Newer Fixed Duration and Continuous Regimens Change Practice in CLL

John N. Allan, MD (Moderator)

Associate Professor of Clinical Medicine

Division of Hematology and Medical Oncology

Weill Cornell Medicine

New York, NY

DISCUSSION QUESTIONS

Consider the data for the SEQUOIA (NCT03336333), ELEVATE-TN (NCT02475681), and CLL14 (NCT02242942) trials:​

• How do you interpret the efficacy and safety data for each study?​
• Based on the results from ELEVATE-TN, would you consider adding a CD20 antibody to acalabrutinib (Calquence)?
• Based on the results from CLL14, would you consider VenG (venetoclax [Venclexta] plus obinutuzumab [Gazyva])? In which patient type?​
• What are your thoughts on BTKi (Bruton tyrosine kinase inhibitor) plus venetoclax continuous therapy?​

John Allan, MD: Considering these data updates, is there a superior drug in your mind, or a superior approach? When you're looking at VenG vs [acalabrutinib plus obinutuzumab or zanubrutinib (Brukinsa) from] ELEVATE-TN or SEQUOIA, do you think that there's a best approach?

Arun Bhandari, MD: I think patient choice is very important, whether they want to have a fixed duration therapy with VenG where after 12 months you are done, or whether they are willing to go for indefinite [treatment] until progression. With 17p deletion or TP53 [mutation], I tend to use BTKi more because I think that's where the data [show benefit] rather than fixed duration. But otherwise, I am willing to use BTKi and venetoclax or fixed duration.

Allan: Can you talk about which BTKi you use? Do you let insurance dictate that, or do you reach for one more commonly?

Bhandari: [Considering] how much the cost of venetoclax is, if ibrutinib [Imbruvica] costs [less], then if I'm cost conscious, I will use that one. [Policymakers] worked very hard to have these 50 drugs under cost control [for patients with Medicare].

Allan: Absolutely. Outside of cost, is there anyone you wouldn't use ibrutinib for?

Bhandari: You can use ibrutinib or acalabrutinib. I don't think there's a big difference.

Huzefa Bahrain, MD: Those with the 17p deletion do better with a BTKi.^1,2 Do you think that's because of the mechanism of action, or do you think because it is continuous therapy?

Allan: The CLL14 study had some subgroup analyses a few years ago. They looked at clonal kinetic growth rates after stopping treatment, and certain mutations: NOTCH1 mutated, unmutated IGHV, deletion 17p, KRAS, certain combinations of mutations or higher-risk disease had a higher clonal kinetic growth rate.³ When you stop treatment, no matter if they're minimal residual disease [MRD] negative or not, those [diseases] will always grow back faster and progress sooner. We've seen that across all VenG studies. We've seen that with ibrutinib plus venetoclax. I don't think we've seen it with acalabrutinib plus venetoclax, but I don't expect it to be any different. Once you give a fixed duration approach, we will see these higher-risk clones grow back and progress sooner.

To answer your question, it is a bit about the mechanism of action, because BTKis shut down proliferation very quickly and very potently. They control the disease very well in the long term, and stop doubling and proliferation, which then translates into controlling the disease for longer. So, it’s a little bit of both. It's the biology of the disease itself, and whether we have continuous antiproliferative pressure onto the cells—which is why CLL17 [NCT04608318] will be important.

I think we will see continuous therapy have improved progression-free survival [PFS] for most, if not all, patients. But at the end of the day, I think overall survival [OS] is going to be very similar. That’s one thing that I'm looking for in the CLL17 study. We've never shown patients with deletion 17p have necessarily an inferior OS compared with those without deletion 17p in any fixed-duration approach, but if we start to see an OS difference in CLL17 and the fixed duration approaches compared with those with BTKi, I think that will answer a big question for us and highlight the need for continuous therapy for these patients.

Is anyone familiar with doublet data with the ibrutinib/venetoclax and the AMPLIFY [NCT03836261] acalabrutinib plus venetoclax regimens? How do you like that compared with VenG as another fixed duration approach?

