Cancer Therapy Advisor: Why is a fixed-duration approach to therapy important in this patient population, and what challenges has the CLL/SLL field faced when attempting to adopt this strategy to date?
Dr Allan: Fixed-duration is obviously important to patients and physicians for various different reasons. Fixed-duration is important for patients because they don’t want to be on drugs. They don’t want to be reminded that they have this disease, and if there’s a way that you can put the disease in remission and you can get years off of a treatment, I would say that most patients in my experience, if given that option, prefer to take that option.
The challenges are that in order to be able to do that, you have to have therapies that can get to deep, deep remissions that allow patients to have significant durable remissions off-of-drug, and that has always been a challenge. Previously, in the era of chemotherapy, those regimens were fixed-duration approaches. They worked for significant numbers of patients, but our highest-risk patients did not respond to those treatments. Therefore, their fixed duration was short-lived. The patients’ disease relapsed soon after, and it typically became more aggressive each time.
With these targeted approaches that work for everyone, even the highest-risk patients get deep remissions, and it’s possible that we might be able to have meaningful, durable remissions for all patients with these new targeted agents.
The challenges have been finding the right drugs with the least toxicity. Providers like fixed durations because they can limit exposure and toxicity to the drugs that are being used. Additionally, hypothetically, you can assume that if you’re not on a continuous treatment, resistant mechanisms may be less likely to arise, therefore making re-treatments easier and using these drugs in a repeated fashion more viable than just sequentially continuing therapy going forward.
And then obviously, fixed durations have an economic impact. Currently, the paradigm is to continue many of these drugs indefinitely, and we know that BTK inhibitors work really, really well for a long period of time, but they are expensive agents and over time they have a societal cost, an insurance cost, and then a personal cost to the patients. For those reasons, fixed-duration approaches are really important, and we’re in a fortunate position where we have very active drugs with low toxicities that can get deep remissions that even allow us to have this potential conversation.
Cancer Therapy Advisor: What implications do the data from the uMRD cohort hold for future management decisions in patients with previously treated CLL/SLL?
Dr Allan: The design of this study, for one, is exploratory: is fixed duration possible? It is also exploring this decision tree based on whether patients achieve MRD negativity. So, if they do achieve MRD negativity, it’s asking the question, ‘do you need any more treatment beyond that? Is that good enough?’
One important implication of this study is that we will get early evidence that if patients are are MRD negative, they can safely stop therapy for a prolonged period of time. There may be subjects who benefit from a maintenance treatment. We will gain that knowledge from this study design. It’s imparting some decision-making based on MRD.
From the patients who are MRD positive, we are also going to learn if we are maximizing that treatment by continuing treatment. Can we deepen their responses over time? We are studying that as well. There’s going to be a lot of knowledge on MRD responses gained from this study design, which will really inform how we might be able to use MRD and incorporate it into decision making for our patients going forward.
Cancer Therapy Advisor: What future research directions do the data from the uMRD cohort illuminate as areas of interest for 2021 and beyond?
Dr Allan: There is a subsequent cohort from this same study looking at fixed-duration therapy irrespective of MRD status. We’ll see data from that cohort at future congresses going forward as the data continue to mature. The cohort enrolled at a later time period than the MRD cohort, which we’ve seen many iterations of. What’s going to be important is maturation of this data and longer-term follow-up.
The primary end point of 1-year disease-free survival that we reported looks great, specifically for the MRD-negative patients and all patients in general, but ultimately what we need to see is how it looks at year 3 and year 5. Will these curves start to separate? And if they do start to separate, are there specific patients or patient characteristics that are the reason for the separation? We can start to focus on how to treat those patients differently.
Additionally, this study is setting a bar in a sense for all studies that come after it in terms of combination treatments. Clinical trials looking at doublets and triplet regimens vs our standard-of-care treatments are currently being designed. This sets the bar that all of those other studies will be judged and assessed against, and so that’s how important this study is to the field and to these patients.
This Q&A was edited for clarity and length.
John N. Allan, MD, reported affiliations with AstraZeneca, Pharmacyclics LLC, an AbbVie Company, Genentech, AbbVie, Ascentage, Cellectar, Celgene, TG Therapeutics, and Janssen.
Some of the other study authors disclosed financial relationships with the pharmaceutical industry. For a full list of disclosures, please refer to the original study.
Wierda WG, Tam CS, Allan JN, et al. 123 Ibrutinib (Ibr) plus venetoclax (Ven) for first-line treatment of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL): 1-year disease-free survival (DFS) results from the MRD cohort of the phase 2 CAPTIVATE study. Presented at: 2020 ASH Annual Meeting and Exposition; December 5-9, 2020. Abstract 123.