BTK Inhibitors and Other B-Cell Malignancies

Nirav N. Shah, MD: Pirtobrutinib as a BTK inhibitor should have efficacy in other histologies. We’ve seen that because we know the covalent BTK inhibitors work in diseases like marginal cell lymphoma, Waldenstrom lymphoma [Waldenstrom macroglobulinemia], and are approved in that setting. I think the most excitement is with their mantle cell [lymphoma] data. We know that patients who fail a covalent BTKi [Bruton tyrosine kinase inhibitor] with mantle cell lymphoma have very few options, and actually until CAR [chimeric antigen receptor] T-cell therapy, which is now approved in mantle cell lymphoma but not every patient is a candidate for this. Outcomes were very poor for patients who progress after covalent BTK inhibitor. The data that came out of the BRUIN study, specifically in mantle cell [lymphoma], were incredibly exciting. Probably the most effective drug I’ve seen in terms of an oral agent after a covalent BTK was pirtobrutinib. It had an overall response rate in the 50% range for patients who had relapsed/refractory mantle cell [lymphoma], of which the majority were either BTK-failed or were BTK-exposed and switched due to intolerance. This is why the study that I mentioned, the new BRUIN study of a head-to-head comparison of pirtobrutinib against the covalent BTK inhibitors, will be very revealing to see whether or not this is more efficacious. I personally have treated many mantle cell [lymphoma] patients with pirtobrutinib who had failed covalent BTK inhibitors. I have a patient right now who is in a second year of therapy in that particular setting, so I’m very excited about that proposition specifically in mantle cell lymphoma.

Nicole Lamanna, MD: From the BRUIN data with pirtobrutinib, which looks at patients with CLL [chronic lymphocytic leukemia], there was also data looking at pirtobrutinib in other lymphomas cohorts including diffuse large [B]-cell lymphoma, mantle cell lymphoma, marginal zone [lymphoma], and so on and so forth. Certainly, as we’ve gained data with the covalent BTK inhibitor, such as zanubrutinib [Brukinsa], which is approved for mantle cell lymphoma, marginal [zone lymphoma] and Waldenstrom [macroglobulinemia] similarly, the noncovalent BTK inhibitors like pirtobrutinib will be active in those patient populations as well. The study also included an unmet need for our CLL patients in terms of patients with Richter's transformation, or mostly diffuse large [B]-cell lymphoma. Certainly, there’s activity in those patients who develop multiple relapsed disease and then transform to an aggressive lymphoma. Albeit we’ll see over time how that data matures and, oftentimes, might be a bridge to more definitive therapy, such as a CAR or a genetic stem cell transplant. Certainly, this is a group of patients that notoriously have been difficult to treat, so we’re always looking for newer agents to treat our patients who transform to an aggressive lymphoma. I think that the noncovalent BTK inhibitors such as pirtobrutinib may be applicable to other disease subtypes besides just CLL.

This transcript has been edited for clarity.