A Unique BTK Inhibitor, Pirtobrutinib for Patients with Pretreated CLL | Jeff Sharman, MD | #ASH24

My name is Jeff Sharman I’m the medical director of hematology research for the Sarah Cannon Research Institute. I'm a practicing community practice oncologist in Eugene, Oregon. This was an exciting year for us. For patients with relapsed CLL. Because we've got a lot of new data at Ash this year. And the Bruin CLL three, two one study, it's probably the most notable study for patients with relapsed or refractory disease.

This is the first prospective, randomized, phase three study for patients who've previously been treated with a covalent BTK inhibitor. Now, covalent is kind of a, complicated term. It's it's for, the first and second generation BTK inhibitors, Ibrutinib, Acalabrutinib, and Zanubrutinib, or what we call the covalent inhibitors. These are drugs that bind to the BTK enzyme and don't let go.

And it's actually a somewhat unconventional way of making drugs, at least historically. But they've served our patients quite well. The problem with those drugs is that when somebody develops resistance to them, they typically develop resistance to all of them. And so what this study did was it used pirtobrutinib, which is a very different type of BTK inhibitor.

It's what we refer to as a non-covalent inhibitor. So instead of binding to the molecule it sort of fits snugly in the pocket. And so even when there's resistance mutations to one of the first or second generation BTK molecules, pirtobrutinib can still have efficacy. And it was that sort of scientific understanding that led us to conduct this study.

In this study, what we did was we randomly assigned patients to either pirtobrutinib or investigator's choice. Investigator's choice could be either bendamustine, rituximab or idelalisib rituximab versus pirtobrutinib. Now, I think it's reasonable to look at that control arm and say, gosh, that's a undesirable control arm. However, I would say that there is no defined standard for these patients.

Many, many docs and patients might use BCL2 inhibitors, but half of our patients had already had BCL2 inhibitors. Furthermore, not every patient is suitable for, a BCL two either by way of biomedical comorbidities or social issues. And even in those patients who do get BCL two inhibitors after a BTK inhibitor, the outcomes aren't exactly as good as they are for patients who haven't had prior BTK inhibitors.

So the control arms, the control arm, it's the standard as accepted by the FDA. And so this was really a study designed to, answer a regulatory question so that we could get the drug fully approved. What we saw, was that in patients randomly assigned to pirtobrutinib, the median progression free survival was about 14 months, which is a little bit lower than we wanted, but it was, significantly better than the control arm, which was only about eight and a half months.

The second thing is, on these studies, patients had a lot of scans. And so sometimes a patient might have a slightly increased lymph node that met criteria for progression. But if investigators and patients felt like the patient was benefiting from pirtobrutinib they could stay on drug. So even though the, progression free survival was 14 months, the time to next treatment or death, which is essentially how long did somebody benefit from pirtobrutinib was about two years in the entire population. And for those patients who hadn't had prior, venetoclax, it was two and a half years, so a patient could get two, two and a half years on pirtobrutinib, which is really clinically meaningful in a population of patients that don't have other options. The other thing that we, really looked at is the safety of the molecule.

Of course, that's an important part of this study. One of the ways we measure that is the rate of treatment related discontinuation. So how often does somebody stop treatment for reasons other than progression? That was very low for pirtobrutinib. Only 5% of patients did so. And when we looked at, side effects that are common to BTK inhibitors, very little atrial fibrillation, very little hypertension, and in fact, the atrial fibrillation pretty much only occurred, well, it happened to three patients, two of whom already had a history of atrial fibrillation, so they were probably more likely to get it anyhow.

In terms of other side effects that are sort of maybe common to the class. Pneumonia was about the same between the two. Anemia was a little bit better with pirtobrutinib, but for all other side effects such as nausea, fatigue, weight loss, GI toxicity, statistically significant differences in favor of pirtobrutinib. So not only does it have advantages in terms of efficacy, but it also has advantages in terms of safety.

And that's really the patient experience we want to be able to deliver. pirtobrutinib already has what we call an accelerated approval by the FDA. That's a situation where the FDA says there's no standard of care, and this drug meets its goal, but it has a, accelerated approval by the FDA for patients who've already received a covalent BTK inhibitor and a BCL two inhibitor.

The purpose of this study is to say, well, can we bring it earlier just for somebody who's had a prior BTK inhibitor alone, for instance, which is a lot of our patients and so this, the information from this trial will be submitted to the FDA fairly soon. And the FDA will set up its timeline. So, you know, if all goes well, perhaps in 2025, we'll have, full approval of this, medication, but there's still a lot of ground to cover from a paperwork perspective before that happens.

I think what's really, exciting to see is just the continued development of new ways of going after just sort of lymphoid malignancies, at large. So CLL is not the only lymphoid malignancy. There's also lymphomas, and a variety of different types of that. And a lot of times what's going on in lymphoma helps benefit those patients in CLL as well.

We're seeing, development of a new class of BTK inhibitors, what we call degraders and degraders really, we saw results from two different degraders here at this ASH looks like very high response rates early on. Those studies haven't gone on long enough for us to know really how durably those those will continue and what the side effect profile is going to be, at least at the superficial level.

Side effects look pretty good, activity looks pretty good. We're also seeing what we call bispecific antibodies, most notably a drug called Epcoritamab. But there are large number of others, either in the commercial space already in lymphomas or moving into CLL. These are going to be exciting drugs as well. And, you know, I think that that we've seen a lot of improvement in CLL over the last handful of years, but I think we're still poised for a lot more, advances.