Future Directions for BTK Inhibitors

Nirav N. Shah, MD: What’s the future of CLL [chronic lymphocytic leukemia]? I think the future is very exciting. There are many drugs that look efficacious. It’s not only about efficacy but improving the safety profile. We talked a little bit about PI3 [phosphoinositide 3] kinases. There’s a new PI3 kinase that’s been approved called umbralisib [Ukoniq]. This drug does seem to have a better safety profile than some of the other PI3 kinases, where there are lots of immune-associated adverse events. This is a drug that’s being studied both in a combination setting and as a single agent in CLL. I think it’s a drug that will potentially become another weapon in the relapsed/refractory state. I think the biggest excitement is going to be around immunotherapy though. This is both CAR [chimeric antigen receptor] T-cell therapy and bispecific T-cell engagement therapy, so BiTE antibodies. CAR T-cell therapy already has shown efficacy in many trials. There are several CD19 CAR T-cell therapies that are under investigation in CLL in particular. Again, we now have a track record from clinical trials that this strategy can lead to durable remissions that can last many years. Patients are off of all treatment together, which is the most exciting part. The patients may get to actually return potentially to some degree of normalcy and not have to take an agent.

In that same line, there are these bispecific T-cell engagers that are also very exciting, drugs like epcoritamab, which binds a CD20 receptor on B cells and engages to the CD3 receptor on T cells, thus bringing them together. These immunotherapeutic drugs are being advanced in non-Hodgkin lymphoma, and early studies show tremendous promise in CLL. What does this mean for our patients? I think that the most important message that I give a patient who has been newly diagnosed with CLL is that the drugs are so good right now. The goal is to turn CLL into a chronic illness, no different than high blood pressure or diabetes. It does require ongoing management, monitoring for toxicities, surveillance and making sure that the disease is not progressing. I think the hope is that it doesn’t impact your longevity or your quality of life. Some of the new strategies, immunotherapy or CAR T, might help us get to that elusive cure in a disease like CLL where cure was really not a word that we used very often. But I am very optimistic for the next decade.

In conclusion, where we are in CLL is that novel agents are dominating the frontline therapeutic options and the relapsed/refractory options. I think the key in CLL is doing a good job in evaluating the patient upfront prognostically so you can help understand what the potentially best treatment option is for the patient. Then, making sure that you monitor them closely to really prevent adverse events associated with these drugs. There are so many options right now that you can switch classes. You can switch between drugs if toxicity becomes an issue. The long-term hope again is that we really get these patients into a state where they’re living a high quality of life. Putting them on minimal oral agent therapy or maybe 1 day, fixed duration therapies, where they can get treatment holidays and truly be free of this disease for periods of time. Again, I think this is just a very exciting field to be part of and it’s been amazing how quickly this field has advanced in the last decade.

Nicole Lamanna, MD: Hopefully, the future of CLL will have more long-term data and more mature data, both from the BTK [Bruton tyrosine kinase] inhibitors and the venetoclax [Venclexta] space combinations. Also, some fine-tuning about how to use minimal residual disease [MRD] to tailor therapy accordingly. Can we truncate therapies in some subtypes depending upon the disease characteristics of the patient? Do we need to extend therapy in a certain particular, maybe high risk, for example, if they still have minimal residual disease, or would they not benefit from being on additional therapy? Hopefully, MRD-guided therapies, given some of these randomized trials and longer follow-ups to some of these, such as CAPTIVATE and GLOW and other studies, might give us a little guidance about how to personalize the current therapies that we have available for CLL. What about other therapies that are being evaluated, too? We neglected a little bit to talk about the PI3 kinase inhibitors. These have been, of course, approved for CLL and some of the lymphoma patients as well. Specifically, idelalisib [Zydelig] and duvelisib [Copiktra] are approved in the relapsed/refractory setting, but not approved in the frontline setting. Obviously, the other PI3 kinase inhibitor to mention is umbralisib. Certainly, this has been working by TG Therapeutics, and they will combine it often with their CD20 monoclonal antibody ublituximab.

