Clinical Implications Continued

EP: 1.Chronic Lymphocytic Leukemia Treatment Landscape

EP: 2.Covalent BTK Inhibitors and Common Challenges

EP: 3.Challenges With BTK Inhibitors

EP: 4.Challenges Continued

EP: 5.Non-Covalent BTK Inhibitors

EP: 6.Clinical Implications of BTK Inhibitors in CLL

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EP: 7.Clinical Implications Continued

EP: 8.BTK Inhibitors and Other B-Cell Malignancies

EP: 9.Future Directions for BTK Inhibitors

Nicole Lamanna, MD: In the relapsed/refractory setting with CLL [chronic lymphocytic leukemia] patients, it’s important to figure out where they’ve come from and to remind yourself about their disease characteristics and re-test their cytogenetics to see if things have changed. If somebody has received, let’s say a BTK [Bruton tyrosine kinase] inhibitor, either ibrutinib [Imbruvica] or acalabrutinib [Calquence] in frontline and then relapses, what can you do subsequent to that? Typically, we’ll go to venetoclax [Venclexta]/rituximab [Rituxan] in that situation, which is 24 months, so 2 years in a limited-duration, time-limited approach.

The MURANO trial [CT02005471] data also has long-term follow-ups that look very good in terms of patients having sustained benefit after completing 2 years of therapy before needing treatment again. In fact, it can buy several years off of needing treatment and doing very well. For patients who are developing resistant mutations to the BTK inhibitors, as I discussed earlier, of course, you can go to venetoclax and rituximab in that scenario. We’ll also be looking for drugs like the noncovalent BTK inhibitors given the very strong data, with over 600 patients treated on that pirtobrutinib study and the BRUIN study. Certainly, that’s an option and, in fact, it’s irrespective of whether or not patients have developed a C481S mutation because many patients responded very nicely. The overall response was I think 66% approximately, but the point being is that we know that the noncovalent BTK inhibitors work.

Hopefully, in the future, there will be approval of some of these noncovalent BTK inhibitors. Hopefully, they will allow us to sequence or alternate some of these medications, so if you started with a BTK inhibitor, you can go to a ven [venetoclax]/ritux [rituximab] or to a noncovalent BTK inhibitor, or vice versa. The point is to extend and sequence therapies and get nice long response durations out of each subsequent therapy to keep your patient going. We will learn more as drugs like pirtobrutinib move up. There are combination clinical trials with pirtobrutinib ongoing, and so we’ll see how time-limited approaches combining pirtobrutinib with venetoclax and an antibody do as well. These are doublets or triplets looking at time-limited approaches, and we’ll see if pirtobrutinib moves up. Currently, I will not off-label, I will not give a noncovalent BTK inhibitor frontline. I want to see that data and wait until the clinical trial. Currently, I’ll still give a covalent BTK inhibitor. Then we have, as I said, venetoclax/rituximab or a noncovalent BTK inhibitor. That’s 1 way to sequence things. If you’ve started with venetoclax/obinutuzumab [Gazyva] in the frontline and then relapsed and need therapy, then, of course, there are a couple of things. It depends on how long their response duration to the venetoclax/obinutuzumab was. If it was very short, within 1 or 2 years, I’ll probably go to a BTK inhibitor or covalent BTK inhibitor. If, let’s say, they bought 4 to 5 years off of therapy, I might consider re-challenging them with venetoclax. Although this data is extrapolating from the relapsed setting from the MURANO study, there’s no doubt that there are patients who can be restarted if they’ve bought a significant time off of venetoclax therapy and re-respond to that therapy again. You have some options where you might be able to re-challenge them with venetoclax if they’ve bought a significant time period off a drug versus somebody who’s relapsed relatively shortly when completing that therapy. That’s less appealing because we’ll be concerned that their response duration to rechallenge might be short. Stay tuned, but there are newer drugs that were presented as well in development in terms of CAR [chimeric antigen receptor] T-cell bispecific monoclonal antibodies and a slew of other agents coming down the pike that are still immature. Hopefully, we’ll have more and more alternative therapies that we can look at for our CLL patients when they relapse. We can figure out how to sequence them appropriately and how to give them time off of therapy so they can enjoy some time off. We’ll learn more about minimal residual disease testing, response durations, and how to fine-tune and tailor therapies accordingly.

This transcript has been edited for clarity.