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BRUIN Trial: Pirtobrutinib and the Impact of BTKis


Callie Coombs, MD, discusses how pirtobrutinib (LOXO-305), a Bruton tyrosine kinase inhibitor (BTKi) being investigated in the BRUIN trial, might impact the BTKi landscape.

Ryan Haumschild, PharmD, MS, MBA: Dr Coombs, we know that pirtobrutinib is a BTKi [Bruton tyrosine kinase inhibitor] that’s being investigated for use in B-cell malignancies in the phase 1 and 2 BRUIN trial. Based on the available data from this trial, how might this investigational agent impact the BTKi landscape?

Callie Coombs, MD: The BRUIN study was a very large phase 1/2 trial including CLL [chronic lymphocytic leukemia] and other B-cell NHLs [non-Hodgkin lymphomas]. Pirtobrutinib is an oral drug that has been successfully administered to over 600 patients in this large trial. It is expected that it will get FDA approval, potentially in mantle cell lymphoma first, though the dates of when that may happen I’m of course not privy to. It would likely also get approved for CLL and SLL [small lymphocytic lymphoma], but it’s not clear whether that would happen prior to the completion of phase 3 trials, which are ongoing. I think the key benefits of the drug are, No. 1, it’s effective, and No. 2, it’s very safe. It’s hard to measure safety, but I like to point out how low the high-grade events are as far as high-grade toxicities and then how low the discontinuation rate is, which is always a good way of knowing how well our patients tolerate the drug. That’s around 2% even with longer follow-up.

As far as efficacy, we talk about 1 major area of unmet need in CLL is the double refractory patient who has been failed by both a covalent BTK inhibitor and venetoclax. Those patients have very dismal survival when looking at large series, on the order of months, as Dr Koffman has already mentioned. Using the available therapies we have, such as PI3 kinase inhibitors or chemotherapy, their progression-free survival [PFS] is around 4 to 5 months, looking at real-world evidence. Pirtobrutinib in this very difficult-to-treat setting, double refractory, has a PFS of around 14 months, which is reflected on the abstract that will be presented at this ASH [American Society of Hematology annual meeting]. Then looking at all comers, which is a median of 3 prior lines of therapy, but not necessarily failed by a covalent BTK inhibitor and venetoclax, the median PFS is just under 20 months.

In my view, it represents a huge area of improvement for a major unmet need. And I think it could definitely change the landscape of CLL in a couple of ways. No. 1, I think venetoclax is a highly effective drug, but it can be challenging to administer, especially in the community setting at sites that don’t have the ability to get the rapid turnaround of laboratory tests that are needed to monitor for potential tumor lysis, which is a very rare adverse effect of that drug. The easy setting to put the drug in, should it become FDA approved, would be post-covalent BTKi and post-venetoclax. However, I could see a world where people would use it post-covalent BTKi, pre-venetoclax in the appropriate setting. I think it could change things a lot for the better when it is more widely available.

Ryan Haumschild, PharmD, MS, MBA: It’s great to know there’s another option that provides really good PFS, but at the same time, reduces some of the abandonment rate we talked about, which is always great. So if the patients are staying on therapy longer, they’re tolerating it well, it’s great to have another option. Dr Koffman, do you have anything else you want to add about this new therapy?

Brian Koffman, MD: I’m really excited about it as a patient for a couple of reasons. One is the BTK pathway has been incredibly successful in controlling disease. So if a patient is doing well on that, wouldn’t it be nice, if they developed a mutation, where the covalent binding is irreversible and doesn’t work anymore, to keep the brakes on that pathway by going to Pirto [pirtobrutinib]? That seems a really exciting way, and that also keeps your powder dry a bit with venetoclax and stuff down the line because [pirtobrutinib] isn’t going to last forever. But if you can keep people on that BTK pathway a lot longer, and especially because it’s so well tolerated, I’m really excited about it not being the third-line, but being a second-line therapy for patients who’ve been failed by the first generations of BTK inhibitors.

Ryan Haumschild, PharmD, MS, MBA: That’s the ultimate goal, to keep patients on therapy, make them successful, and then have further options down the line if they need it. I think that’s a great summary. I’m also excited about that agent.

Transcript edited for clarity.

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