There were many studies looking at the doublet or even adding venetoclax as a triplet into that. Certainly, there’s been data looking at doublets and triplets with the combination. I think there’s no doubt that some of the studies, such as UNITY, show efficacy with the PI3 kinase inhibitors. As a group, they’ve been plagued a little bit by the toxicity profile, mostly the immune-mediated toxicity profile, such as diarrhea and colitis, which has limited their usage. Clearly, I think umbralisib has less toxicity than the first to market, which was idelalisib. But still more difficult to use. Then, when you think about where that might fit in the paradigm, given the BTK inhibitors and the venetoclax-based combinations, it’s a little tricky because the space is getting a little bit full. We’ll still see it used a little bit further down the line in terms of salvage regimens. Certainly, if it's used in a time-limited fashion, which is when they combine it with an antibody or another agent, I think then you know what the toxicities may be. If you’re using it for a short period of time, then certainly you can benefit from the efficacy and have a time-limited approach. Maybe that will mitigate for some of the long-term toxicities, particularly the immune-mediated toxicity. I think we will see more of this, and perhaps lead to an approval for umbralisib in that sense.

Certainly, when we talk about immunotherapies or immune-based therapies for CLL, for example Richter’s [transformation], we can also look at when to consider PD-1 [programmed cell death protein 1] inhibitors and other more aggressive strategies for patients with Richter’s transformation. There was data on pembro [pembrolizumab; Keytruda] many years ago. Now, recently the MD Anderson [Cancer Center] group looked at atezolizumab [Tecentriq] for the Richter’s [transformation] patients as well, so that’s some emerging data that might be helpful for patients who have multiply relapsed and refractory disease that have transformed. Then, with CAR T-cell [therapy] we know that it has been approved for ALL [acute lymphocytic leukemia] and for relapsed/refractory non-Hodgkin lymphoma patients, such as DLBCL [diffuse large B-cell lymphoma]. In CLL, it is not yet approved, but there’s lots of data with differing types of CAR T-cell [therapies] looking at CD20-mediated CAR T-cell, looking at different ways to mitigate some of the toxicities of CAR T-cell combining with BTK inhibitor. Clearly, NK [natural killer] CAR-T cells. Certainly, it’s coming a long way, which is to obviously mitigate the concerns for the cytokine release syndrome and also the neurocognitive issues that we see with CAR-T cells in our patient population. The efficacy of some of the data looks really good. We know that there are some patients who’ve had derived responses and complete responses upwards of 50%, 60%, with some durable responses. I think that’s very meaningful.

Given again all the therapies that we have for CLL, it’s still been relegated into the salvage setting, meaning multiply relapsed patients because of some of the side effect issues that have been associated with CAR T-cell [therapy]. I think if we continue to improve upon the side effect profile and continue to show longer follow-ups with durable remissions, particularly in some of our high-risk patients, certainly then I think this will be more widely used for patients. It will be much more of a consideration than it currently has been and relegated to clinical trial. I think that the continuation of the data and more tweaking of how we’re doing with the CAR-T cells designed to mitigate for some of the side effects will improve its usage over time and continue to have a role in our high-risk or multiply relapsed patients. Stay tuned for that information as well.

Then, of course, we have newer data on the bispecific monoclonal antibodies. I think that’s data that is intriguing and will have a role for our CLL patients. Combinations of some of these newer agents with other therapies will certainly be appealing as well. I think that there’s lots of new drugs in the pipeline for our patients with CLL that hopefully will be able to be fruitful and show efficacy with decreased toxicity. Hopefully there will be more continuation about time-limited approaches so that we can get patients on a period of time of therapy and have a durable response duration. This will hopefully translate into a nice progression-free survival and continued improvement in overall survival in our patients with CLL as we continue to move forward. I think we’ll learn more about which therapies might be appropriate for different patients, depending upon their disease characteristics, i.e., good-risk versus high-risk patients. Hopefully, we can tailor that therapy accordingly in the future based on longer-term data of what we currently have available.

This transcript has been edited for clarity.