Updates in CLL From ASH 2021 Are Expected to Be Impactful in Future Treatment Decision-Making

Matthew Davids, MD, MMSc

The American Society of Hematology (ASH) Annual Meeting & Exposition is one of the most important conferences of the year for advances in hematologic malignancies. It highlights findings from major trials and lays the ground-work for significant research for the year ahead and potential FDA approvals. According to Matthew Davids, MD, MMSc, these studies are looking to answer substantial questions in the treatment of patients with chronic lymphocytic leukemia (CLL).

“There were several very impactful abstracts at this year’s ASH meeting in CLL,” Davids, director of clinical research in the Division of Lymphoma at Dana-Farber Cancer Institute and an associate professor of medicine at Harvard Medical School in Boston, Massachusetts, told Targeted Oncology™. He detailed which ones he found to have the most impact and be potentially practice changing.

During the meeting, Davids also discussed data from a significant trial in progress, the phase 3 MAJIC trial (NCT05057494),¹ which he believes may also have implications for future treatment decision-making in CLL.

Targeted Oncology™: Which abstracts or data do you feel are most important from the ASH meeting this year?

Davids: I think one of the more exciting ones that I saw was the CLL13 abstract.² This is an almost-1000 patient study going on in Europe largely, which is comparing various venetoclax [Venclexta]-based combinations to chemoimmunotherapy. At this ASH meeting, we saw for the first time the MRD [minimal residual disease] data from the study. Some of the takeaways for me were that the venetoclax plus obinutuzumab [Gazyva] combination performed very well—high rates of undetectable MRD, certainly much higher than [with] chemoimmunotherapy, which wasn’t a huge surprise, but much higher also than venetoclax with rituximab [Rituxan], which is a little bit surprising that the CD20 antibody made such a big difference. The study also had a triplet regimen—ibrutinib [Imbruvica]/venetoclax/obinutuzumab—[and] although it looked a little bit more potent than venetoclax-obinutuzumab on its own, I do think that the doublet performed quite well. So I think it’s an open question whether the third drug is actually needed in the upfront setting.

We also saw data from the SEQUOIA study [NCT03336333], cohort 1 for the first time.³ This is a registrational study looking at zanubrutinib [Brukinsa], a newer, more specific BTK [Bruton tyrosine kinase] inhibitor compared with bendamustine and rituximab. This was a positive study favoring the PFS [progression-free survival] with zanubrutinib and is likely to lead to a label for zanubrutinib, hopefully in the near future, for CLL.

[Findings from] several other impactful studies were presented of various combinations of ibrutinib plus venetoclax, both in older patients, for example, in an update to the GLOW study [NCT03462719], as well as in younger fit patients,⁴ and an update to the CAPTIVATEstudy [NCT02910583] showing very nice durable responses.⁵ And we presented some of our data on the combination of ibrutinib plus FCR [fludarabine, cyclophosphamide, rituximab] for young patients with CLL.⁶ This also has proved to be quite durable in terms of deep responses, [with a] 97% PFS rate with about 40 months of follow-up. [This is] not something that would be broadly applied to a large population of [patients with] CLL, but for those very young, fit [patients with] CLL who might want the potential for a functional cure of their disease, we think that this is the type of regimen that should be explored in larger comparative studies.

Looking forward to 2022, are there any developments we might see in the CLL space?

There are a lot of exciting things going on right now in CLL. I do expect, in 2022, you’re likely to see a label for ibrutinib plus venetoclax in the frontline setting, which is the first time we’ll have the option to have an all-oral, novel-agent, time-limited regimen for frontline CLL, so I think that’s exciting. We also have data emerging for noncovalent BTK inhibitors, for example, pirtobrutinib. We saw some great data at ASH suggesting [that] this drug can work even for patients who have progressed on the first generation of covalent BTK inhibitors, even if they’ve already had venetoclax.⁷ It’s hard to know what the time frame is for these types of approvals, but I do think we’ll see at least evolving data sets for pirtobrutinib in 2022.