Ligeng Tian, MD: It probably [leads to] deeper responses, PFS and never true OS. I was very surprised that BR [bendamustine plus rituximab (Rituxan)] upfront vs other BTKi or venetoclax, [did not show] OS benefit. That makes me feel a bit better, because I do have patients who end up doing BR simply because they don't want to take the pills forever, the cost issue, and they want to be done with it after some BR. The fixed duration is shorter than venetoclax, and you’re not worried about tumor lysis.

Similarly, I think at this moment with BTKi/venetoclax continuous therapy, there's no survival benefit; I haven't tried it yet, and I am not sure where I would put it if there's a lot of disease burden. I’m worried more about tumor lysis syndrome. In patients with deletion 17p, acalabrutinib plus obinutuzumab is not necessarily better and then there are toxicity considerations.

Allan: I don't think we know where to use the doublet. The CAPTIVATE study [NCT02910583] as a fixed duration approach with ibrutinib/venetoclax seems to be tracking historically well with the PFS curves from VenG.^4,5 It has some advantages in that it's an all-oral approach. We don't have the antibody to deal with and the immunosuppression that comes with it. I thought that this is going to be the standard and be so much better than VenG. But I think what we're learning is that it's at least the same. It's hard to know right now, if there is one that's better than the other. Historically speaking, they're all tracking along the same time points and timeline, and so I think that it's at least equivalent and offers some advantages in terms of an all-oral approach, etc.

One thing that was shown is that with VenG, bulky disease greater than 5 cm at study entry was an independent predictor for inferior PFS, and on the CAPTIVATE study, they showed that bulky disease did not identify a patient who is going to have inferior PFS.^4,6 They got MRD at the same rates, etc. If there is a patient population that might be best for doublet or even triplet, it might be a patient with disease bulk, because it's so good at getting control of disease, mitigating tumor lysis, and seemingly having very good outcomes, etc. That’s something I want to watch in the head-to-head studies as well.

_{DISCLOSURE: Allan disclosed roles as consultant for AbbVie Inc.; AstraZeneca Pharmaceuticals LP; Genetech, Inc; Janssen Pharmaceutical Company; KLJ Associates, Inc.; Lilly USA, LLC; professional services for Merck and Projects in Knowledge, Inc, and advisory/scientific board membership for NeoGenomics Laboratories, Inc.}

_References:

_{1. Shadman M, Munir T, Robak T, et al. Sustained superiority of zanubrutinib vs bendamustine + rituximab in treatment-naive chronic lymphocytic leukemia/small lymphocytic lymphoma (TN CLL): 5-year follow-up of cohort 1 from the SEQUOIA study. Blood. 2024;144(suppl 1):3249. doi:10.1182/blood-2024-194864}

_{2. Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib ± obinutuzumab vs obinutuzumab + chlorambucil in treatment-naive chronic lymphocytic leukemia: 6-year follow-up of Elevate-TN. Blood. 2023;142(suppl 1):636. doi:10.1182/blood-2023-174750}

_{3. Tausch E, Schneider C, Robrecht S, et al. Prognostic and predictive impact of genetic markers in patients with CLL treated with obinutuzumab and venetoclax. Blood. 2020;135(26):2402-2412. doi:10.1182/blood.2019004492}

_{4. Al-Sawaf O, Robrecht S, Zhang C, et al. Venetoclax-obinutuzumab for previously untreated chronic lymphocytic leukemia: 6-year results of the randomized phase 3 CLL14 study. Blood. 2024;144(18):1924-1935. doi:10.1182/blood.2024024631}

_{5. Wierda WG, Jacobs R, Barr PN, et al. Outcomes in high-risk subgroups after fixed-duration ibrutinib + venetoclax for chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL): Up to 5.5 years of follow-up in the phase 2 CAPTIVATE study. J Clin Oncol. 2024;42(suppl 16):7009. doi:10.1200/JCO.2024.42.16_suppl.7009}