Exploring Potential Options for Treating Patients With Chronic Lymphocytic Leukemia With Pirtobrutinib

At the 2023 Lymphoma, Leukemia & Myeloma Congress in New York, New York, Nicole Lamanna, MD, Columbia University Medical Center, New York, New York, discusses the potential for non-covalent BTK inhibitor pirtobrutinib in treatment regimens for patients with chronic lymphocytic leukemia (CLL), focusing on the BRUIN study. 

Transcript:

Hi, I'm Nicole Lamanna, professor of Medicine at Columbia University Medical Center. I'm a leukemia physician, and I'm here at the Lymphoma, Leukemia & Myeloma Congress Fall 2023. I had the pleasure today of talking about the non-covalent BTK inhibitor pirtobrutinib. We talked about all the BTK inhibitors this morning, the covalent ones, but I had a focus on pirtobrutinib, the new kid on the block.

These are agents that are not yet approved for chronic lymphocytic leukemia (CLL), but I had the pleasure of talking about a very important study called the BRUIN Study. This was [on] the use of pirtobrutinib in chronic lymphocytic leukemia patients, but also there was a subset of patients with other [lymphoma] subtypes. I focused specifically on the CLL patients. This was a study that was the phase 1/2 study of pirtobrutinib in patients who all had to have prior covalent BTK inhibitor-based therapy, so they all had been treated either with one of the covalent BTK inhibitors and then were allowed to be enrolled on this study.

The [maximum tolerated dose] (MTD) was settled at 200 mg a day, so that's what the patients received. There [were] 247 evaluable [patients with] CLL for efficacy. This drug was very well tolerated, and the responses were [as] well. Interestingly enough, remember all the patients on this study had to have prior covalent BTK inhibitors. The majority of those patients, 80% of those patients, had to have progressive disease on one of their prior covalent BTK inhibitors. But certainly, there was a small subset of patients that had intolerance to a prior covalent BTK inhibitor, about a quarter of patients. About 40% of these patients also had prior BCL2-based therapy, the majority being venetoclax in that setting.

What it was showing is that even in these patients who had prior covalent BTK inhibitors or prior venetoclax-based therapy, there were some durable responses seen. This is important because we now have patients with CLL who are having covalent BTK inhibitors, who are either intolerant or progressing, have now also had prior venetoclax based therapy and [are] progressing on those agents. [So], what do we do with these patients? This is truly a new unmet need. We have patients who are what we call double refractory, so patients who have progressed on both of our most potent agents that we have for CLL currently. This was a study that looked at a subset of that population with the majority of those patients responding.

We know that patients who progress on covalent BTK inhibitors and venetoclax really have a poor overall median survival, on the order of months, so we're always looking for newer agents in this setting. The median [progression-free survival] (PFS) of this study has been reached for all. It was about 19 months and in double refractory, so patients who had failed covalent BTK and prior venetoclax, the median was a little bit shorter [of] about 16 months. But [these are] still much more durable responses than what we were seeing in other settings. There's no doubt that I think this agent will move forward in CLL. It is already approved in mantle cell lymphoma (MCL) in patients who have had greater than 2 prior regimens. Hopefully the FDA will view the data from the BRUIN setting very strongly, or other clinical trials that are currently running with pirtobrutinib, and hopefully we'll get approval for CLL [soon].

The safety profile is very well-tolerated. When we think about the covalent BTK inhibitors, we think about the common adverse events that we see with this class, i.e., arthralgias, hypertension, cardiac issues, bleeding issues, [and] hypertension. Certainly, we can see this with the non-covalent BTK inhibitors such as pirtobrutinib as well, but we have over 12 months of follow-up in over 300 patients. There doesn't seem to be any new adverse events that we've seen. This was updated recently at ASCO by [Catherine C. Coombs], and there's no new safety signals and the majority of adverse events that are grade 3 and up are relatively few in frequency, less than 4%. The cardiac issue is less than 3%. This is a well-tolerated BTK inhibitor.

Now of course, we're going to need much longer-term follow-up with this drug because we know that with the covalent BTK inhibitor, some of the side effects we used to see increase later so we're going to be looking for that with pirtobrutinib as well with longer follow-up to these studies. There's also lots of new combination studies of pirtobrutinib, so stay tuned. This was just the biggest study, the BRUIN Study, as I said that I presented here today. But there's lots of combination studies looking at pirtobrutinib with venetoclax or pirtobrutinib with venetoclax and a CD20 mono-antibody versus standard of care. There are studies running both in the frontline as well as in the relapse setting. I think we'll see more data with pirtobrutinib in the future, and hopefully this agent will get approval for CLL in the near future. Thank you.

Source:

Lamanna N. BTKi as a Target/ Pirtobrutinib: The New Kid on the Block. Presented at Lymphoma, Leukemia & Myeloma Congress; October 18-21, 2023. New York, NY