta inhibitor, umbralisib. In this randomized trial, the comparator arm was obinutuzumab with chlorambucil and it was interesting because the trial actually included both previously untreated as well as previously treated patients. Jennifer, do you want to talk about some of the results from this trial?

Jennifer Brown, MD: Sure. As you mentioned, it was a little bit odd, the combination of both previously untreated and relapsed/refractory patients, and also initially having single arms in the trial that were closed. But at this point we’re really focused on the two major arms, one being umbralisib-ublituximab and the other being obinutuzumab-chlorambucil.

The primary endpoint was a progression-free survival, which was quite significantly different at about 36 months for the umbralisib-ublituximab versus about 26 months, I think, in the combined arm for obinutuzumab-chlorambucil. That was obviously a positive study.

I think it’s easier to interpret the results if we look at the treatment-naive versus the relapsed/refractory separately. With the treatment-naïve, the U2 had about a 38-month PFS and the obinutuzumab-chlorambucil was around at 26 months. Whereas in the relapsed/refractory the U2 was at still, I think…

Dr. O’Brien: 19.

Dr. Brown: 19. Okay. That’s actually quite similar to other relapsed/refractory PI3 kinase registration trials, so perhaps not surprising.

In the upfront setting, 38 months is perhaps not as much as we would expect, certainly with a BTK inhibitor or a BCL-2 inhibitor, which means that this probably will be used more in later lines after those drugs, with the possible exception, I think, of older patients with significant cardiac or renal comorbidities, which are places where I have used PI3 kinase inhibitors prior to those other classes sometimes.This does provide a good option for those patients, even front line.

The toxicity was quite a lot better than we would expect, certainly frontline, with a PI3 kinase inhibitor. There was still significant diarrhea, which was over 50% all-grade and 12% grade 3 or higher — which is a typical side effect of PI3 kinase inhibitors, as we know — and transaminitis was about 8% grade 3/4. Infections and neutropenia were also noted.

I think that the side effect profiles still carried many of the PI3 kinase inhibitor type toxicities, just at a lower rate than we would have seen with the other drugs.

Anthony Mato, MD: I think where you hit the nail on the head… because this trial, for me, represented a potential to bring the class to the frontline setting and obviously that may or may not be the approval. I suspect it would be. But I think practically speaking I’m trying to determine whether or not this brings the class any closer to the front line than the other drugs that are already approved, which are largely relegated to the third line in the relapsed/refractory setting, and that’s still what I’m trying to process now.

I think you’re right, though, that most patients this will still fall into that same place where you would have considered idela or duvelisib. Do you feel that way at this point?

Dr. Brown: I do, although I think that here this does at least open the possibility of using it earlier because we have reasonable safety data. I have to say, actually, the changing landscape of BTK inhibitors, I think, influences me here. When the options were just ibrutinib or venetoclax, I did have older patients with significant cardiac problems and renal problems in whom I wasn’t so comfortable with either. But as we’re getting the next-generation covalent BTKIs, I have become a little more comfortable with those BTKIs, even in the setting of some of those patients. The competitive landscape is broadened for those very comorbid older patients, in my mind.

Dr. O’Brien: Right. I cannot see this at all fitting in in the frontline setting, I have to admit. Actually, it’s a little bit tricky to figure out where in the relapsed setting it goes, assuming we’re not at combo therapy yet, which we’re not… combo small molecule… because it’s not FDA-approved. Presumably, most people are going to get either ibrutinib-based therapy or venetoclax-based therapy upfront. I think in the community mostly ibrutinib because of the ease of administration, and also we have really good long-term data with ibrutinib from the RESONATE-2 where last year we saw at five years 70% of people were still progression-free, so these are really durable remissions.

Then, of course, with the venetoclax-obinutuzumab, some of the advantages there are the finite therapy and the ability to get very deep remissions with MRD undetectability. No matter how you look at it, I certainly don’t see this as fitting in front line.

Then in second line, if we gave ibrutinib or even if there is still some use of chemo, then you’ve got venetoclax and probably coming are covalent inhibitors, so I just don’t see this sort of being anything more than a third-line therapy at this point. What do you think about that, Anthony?

Dr. Mato: I tend to agree with you. I do think, though, that even in the third line the AE profile looked more… were better-tolerated than the other PI3Ks that are out there at the moment. Of course, that has to be interpreted through the fact that these are very different patient populations that were studied across time and across different agents. But I think that what will likely happen is this potentially will shift my practice towards using it over the other PI3K inhibitors.

Partly my own bias that I have been an investigator on studies and so I’m comfortable with it, and I’ve kind of lost my… if there ever was a skill in using some of the other ones, I haven’t used them enough lately that I actually need to go back and relearn how to use the class. It’s been a while. I only have like one patient on a PI3K inhibitor in my practice right now, but I think it’ll probably shift use more for this agent as compared to some of the others just because the AE profile looks fairly favorable.

Dr. O’Brien: I think what clearly demonstrates that is we know that at least when we took idelalisib into the frontline setting that was hugely problematic. I think because of that duvelisib never really went there. In the original phase I, II trials, there was a small cohort of 20 patients previously untreated, but because of the problems with idelalisib they never went towards a frontline indication.

Given that more than half the patients in this trial were previously untreated, where we know we tend to see a higher level of toxicity, I think the safety data is clearly demarcated and much more favorable for this agent.

Dr. Brown: It doesn’t really help us in terms of the problem that we still don’t have much data in patients who’ve previously had BTK or BCL-2 inhibitors. There were, I think, 12 or 14 patients on either arm, so…

Dr. Mato: 28

Dr. Brown: … prior BTKs.

Dr. Mato: 28 was the number, I think, on the U2 arm. It’s still not enough and they …

Dr. O’Brien: 28 was the total. It was about that.

Dr. Brown: Yeah. It was half that.

Dr. Mato: Oh, it was half. Okay. Sorry. But they still didn’t break down if those were progressors or intolerant. For me, intolerant wouldn’t mean as much because there is already data on that topic. But if they were truly progressors, I would care about that a bit more and they really should present that data, I think. Maybe in the manuscript they’ll include that.

Dr. O’Brien: Okay. Thanks for participating, everybody.

  • Greg Laub joined MedPage Today in 2005 as Production Manager and led the launch of the video department in 2007. He is currently responsible for the website’s video production. Follow

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