Future Potential of Noncovalent BTK Inhibitor Therapy for Patients With Chronic Lymphocytic Leukemia

Susan M. O'Brien, MD, University of California, Irvine, Orange, California discusses the possible future applications of pirtobrutinib, a noncovalent BTK inhibitor recently approved for the treatment of mantle cell lymphoma (MCL), as a potentially beneficial future option for the treatment of patients with chronic lymphocytic leukemia (CLL). 

Transcript:

Hi, I'm Dr. Susan O'Brien from the University of California Irvine, and I'm a professor of medicine in the division of hematology and oncology. I wanted to talk briefly today about pirtobrutinib. This is an exciting drug that was recently given accelerated approval for the treatment of mantle cell lymphoma. It's a drug that we're really hoping that we might get accelerated approval in CLL also.

So what makes this drug important? Well, it is a noncovalent inhibitor of BTK. What's so attractive about being noncovalent? Nothing specifically, but that's used to differentiate it from the covalent inhibitors—the covalent inhibitors being all of the BTK inhibitors we currently have in CLL, namely ibrutinib, acalabrutinib, and zanubrutinib.

As we know, many patients who develop resistance to those drugs have resistance mutations in the BTK binding site, particularly in the [cysteine]-481 (CYS-481], but other mutations can be seen. And generally, if you have resistance to one of those BTK inhibitors, you have resistance to all of them. So you're pretty much done with the class once you develop resistance to either of the 3. 

The advantage of pirtobrutinib in that setting where we are hoping to get accelerated approval is that because of its different way of binding, it's extremely effective not only in the wild-type but also in patients with the mutation. Also, in patients who have become resistant to BTK inhibitors but don't have the mutation, we've also found from the BRUIN trial that it works very well there. The BRUIN trial was a very large phase 1 trial that looked at a number of different disorders, including mantle cell [lymphoma], which I already mentioned as an accelerated approval, and there was a very big cohort of patients with CLL, all of whom had had a prior BTK inhibitor.

About 77% were truly resistant to that inhibitor rather than just coming off for intolerance. So mostly, a BTK [inhibitor] resistant population. Many of them had also had venetoclax, too, most of them had prior chemotherapy. And what the trial showed was that the response rate was excellent to pirtobrutinib, over 80% in this very refractory population, and the median progression-free survival in this group who had a median of 3 prior regimens was 19 months. And even in the patient population who had a BTK inhibitor and venetoclax and sometimes the PI3K inhibitor also, the median progression-free survival was almost a year and a half, and that group had a median number of prior therapies of 5, so a very heavily pretreated population.

The other exciting thing about this drug is the toxicity profile, which is really excellent. If we look at the side effects, most side effects were not seen in above 20-something-percent of patients, and most of them were grade 1 to 2. If we look at some of the side effects of clinical interest in terms of BTK inhibitors, we might think of atrial fibrillation, which was less than 3% in this trial for the total safety population which was over 700 patients. 

I would actually make an argument that that might be background for that larger number of patients, particularly with an advanced age, as we see in these patients. The other side effects were very low, arthralgia, diarrhea, et cetera, low incidence, and interestingly, the discontinuation rate for adverse events was less than 3%, which is one of the lowest discontinuation rates I've seen on any trial. So that's why we're so excited by this drug. Because it gives us another option once patients have failed the first and second generation BTK inhibitors, and it has such an excellent safety profile.

There are a number of registration trials ongoing in CLL, 4 of them. If you are interested in potentially accessing this drug for your patients, these are multicenter trials all over the US and in Europe too, so you could look them up on Clinicaltrials.gov. But in the meantime, as you all know, it takes a while for registration trials to read out and then for the submission to the FDA, so we'll see if we are going to be able to get an accelerated approval, which then would allow us of course to use this drug sooner rather than later. We hope that in the CLL setting, like in the mantle cell [lymphoma] setting, we might get this approval, but stay tuned.

Sources:

FDA grants accelerated approval to pirtobrutinib for relapsed or refractory mantle cell lymphoma. Press Release. The US Food and Drug Administration. Published online January 27, 2023. Accessed January 27, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pirtobrutinib-relapsed-or-refractory-mantle-cell-lymphoma

Mato AR, Woyach JA, Brown JR, et al. Pirtobrutinib after a covalent BTK inhibitor in chronic lymphocytic leukemia. N Engl J Med 2023. Published online: July 6, 2023. doi:10.1056/NEJMoa2300696