We also have the U2 regimen in development that the FDA will be reviewing in 2022 and deciding whether that will get a label.

And we have a number of important ongoing studies around the world looking to answer some of the key questions in the field. A couple of them that I’m most excited about [include] the CLL17 study [NCT04608318], which has already launched in Europe [and is] being led by the German CLL study group, helping to answer this key question of continuous vs time-limited frontline therapy [and] which is better. That study is ibrutinib continuously vs 1 of 2 time-limited combinations: ibrutinib plus venetoclax or obinutuzumab plus venetoclax.

We also are launching the MAJIC study in 2022 here in the United States and around the world.1 This is looking at the optimal combination partner for venetoclax in the frontline setting, the BTK inhibitor acalabrutinib [Calquence] or obinutuzumab. It’s a phase 3 randomized trial comparing those 2 regimens, both given in an MRD-driven fashion. We’re hoping that eventually that will also answer an important question about time-limited therapy in the field.

Can you discuss the rationale behind testing the combination of venetoclax and acalabrutinib in this patient population?

We’re fortunate now in CLL that we have several very active novel agents, we have strategies that include continuous BTK inhibitor therapies, and then we have strategies that include time-limited therapy in the frontline setting with the venetoclax plus obinutuzumab regimen. But increasingly, I think in the future we’re going to be looking more at time-limited therapies in CLL because it allows for a shorter duration of therapy. That means fewer adverse events and less cost, and hopefully, a better lifestyle for patients who don’t need to be continuously reminded that they’re taking [pills for cancer]. So the idea with the MAJIC study is to look at the newer, more specific BTK inhibitor acalabrutinib in combination with venetoclax. That’s the experimental arm that’s being compared with the more standard regimen of venetoclax plus obinutuzumab. It’s a randomized phase 3 trial to help define what the optimal combination partner is for venetoclax in the frontline setting. Is it a BTK inhibitor, or is it obinutuzumab?

The study will [include] about 750 patients recruited and randomized 1:1 to these 2 arms. The unique aspect of the study is that the duration of therapy in both arms is guided by MRD. So it could be 1 or 2 years of venetoclax therapy in either arm. And we’re hoping that that will help to minimize the amount of therapy needed for patients who have more sensitive disease but potentially extend therapy for those patients who have more resistant disease and need a longer course [of treatment].

Can you discuss the strategy behind discontinuing therapy at 24 months and why this is potentially advantageous?

We think that time-limited therapy, by discontinuing at 24 months, will be advantageous for several reasons. Some of these, of course, include minimizing toxicity and reducing cost. But there may also be certain scientific reasons as well. We know that if we expose cancer cells to a particular therapy over a long period of time, in many cases, eventually the cancer cells will develop resistance—resistance mutations are other functional mechanisms that will make the therapy no longer effective. So the idea of that hypothesis is that if we give a very active time-limited regimen for a short period of time, 1 year or 2 years, we can get patients into very deep remissions with high rates of undetectable MRD, and that this will provide a durable benefit without the need for ongoing treatment. And the hope would be then if the patient did relapse at a later time, they could potentially even be retreated with the same regimen and that their cancer would still be sensitive to that treatment. In the MAJIC study, one of the unique aspects is that it is an MRD-guided strategy for both arms. So even the venetoclax plus obinutuzumab, which is approved as a 1-year regimen—and essentially all other phase 3 studies that are under way right now in CLL are using a fixed duration of 1 year—our study is unique in that you can get a second year of venetoclax in that arm of the study to make it more equivalent to the 2 years of acalabrutinib/venetoclax in the other arm.

Based on the patient population explored in the study, should you treat younger patients differently from older patients?

