SOHO 2026 | Sequencing pirtobrutinib in CLL: overcoming covalent BTKi resistance and future first-line use

Right, so pirtobrutinib is a non-covalent BTK inhibitor and it does not need binding to a site called cysteine 481, which is the site where the covalent BTK inhibitors binf, ibrutinib, acalabrutinib, and zanubrutinib, bind. And one of the major resistance mechanisms for covalent BTK inhibitors is that you get a mutation at the cysteine 481 locus, where most commonly it’s a cysteine 481s mutation. And because of that, ibrutinib, acalabrutinib, and zanubrutinib are not able to bind to that protein. Pirtobrutinib, as the name suggests, is a non-covalent PTK inhibitor. It does not need binding to that particular site. It kind of fits in the pocket, maybe forms some hydrogen bonds, but not really a covalent bond to the cysteine-481s site. And so it doesn’t really care if there’s a mutation present or not. It’s still able to inhibit the BTK because of some other non-covalent interactions. And that was well established in the preclinical model. And then when this drug came about in clinical trials, it was very evident that patients who are failing a covalent BTK inhibitor, and including patients who have this bonafide resistance mutations, they were responding very well to pirtobrutinib. So currently non-covalent BTK inhibitor, the only one which is approved is pirtobrutinib and is approved for patients with relapsed CLL who have failed at least or have been exposed to at least a covalent BTK inhibitor therapies. And that’s where I think the major use of pirtobrutinib is these days. Having said that, there have been several trials looking at pirtobrutinib in the first-line setting, including Phase II randomized studies. Phase III randomized studies have used more of a continuous BTK approach, as opposed to some of the studies which have looked at time-limited approach, such as at our center. I think the time will tell when pirtobrutinib gets approved in the frontline setting. Certainly, it’s a very safe drug and probably will be a consideration for older patients with CLL who you think you’re going to use a single-agent BTK inhibitor continuous therapy because they’re on the older side. You don’t want to use doublet or triplets. And I think this would be one of the options where you think patient may just need one therapy in their lifespan. Because we know BTK inhibitors in first-line setting can give you 9, 10 plus years of remission with ongoing therapy. So I think that would be the group of patients where it may be used. I think for younger patients, I personally would kind of stay away from it unless we know more because, you know, you may want to consider time-limited approaches or a more conventional covalent BTK inhibitors, realizing that you could use a non-covalent BTK inhibitor at the back end.

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