Anti-CD20 Regimens and Triplet Therapies in CLL

Anthony R. Mato, MD, MSCE: The next topic we want to talk about is a bit more on combinations. We saw 2 trials recently presented, the updated 5-year data for CLL14, which is venetoclax and obinutuzumab vs obinutuzumab and chlorambucil in a comorbid patient population, overwhelmingly favoring venetoclax and obinutuzumab. [There was] almost an overall survival advantage there as well, not quite, but close. Then we saw the CLL13 [GAIA] trial, which was a 4-arm randomization of chemoimmunotherapy vs rituximab and venetoclax vs obinutuzumab and venetoclax vs obinutuzumab, ibrutinib, and venetoclax with 2 coprimary end points presented.

Without getting into all of the details because we could spend a half an hour just going over the results that were presented, my takeaway from the 2 presentations in combination was that venetoclax plus obinutuzumab induces very high rates of undetectable MRD [minimal residual disease] in fit and unfit patients. My takeaway was that this is the fixed-duration combination to beat. I didn’t see anything that swayed me toward starting a triplet from the perspective of MRD or PFS [progression-free survival]. I didn’t see anything that swayed me toward using rituximab over obinutuzumab. I think we learned that the standard of care is the standard of care for a reason. [Does anyone] agree or disagree with what I’m saying? Does anyone have any other major takeaways from the data from those 2 that were presented? I’ll leave that open ended.

Brian T. Hill, MD, PhD: I agree completely. I thought the CLL13 data were fascinating because they compared venetoclax and rituximab to venetoclax and obinutuzumab in the study. It was dramatically better with obinutuzumab. I know some have questioned whether it’s really that much better, but I think these data are compelling. There was also a third arm in which ibrutinib was added to venetoclax and obinutuzumab, and it really didn’t do much except add toxicity. I agree with you that I think the standard of care for time-limited therapy is venetoclax and obinutuzumab.

Anthony R. Mato, MD, MSCE: Anyone else have any comments?

Matthew S. Davids, MD, MMSc: My only comment would be, in light of the data from CLL13 in the frontline setting showing the superiority of obinutuzumab with venetoclax, I think it’s tempting to extrapolate that into the relapsed population. There, we tend to use venetoclax and rituximab based on the MURANO [trial] data set, but it is hard to ignore that compelling MRD difference in the frontline setting, and now also a PFS difference. I think it would be an off-label use, but I would consider using venetoclax and obinutuzumab in the relapsed setting [as well].

Anthony R. Mato, MD, MSCE: Matt, do you think it muddies the waters a bit that they didn’t give the MURANO regimen in CLL13, so we’ll never know whether it’s just less venetoclax or a better antibody there?

Matthew S. Davids, MD, MMSc: It’s a good point. It’s only 1 year of venetoclax in that frontline population with rituximab. So it is different from MURANO where it’s 2 years in the relapsed setting. It’s not a direct comparison, but I do think the data with obinutuzumab are pretty compelling

Anthony R. Mato, MD, MSCE: I’ll follow up again, Matt. We heard Michael definitively say that the future in mantle cell lymphoma [MCL] are the triplets. Do you want to be bold enough to make the same comment about CLL [chronic lymphocytic leukemia], specifically talking about the obinutuzumab, ibrutinib, venetoclax regimen?

Matthew S. Davids, MD, MMSc: I am not as enthusiastic in CLL as Michael is about triplets in MCL. I think there’s a burden of proof on us to show that there’s a benefit to a triplet over doublet because it adds toxicity, it adds cost, it adds inconvenience. I think most patients with CLL are going to do very well with doublets. It may be a subpopulation that benefits from triplets, but we have to figure out who those patients are, and it’s not going to be everyone.

Anthony R. Mato, MD, MSCE: Callie, I want to switch back to you now and talk again about real-world data. You’ve been participating in [and] leading these types of studies for a long time now. Rather than generalizing what’s happened, because it’ll take us an hour to do or longer, maybe I could ask you the question, what do you want to see real-world studies do next?

Catherine C. Coombs, MD: I would love more data on venetoclax retreatments. I know some are coming, but I think that would be extremely helpful. The other big controversy that comes up a lot among CLL communities is whether you can do a time-limited venetoclax-based approach for patients [with] 17p deletions. A lot of people feel very strongly that venetoclax needs to be used continuously in the setting of 17p or TP53 deletion or mutation. I would love to see more data on that from the real world.

Anthony R. Mato, MD, MSCE: We’ve been talking about trying to get our network together to try to gather some data on that. I think it is probably time to do that. I forget the total number of patients on CLL14, but it was 25 patients or so. Maybe that’s a topic we should try to address.

Brian, I want to switch gears to you here. Alexey already mentioned the question of sequential monotherapies. Can you help us to understand, are there any data to support whether a BTK [Bruton tyrosine kinase inhibitor] should precede venetoclax or the opposite sequence when we’re jumping from one class to another, or is that a black box at this point?

Brian T. Hill, MD, PhD: I don’t think we can say one sequence is better than the other. I think the more common sequence because of the chronological order in which the drugs were approved has been that patients have gotten [a] BTK inhibitor until intolerance or progression, and then when they need treatment again, they get venetoclax. We know that it works. In the case of time-limited venetoclax as frontline therapy, there are so few patients who’ve gotten that treatment and subsequently relapsed and needed a BTK inhibitor. We know that it works in that limited number of patients, but we certainly don’t have enough data to say that one sequence is better than the other.

Anthony R. Mato, MD, MSCE: Matt, do you want to weigh in and tell us whether we should start with a BTK inhibitor or venetoclax?

Matthew S. Davids, MD, MMSc: I agree with Brian. I really don’t think we have data one way or the other. The data that you’ve published from retrospective series suggest that both orders of administration are probably comparable, and we need much longer-term follow-up from existing data sets to understand this better.

Anthony R. Mato, MD, MSCE: I agree with that too. I don’t know the answer either.

Transcript has been edited for clarity.