Fixed-Duration Therapy in Frontline CLL: Ibrutinib Plus Venetoclax

William Wierda, MD, PhD: We talked about BTK [Bruton tyrosine kinase] inhibitors. There have been recent updates. Obviously, it’s a highly active, highly effective group of drugs. We’ll talk a little about them later when we talk about the reversible inhibitors to BTK, but let’s move on to the evolving landscape of treatment options and where the field is going. We’ll start with you, Anthony. We had an update at ASH [American Society of Hematology Annual Meeting] on the CAPTIVATE study that Dr Paolo Ghia presented. Could you summarize the study, the design, and what the updated data revealed?

Anthony Mato, MD, MSCE: CAPTIVATE is a complicated study in that it’s 2 studies in 1. Essentially, it’s looking at the combination of ibrutinib [Imbruvica] plus venetoclax [Venclexta], and it’s treating 2 different strategies for administering that combination. One is the strategy of a fixed-duration schedule. Everyone gets 3 months of ibrutinib, everyone gets 12 months of combination, then they stop. The second strategy is MRD [minimal residual disease] driven, where everybody gets 3 months of ibrutinib, 12 months of combination, and then an MRD test. If you’re undetectable on that study, you were randomized to ibrutinib vs placebo. If you were detectable, a sensitivity of the 10-4, you were randomized to ibrutinib vs I+V [ibrutinib plus venetoclax]. The primary end point of the MRD-driven study was the 1-year rate of disease-free survival with a comparison between the placebo-vs-ibrutinib curve. And the 1-year disease-free survival was nearly identical for both groups: 100% vs 95%-something. P value is statistically not significant.

The update at ASH and the headline—maybe somebody could comment if there’s any more information to it—was that they had another year’s worth of follow-up and, in particular, that cohort demonstrated no events in either arm. The 2-year disease-free survival was the same as the 1-year disease-free survival—2 for the price of 1. If you memorize those numbers, you’ll be right at either time point. Those values were not significantly different, of course. The take-home was that with I+V [ibrutinib plus venetoclax], particularly for an MRD-undetectable patient, 15 months of total therapy is enough. You can stop. You’re fine. There’s no reason to continue ibrutinib as a maintenance strategy, regardless of your molecular genetic profile.

Data for the MRD-detectable patients is a different story. There, the headline has been and remains that probably 15 months’ worth of therapy is not enough. If you want to deepen your remissions, you need to have venetoclax as part of the backbone for further deepening of MRD response.

William Wierda, MD, PhD: I would add that, for the other arm, the unconfirmed undetectable MRD arm, those patients could continue ibrutinib monotherapy vs continued combined therapy. What you see with the follow-up in that group is a larger improvement in undetectable MRD status favoring those patients who continue combined therapy. We’ve seen that in our own trial at [The University of Texas] MD Anderson [Cancer Center], where we were giving routinely 2 years and we modified the protocol to allow 3 years. [We saw] continued improved responses with continued therapy in those patients who hadn’t converted after 12 cycles. That highlights that the jury is out about optimal duration of treatment. We need trials designed with MRD end points to get better clarity around what the optimum duration of treatment is with an objective to achieve undetectable MRD status.

As mentioned, we did a trial with ibrutinib-venetoclax at MD Anderson. The CAPTIVATE study that Anthony just reviewed was a multicenter international trial. There was also the randomized phase 3 GLOW trial, which included the investigational arm of ibrutinib plus venetoclax. Callie, can you talk about the GLOW study? There was an update of the GLOW study at ASH.

Catherine Callaghan Coombs, MD: The main thing to keep in mind about GLOW, is that it’s a randomized study. That’s an important distinguishing feature. The other is that the patient population was different. CAPTIVATE had a maximum age of 70. GLOW had a minimum age of 65. If patients were younger than 65, they had to have a high SEER [Surveillance, Epidemiology, and End Results] score. So it was largely an unfit patient population.

This is a randomized study of ibrutinib plus venetoclax at the same schedule of the fixed-duration cohort of CAPTIVATE, a 3-cycle ibrutinib lead-in, followed by 12 cycles of the I+V [ibrutinib plus venetoclax] combination. This was an unfit older-patient population. The median age was 71, and the SEER score was an 8 or a 9 depending on the arm; it was a sick group. We see that this regimen is effective and, in comparison with chlorambucil-obinutuzumab, quite superior with respect to PFS [progression-free survival] and rate of undetectable MRD. They measured MRD in 2 ways: NGS [next-generation sequencing] testing and by flow. The rates by flow were 10-4 or a little over that—50% of patients in the I+V [ibrutinib plus venetoclax] arm attained MRD negativity. It was lower when using NGS and going down to 10-5.

They don’t have a long follow-up in this cohort, but it does look like patients are attaining deep remissions without many relapses. The abstract quotes greater than 90% are progression free with the limited amount of follow-up that they have. There seems to be a bit higher discontinuation in this trial. It was just over 10% because of toxicity, and that may be related to the slightly less fit and older-patient population with comorbidities having some more tolerance issues, which is not unexpected.

William Wierda, MD, PhD: Great. We have several trials with combined ibrutinib-venetoclax. We didn’t report any safety concerns on our trial. I did appreciate that there were no safety concerns identified on the other trials with ibrutinib-venetoclax—only those that we expect to see with either agent, but no safety or adverse events that would indicate significant concern or toxicity with the combination. Fast-forward a year or so, and the FDA has reviewed the data and feels that it would warrant approval for the combination.

Transcript edited for clarity.