Chapters Transcript Video Jorge J. Castillo, MD discusses results from a multicenter phase 2 Study High VGPR/CR rates with pirtobrutinib plus venetoclax in previously treated Waldenstrom macroglobulinemia This is a phase 2 study, uh, specifically for patients with Waldenstrom's macroalbulinemia who have been previously treated, and what we're doing, we're combining two agents, uh, one of them is a new non-covalent BTK inhibitor called pytobrtinib, and the other one is a BCL-2 antagonist called Benetoplax. In our laboratory, the combination of a BTK inhibitor and a BCL-2 antagonist have shown to have a much higher power. To kill Walterstrom's macroromia cells. Uh, we have done previous studies in other malignancies in which we have combined these two, these agents and these regimens have been highly effective. So inspired by that, we decided to run the study and the idea of the study was to accrue about 42 patients. With Walterstrom's microalbulinemia, we'll give them about 1 month of ptolutinib, and then we will add Beretolax during the 2nd month in a ramp-up phase and then we will continue this concurrent regimen for about 2 years and at that time, we will stop therapy. The idea of this study is to provide patients with Walderstrom's with a new treatment option that will be all oral, non-chemo, finite duration. So, our study, we, what I'm presenting this time is about our experience on the 1st 27 patients who have been on treatment, on study treatment for at least 6 months, and for us to, to think about how we design a study, how successful the study is, we decided that if we can induce a very good partial response, which means a decrease of at least 30% on serum IgM. In at least 35% of patients compared to a 15% of patients, which will be the null hypothesis, we, we will call this uh study successful. For that, we will need at least 12 patients to have obtained a very good positive response. So between May 2023 and July 2025, we actually enrolled 36 patients, but I'm going to present data on the 1st 27, and when we looked at the 1st 27 patients who complete 6 months of completed 6 months of therapy, we see that we have been able to attain at least a very good partial response rate of 56%. That means 15 patients have actually gotten to the outcome that we wanted, so we have exceeded the expectations of the study and for that reason, the study has met its end point. Interestingly enough, we have been able to observe that 3 patients have gotten to what we call a complete response, and a complete response is hard to achieve in patients with Walderstrom's microalbumia with standard regimens, typically the complete response rates are in the single digits, so being able to obtain, you know, uh, more than a 10% complete response in patients with Walderstrom's is very encouraging for us. Now, obviously, this study will continue um to complete the accrual and to uh at some point stop therapy in all patients. In that way, we will get a better sense of what the duration of the response and the progression of free survival is going to be in patients once we stop therapies, and an interesting aspect of things is the genomic makeup of the cancer cells. So we do have patients who have NYDADA mutations and that includes all the patients in this trial. We do have patients with CXCR4 mutations that were about 40% of the patients in the study, and we also see patients with TP53 mutations that included about 20% of the patients in the study. Uh, so far with the data that we have, which is a little early, uh, we have been able to see that CXCR4 mutations might delay the time to the response a little bit. What and also TP 15 mutations, so it looks to me that these mutations might actually have a role in terms of how we treat these patients. Obviously, it's a little early and we need much longer follow-up to understand, you know, what the impact of these mutations is on these treatments, but on, on the global scale, I do believe that this combination has shown a depth of response that if it is sustained. Uh, will provide patients with Walterstrom's with an additional, uh, new, uh, treatment option that was not available before. The toxicity of these, uh, treatments are, were as expected, you know, with the most common side effects being, uh, hematological, meaning decreased white blood cell counts, and some anemias and thrombocytopenia, but these tend to be transient and, uh, uh, as the treatment continues and stops, these end up, uh, resolving. Uh, and so far, I think this is important. We have not seen any concerns of tumor lysis. We have not seen any concerns of arrhythmia, which is what we have seen with previous versions of BTK inhibitors and therefore seems to be not only an effective regimen, but also a very safe regimen. Published December 18, 2025 Created by Related Presenters Jorge Castillo, MD Medical Oncology View full profile
