Clinical Trials in R/R CLL: Venetoclax + Ibrutinib Combination Therapy


Key updates from clinical trials evaluating the combination of venetoclax and ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia.


Sonali M. Smith, MD: We’ve talked a little bit about combinations, but combining a BTK [Bruton tyrosine kinsase] inhibitor and a BCL2 inhibitor is 1 of the initial ways that the field has gone, particularly with ibrutinib. I’ll start with John. Give us an update on the phase 2 CAPTIVATE study.

John N. Allan, MD: The CAPTIVATE study is a very interesting and valuable study. This is looking at a combination of ibrutinib and venetoclax—an all-oral once-daily approach for patients [with chronic lymphocytic leukemia (CLL)]. CAPTIVATE is a large phase 2 study. It has 2 interesting aspects to its study design. I guess I should say 3. One is that it’s in young patients. All patients enrolled were less than 70 years of age, and the median age of the patients enrolled in this was 58 to 59 years old. We’ll understand how the young, fit patients do with this regimen. Two is that there were 2 cohorts. One cohort was in the MRD [minimal residual disease] response adapted treatment decision algorithm incorporated into the study where those patients who had a definition of MRD-negative remissions after a year of combination ibrutinib-venetoclax were randomized to placebo or ibrutinib. Patients who were MRD positive at the end of this year were randomized to ibrutinib or continuation of up to 2 more years of ibrutinib and venetoclax. The second cohort is a fixed-duration cohort, where all patients enrolled received 12 months of combination ibrutinib-venetoclax after ibrutinib lead-in and stop treatment regardless. We’ve seen primary end points reported for these studies and published.

At ASH [American Society of Hematology Annual Meeting], [we learned that] follow-up is getting a little longer. We’re over 4 years of median follow-up for patients in the MRD cohort. What was reported this year at ASH focused on those patients who achieved an MRD-negative state and were randomized to placebo or ibrutinib. What we see at 4 years is excellent progression-free survival, whether you’re on placebo or maintenance ibrutinib. Patients have maintained their MRD negativity. The disease-free survival rates in patients on placebo are about 85% at this 4-year mark. Patients on ibrutinib typically aren’t having any disease-free events. [These were] excellent outcomes. Basically, they reinforce that this is a very viable fixed-duration approach. Particularly if you can achieve this end point of MRD negativity, then you’re going to have phenomenal outcomes. It calls into the question of maintenance ibrutinib.

This looks at high-risk patients as well, and we’re trying to understand that outcomes look great, whether these high-risk patients with complex care attack deletion 17p. They have similar outcomes whether they’re on placebo or ibrutinib. Numbers are small; that’s the caveat But in a sense, it reinforces what we learned from some of these combination studies—that they are highly effective, can achieve high rates of MRD negativity, and offer an ability to have another fixed-duration approach that’s actually an anti-CD23 therapy with excellent long-term outcomes.

Sonali M. Smith, MD: That’s exciting. There’s also a phase 3 FLAIR trial. Give us a little information about the interim analysis?

Susan M. O’Brien, MD: This trial has a bit of a different design from other ibrutinib-venetoclax trials. It’s a randomized trial of ibrutinib alone vs ibrutinib and venetoclax. The primary end point is MRD undetectability. The way they do it in this trial is that, No. 1, they look at the MRD in the peripheral blood starting at 9 months. If it’s negative, they measure it 3 months later. Then if that’s negative, they measure it in the bone marrow and the blood 3 months later. Finally, if all of that is negative, the patient can come off study. But what makes it interesting is they don’t come off at the time when they become MRD undetectable. The thinking in this design is that if you’ve just become MRD undetectable, then you might be right below the surface. But if we keep going and we continue to reduce the level of disease, that might be beneficial in the long run when you stop. If it takes 12 months to become MRD undetectable, then the patient gets 12 more months of therapy before they stop. That’s the only IV [ibrutinib-venetoclax] combination trial that I’m aware of that has that kind of design. Whether and when they stop is based on how long the patient takes to achieve MRD undetectability. In that trial, you won’t be surprised to hear that individuals getting single-agent ibrutinib don’t become MRD undetectable, but many of the patients who got IV [ibrutinib-venetoclax] did.

Another interesting finding—this is a little hard to explain, but we’re seeing this consistently in all the ibrutinib-venetoclax trials—is that if we look at the immunoglobulin status, the patients who are unmutated, which we think of as a higher-risk group, have a greater incidence of becoming MRD undetectable. That was true in CAPTIVATE also. We’re also going to hear about GLOW, where that was also true. That’s interesting because there’s not a priority reason to easily explain why the unmutated would have a higher likelihood of achieving MRD undetectability. That said, both groups have very good rates of MRD undetectability, which then allows many of the patients to go on and stop therapy. It’s an interesting design because you don’t stop when you become MRD undetectable. You keep going for a period of time.

Sonali M. Smith, MD: Speaking of the GLOW trial, I’ll turn it over to John to tell us a little about that.

John N. Allan, MD: The GLOW study is another ibrutinib-venetoclax oral combination therapy. This is a phase 3 clinical trial in frontline CLL in older patients. Another unique aspect of this study is that it was done in patients 65 years or older. Their median age is close to 70 years of age compared with CAPTIVATE, which had younger patients. In this study, there was no response adapted, and there was no treatment duration change based on the achievement of MRD. It was similar to the fixed-duration cohort in CAPTIVATE, in which all patients enrolled on the IV [ibrutinib-venetoclax] arm received a fixed-duration approach of a 3-month lead-in and 1 year of combination treatment.

These patients were without deletion 17p, because that was excluded, were randomized against chlorambucil-obinutuzumab. What we’ve seen is long-term follow-up data. Clearly, progression-free events are favoring the ibrutinib-venetoclax arms. These patients are doing phenomenally well. Now we have close to 3 years of meeting follow-up time. We have about a year and a half of patients being off treatment, showing that these remissions remain stable. Patients have high rates of CR [complete response]. They remain MRD negative. That’s a durable remission at this time point. At ASH, we saw a bit more of a deep dive into the responses of specific subgroups. Dr O’Brien spoke about this difference in MRD negativity rates. We see this in this study as well. Unmutated patients have higher rates of MRD negativity. Those with this good-risk feature of mutated IGHV have a slightly lower rate, but close to half are still getting there.

What was unique is that they broke it down by MRD status and IGHV mutational status. Low-risk patients who are MRD positive still do phenomenally well at this 3-year mark. They might be getting to a lower state, a lower MRD-negative rate, but they’re still doing very well with these very low levels of CLL floating in the blood. Obviously, we see some separations of the curve of these higher-risk patients. The majority of them are MRD negative. They have excellent progression-free survival. But in that patient group, if they’re MRD positive, they’re relapsing sooner. We need to think about them differently, particularly these higher-risk features. For patients who harbor higher-risk features, the clonal growth rates are faster. Therefore, it’s not unexpected that they might relapse sooner. What’s nice in some of these studies—in general and in total—is that when we’ve re-treated them, the small numbers who have been re-treated upon relapse seem to have disease sensitivity to these agents remaining. Follow-up is still important, and we need to understand that many of these studies are ongoing. They’re going to be following these patients long into the future to home in on these aspects.

Transcript edited for clarity.

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