I think that the decision of [how] to treat is certainly still influenced by the age of the patient; it’s also, of course, influenced by the biology of a particular patient’s disease. So, for example, if you had an older patient who had low-risk disease, you could imagine using a continuous BTK inhibitor for some relatively short amount of time. You could imagine time-limited regimens also being appealing there. For younger patients, I find that they often desire a more aggressive approach and like the idea of putting several drugs together to develop a very potent time-limited therapy. For very young patients who may have decades of life ahead of them, that’s where, particularly if they have the mutated IGHV, either FCR chemoimmunotherapy or combinations with FCR can still be considered, as long as we counsel our patients about some of the risks of those regimens. But for the majority of [patients with] CLL, and including young patients, I do think that novel agent combinations that are time limited are where the field is headed. And I think a lot of the studies that are ongoing now will help to define what those optimal combinations are that can be broadly applied to [patients with] CLL.

_References

_{1. Davids MS, Mato AR, Hum J, et al. Majic: a phase 3 prospective, multicenter, randomized, open-label trial of acalabrutinib plus venetoclax versus venetoclax plus obinutuzumab in previously untreated chronic lymphocytic leukemia or small lymphocytic lymphoma. Presented at: 2021 American Society of Hematology Annual Meeting & Exposition; December 11-14, 2021; Atlanta, GA. Abstract 1553. https://bit.ly/3nhLoxv}

_{2. Eichhorst B, Niemann CU, Kater AP, et al. A randomized phase III study of venetoclax-based time-limited combination treatments (RVe, GVe, GIVe) vs standard chemoimmunotherapy (CIT: FCR/BR) in frontline chronic lymphocytic leukemia (CLL) of fit patients: first co-primary endpoint analysis of the international intergroup GAIA (CLL13) trial. Presented at: 2021 American Society of Hematology Annual Meeting & Exposition; December 11-14, 2021; Atlanta, GA. Abstract 71. https://bit.ly/31rePpd}

_{3. Edeschi A, Ferrant E, Flinn IW, et al. Zanubrutinib in combination with venetoclax for patients with treatment-naïve (TN) chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) with del(17p): early results from arm D of the SEQUOIA (BGB-3111-304) trial. Presented at: 2021 American Society of Hematology Annual Meeting & Exposition; December 11-14, 2021; Atlanta, GA. Abstract 67. https://bit.ly/3FmfFRO}

_{4. Munir T, Moreno C, Owen C, et al. First prospective data on minimal residual disease (MRD) outcomes after fixed-duration ibrutinib plus venetoclax (Ibr+Ven) versus chlorambucil plus obinutuzumab (Clb+O) for first-line treatment of CLL in elderly or unfit patients: the GLOW study. Presented at: 2021 American Society of Hematology Annual Meeting & Exposition; December 11-14, 2021; Atlanta, GA. Abstract 70. https://bit.ly/31o5ZZ8}

_{5. Ghia P, Allan JN, Siddiqi T, et al. First-Line Treatment with Ibrutinib (Ibr) Plus Venetoclax (Ven) for Chronic Lymphocytic Leukemia (CLL): 2-Year Post-Randomization Disease-Free Survival (DFS) Results from the Minimal Residual Disease (MRD) Cohort of the Phase 2 Captivate Study. Presented at: 2021 American Society of Hematology Annual Meeting & Exposition; December 11-14, 2021; Atlanta, GA. Abstract 68. https://bit.ly/3qJp1C2}

_{6. Davids MS, Brander DM, Tyekucheva S, et al. Longer term follow-up of a multicenter, phase 2 study of ibrutinib plus fludarabine, cyclophosphamide, rituximab (iFCR) as initial therapy for younger patients with chronic lymphocytic leukemia. Presented at: 2021 American Society of Hematology Annual Meeting & Exposition; December 11-14, 2021; Atlanta, GA. Abstract 640. https://bit.ly/3rjIoSC}

_{7. Mato AR, Pagel JM, Coombs CC, et al. Pirtobrutinib, a next generation, highly selective, non-covalent BTK inhibitor in previously treated CLL/SLL: updated results from the phase 1/2 BRUIN study. Presented at: 2021 American Society of Hematology Annual Meeting & Exposition; December 11-14, 2021; Atlanta, GA. Abstract 391. https://bit.ly/3nnpV6a}