Using Noncovalent BTK Inhibitors for the Management of CLL

Richard R. Furman, MD: Nitin, what are some of the BTK [Bruton tyrosine kinase] inhibitor options for patients who’ve developed resistance to our covalent inhibitors?

Nitin Jain, MD: As you mentioned, we’re seeing the BTK mutations, including cysteine 481S, which is the most common, and other rare mutations of BTK or PLCG2. At least in that square, we have 2 emerging BTK inhibitors. One is LOXO-305, which is called pirtobrutinib. We also have ARQ 531, which is now with Merck. Both drugs bind noncovalently to the BTK, as opposed to ibrutinib, acalabrutinib, and zanubrutinib, which all bind to the same pocket.

The data we have seen so far, especially the most advanced data with pirtobrutinib, show that this is able to overcome the resistance made by the cysteine 481S. For example, in the phase 2 study, which was reported in The Lancet earlier this year—we’ll see an update at ASH [American Society of Hematology Annual Meeting]—patients who’d been exposed to ibrutinib before and had a documented cysteine 481S mutation responded equally well to pirtobrutinib compared with patients who didn’t have a cysteine 481S mutation.

The data with pirtobrutinib appears quite encouraging, not just for the efficacy part of it but also more important the toxicity part of it, where we saw very limited toxicity—especially grade 3 or 4 events—and very limited atrial fibrillation. Of the pooled analysis of 300-plus patients, they had only 2 with both CLL [chronic lymphocytic leukemia] and NHL [non-Hodgkin lymphoma] with atrial fibrillation, likely representing a background rate in that patient population.

Similarly, for the ARQ 531 compound, there will be updated data presented at ASH. What we know from the abstract is that there are high rates of efficacy in a refractory patient population, including patients with the BTK cysteine 481S mutation. Those data appear to be less mature. A smaller number of patients have been treated with that compound compared with pirtobrutinib. Pirtobrutinib is already in phase 3 and registrational studies. Both agents look pretty exciting. In the next year or 2, we should see longer follow-up of these trials, and hopefully these agents will become FDA approved for specific subgroups within CLL. That’s a very exciting area of development, which has just come along in the last 1 to 2 years.

Transcript Edited for Clarity