Role of Fixed-Dose Regimens in CLL

Nitin Jain, MD: We’ll move on to segment 2 of our discussion, where we’re going to talk about the evolving treatment landscape and specifically fixed-dose regimens for patients with CLL [chronic lymphocytic leukemia]. We already have 1 fixed-dose regimen, venetoclax [Venclexta] plus obinutuzumab [Gazyva], in frontline CLL, but there are other oral doublet regimens which have come along, namely the combination of ibrutinib [Imbruvica] plus venetoclax.

I want to talk about 2 trials. One is the CAPTIVATE study, which is a large international effort where patients with CLL who were previously untreated and needed treatment were given a combination of ibrutinib plus venetoclax. The design of these trials had patients given ibrutinib for 3 months and then venetoclax was added. Venetoclax was added for a combination duration of 1 year. At that time, there were 2 arms to the study. In 1 arm that was the only treatment given. That was a fixed-duration cohort. Then there’s another arm in the study where patients were randomized based on MRD [minimal residual disease] to subsequent therapies.

These data were updated more recently, and they will be updated at the upcoming ASH [American Society of Hematology Annual Meeting] as well. But what was clear from these data was that the combination of ibrutinib plus venetoclax leads to high rates of bone marrow MRD negativity, at about 65% to 70% at the 1-year mark for these patients. These data were consistent with other phase 2 data from other centers as well, where it was about 60% to 70% MRD negativity in the bone marrow. That was the large multicenter phase 2 CAPTIVATE study.

Importantly, at the EHA [European Hematology Association] meeting over the summer, the phase 3 data from the GLOW study was reported. In the GLOW study, the same regimen was taken: ibrutinib plus venetoclax for a total duration of 1 year. There’s 3 months of ibrutinib, then venetoclax starts, and then venetoclax plus ibrutinib goes on for 12 months. That’s a total of 15 months of the regimen. That regimen was compared with chlorambucil plus obinutuzumab.

Obviously, the comparator here isn’t the most optimal comparator for randomized studies. It’s probably the last study using that randomized arm. But the investigator showed that the progression-free survival was in favor of ibrutinib plus venetoclax as opposed to chlorambucil plus obinutuzumab. That’s not a total surprise. That was a phase 3 registrational study.

Based on those data, I expect that this regimen of ibrutinib plus venetoclax may eventually get approved by the FDA in the United States. Then we’ll have 2 different venetoclax-based regimens for time-limited approaches. We’ll have venetoclax plus obinutuzumab based on the CLL14 study, which is also a 1-year regimen, and we’ll also likely have the regimen of venetoclax plus ibrutinib, which is also about a year, and doesn’t have any IV [intravenous] drugs or infusions involved.

Strategy will change when that regimen becomes FDA approved. One of the important things at that time will be how we incorporate that regimen of ibrutinib plus venetoclax for our patients when we already have very effective regimens, including acalabrutinib [Calquence] and venetoclax plus obinutuzumab. That will be another regimen to add to the mix for our patients for discussion.

Richard, we talked about this combination, double oral strategy. How do you think that will play out for the patients if the FDA approves that regimen? In which patients would you think about using the doublet of ibrutinib plus venetoclax?

Richard R. Furman, MD: These are great treatment strategies. As an aside, the GLOW study had to be done for the purposes of approval, but it doesn’t tell us or teach us anything of relevance. It’s unfortunate that those types of studies need to be done. We always talk about CAPTIVATE as a phase 2, but CAPTIVATE is probably one of the most important studies we’ve recently done that’s really going to help us understand whether fixed-duration therapy is the best option for our patients. When people start receiving either 12 or 24 months of venetoclax as part of the CLL14 or the MURANO trial regimens, the treatment duration is relatively arbitrary. We don’t know whether we’re harming our patients and leaving efficacy on the table by discontinuing the therapies at these fixed durations.

One of the things I appreciate about the CAPTIVATE study is the idea that in the MRD treatment arm, patients will be randomized to either stay on ibrutinib alone or go on placebo to see whether that makes a difference. When patients relapse on placebo, they’re going to be able to go back on ibrutinib to show that we didn’t breed any resistance. The patients in the fixed-duration trial are going to have the same options, and that will also show us that we’re able to intermittently treat our patients without the development of resistance. These being oral agents and the ibrutinib being able to debulk the tumors and avoid the tumor lysis from venetoclax make it such a great strategy that can really benefit the patients.

Nitin Jain, MD: Yes. That’s fantastic. There are more longer-term follow-up data with venetoclax/obinutuzumab, but taking 2 oral drugs together has some appeal to it without worrying about things like infusion reactions and chair time with obinutuzumab. There are ongoing randomized studies, including CLL17, which is comparing these regimens head-to-head. It’s ibrutinib alone vs ibrutinib plus venetoclax vs venetoclax plus obinutuzumab. There are other studies being planned as well. Eventually, in due course, we’ll know in a randomized fashion if one is better than the others in terms of the efficacy or safety profile. But for now, we’ll certainly have more options available for our patients. A lot of patients, at least in my practice, prefer time-limited approaches over taking the continuous daily therapy. That would appeal to them.

Transcript Edited for Clarity