The Potential Role of Venetoclax Combination Approaches in CLL

Anthony R. Mato, MD, MSCE: Alexey, I want to jump into the combination therapy and talk about ibrutinib plus venetoclax, specifically ibrutinib. We’ve seen some updates at the recent meetings. Bill Wierda, [MD, PhD,] presented the CAPTIVATE [trial], fixed-duration schedule, frontline [setting]. Peter Hillman, [MB ChB, PhD,] talked about the NCRI [National Cancer Research Institute] FLAIR trial in the frontline setting. This is an MRD [minimal residual disease]-driven approach. We’ve seen GLOW presented, the randomized study. Then there’s the HOVON 141/VISION trial of ibrutinib plus venetoclax in the relapsed/refractory setting. Ibrutinib plus venetoclax has been studied [with an] MRD-driven [approach], it’s been studied as fixed-duration front line, relapsed/refractory [settings], in older and younger patients. Ultimately, I think the approval will be based on the GLOW dataset.

Can you please help us understand how this regimen will fit into our frontline management for patients with CLL [chronic lymphocytic leukemia]? The harder question is, given that almost everybody has either seen a BTK [Bruton tyrosine kinase] or venetoclax in the frontline [setting], is there really any value in studying ibrutinib plus venetoclax in the relapsed/refractory setting any further?

Alexey V. Danilov, MD, PhD: Anthony, you mentioned the number of studies [that] have been recently reported. As you mentioned, a couple of these studies used fixed-duration [therapy], that would be essentially the CAPTIVATE and GLOW [trials]. A couple of studies used an MRD-driven approach in terms of duration of venetoclax, which are the FLAIR and VISION studies. At this point, there are already multiple ways to skin the cat in terms of the ibrutinib plus venetoclax combination. The unifying feature of all the studies [is that] they’re all associated with a very high response rate of close to 100%, a complete response rate of about 60%, which of course, is partially driven by venetoclax. Undetectable MRD rates are also very high. After stopping therapy, the curves don’t seem to drop off. The progression-free survival [PFS] is 80% to 90% at 3 years. We also have some data now that the treatment with ibrutinib in patients who progress after using the doublet therapy is possible, inducing responses in that setting.

Overall, the advantage of this regimen is that this is the first oral combination therapy of fixed duration that stands in context of the CLL14 [trial] regimen [of] venetoclax and obinutuzumab, which is fixed duration, however, it is a combination of oral and IV [intravenous] therapy. Still, the issue of tumor lysis syndrome [TLS] is not fully addressed, and TLS cases have occurred on some of the studies. But it’s significantly mitigated by using a run-in of ibrutinib for either 2 or 3 months as [the] majority of the studies have done. There is a significant shift in TLS in this category over time. While patients are on ibrutinib and [have] laboratory monitoring, TLS monitoring can be significantly reduced when venetoclax ramp-up occurs. I do think this is a regimen that has a significant role in future treatment of CLL. What we don’t know still is whether treatment with concurrent ibrutinib plus venetoclax is better than sequential treatment with venetoclax and obinutuzumab followed by a routine or vice versa. GLOW will likely give us an approval of this regimen. However, the comparison there is chlorambucil-based therapy, so it will be much more interesting to see a comparison with sequential novel agents. Certainly, that would…be a smart business strategy to pursue regulatory approval.

Anthony R. Mato, MD, MSCE: Go ahead, the relapsed/refractory question.

Alexey V. Danilov, MD, PhD: With [the] relapsed/refractory question, yes there are data with smaller studies. It is also an active regimen there, and I do think it’s worth pursuing this question in patients who progress on venetoclax in an effort to optimize response and durability of response in these patients.

Anthony R. Mato, MD, MSCE: Matt, Alexey mentioned skinning a cat. I’m going to ask you about building a better mouse trap since you’ve been very interested in using acalabrutinib in combination with venetoclax. We can’t see the crystal ball in your office, but I’m sure it’s right outside of the window there. Can you comment on in the future, will we be using next-generation [BTK inhibitors] plus venetoclax? [Are there] trials that may help us sort that out?

Matthew S. Davids, MD, MMSc: I do think that is the direction we’re heading in CLL. We’ve seen great data for ibrutinib plus venetoclax, as Alexey eloquently described. But we also know from the head-to-head studies that the next generation of BTK inhibitors are better tolerated, and at least equally efficacious, if not even maybe a little more efficacious, as we’ve seen in the ALPINE study. I do think the future will be second-generation covalent BTK inhibitor plus venetoclax. I think one question is whether that’s going to be best served in a triplet with obinutuzumab or as a doublet. We’ve seen very nice data from triplet-based studies published this past fall from our own AVO [acalabrutinib, venetoclax, obinutuzumab] study, and then the obinutuzumab study with zanubrutinib [and venetoclax].

I think the doublets also look very good with ibrutinib plus venetoclax, so we need more data with acalabrutinib plus venetoclax and zanubrutinib plus venetoclax. We’ve seen a little bit of zanubrutinib plus venetoclax data presented at the 2022 ASH [American Society of Hematology] meeting from the SEQUOIA study. It was only about 30 patients, but so far so good. [There were] very high response rates and very good tolerability of that doublet. Based on the promising doublets, Anthony and I along with Jeff Sharman, [MC,] [have] developed the MAJIC study, which is comparing 2 of the best doublets we could think of for venetoclax: acalabrutinib plus venetoclax vs venetoclax plus obinutuzumab. In this study, both of the arms are MRD-guided, so patients can have either 1 or 2 years of venetoclax-based therapy. That decision is based on an adaptive MRD test [that has] a level of 10-5, so it’ll hopefully allow us to individualize therapy duration for patients and maximize PFS. Hopefully that study will be opening later this year.

Transcript has been edited for clarity.