ASH 2025 | Results of a Phase II trial of pirtobrutinib plus venetoclax in previously treated WM

So this year at ASH 2025, we had an oral presentation, and we talked about a phase 2 study combining a non-covalent BTK inhibitor called pirtobrutinib with a BCL2 inhibitor called venetoclax. The idea behind this study is to provide patients with Waldenström’s macroglobulinemia with a treatment that is non-chemotherapy, fixed duration, all oral. So, pirtobrutinib starts at 200 milligrams daily, and we do that for about four weeks. And then we continue pirtobrutinib, but we add, during the second month, venetoclax. This is a BCL2 inhibitor. And we start about 100 milligrams daily for a week, then 200 milligrams daily for another week, and then 400 milligrams daily for two additional weeks. That’s cycle two. And in study on cycle three, we basically give full doses, or standard doses, of pirtobrutinib 200 and venetoclax 400 once a day for the duration of the study, which is a total of 24 cycles for a week each cycle. And once we reach that point, we stop therapy. So, what I presented was the initial experience on 27 patients who have completed at least six months on study. And the reason we chose that point is because, based on the assumptions of our study, in which we wanted to induce a very good partial response of 35% or better versus a 15% or lower, that would be our undesirable level, we needed about 42 patients. And for that, we needed to have at least 12 participants attaining a very good partial response or better. So when we did the analysis at that moment on the first 27 patients, we actually got 15 patients who got into a very good partial response and complete response. And therefore, the study met its endpoint. And I think that made it so interesting that ASH decided that it was, you know, worthy of an oral presentation. So our patients were patients who had at least one line of therapy for their Waldenström’s. So this is for patients with relapsed disease. And the range was between one and four, but the median was one. And some patients had already been exposed to covalent BTK inhibitors, about half of the patients. And most patients have gotten exposed to rituximab and chemotherapy, as we do normally in these type of patients. I would say 40% of patients were women, and all the patients have mutations in MYD88. There was about 40% of patients who had CXCR4 mutations, and about 20% of patients with TP53 mutations. TP53 are really interesting for us, because there’s emerging data showing that those patients tend to have worse outcomes with any treatment. So, that was an important aspect of what we did. So, when we analyzed our data, you know, we not only were able to see that 15 patients got into a very good partial response, but we also saw that three patients got into a complete response. Now, complete responses is something that, you know, we are very interested in. Specifically, when we compare outcomes of patients with other conditions like chronic lymphocytic leukemia or multiple myeloma, we do obtain very high rates of very good test responses on those patients to the point that we’re talking about minimal residual disease and things of this nature. Those concepts are foreign to Waldenström’s because we don’t get to complete responses to begin with. So the fact that three out of the 27 patients attain a complete response in the first six months of therapy, then I think that really is very interesting for us. So hoping that we can induce deeper responses, typically deeper responses translate to longer responses. And that’s the idea behind it. So the accrual of this study continues. We have one more patient to go before we can complete the accrual of this study. And I’m really looking forward to actually show the data from the complete group sometime in the near future. I think I can safely say that the combination of pirtobrutinib and venetoclax induces fast and deep responses in patients with relapsed disease and with Waldenström’s disease. The important part, the second important part is going to be how durable this response is going to be once we stop therapy. So I think it’s an innovative regimen. And if everything goes well, I think this is going to become a new treatment option for patients with Waldenström’s.

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