ASH 2025 | Sonrotoclax monotherapy in R/R MCL previously treated with a BTKi: early Phase I/II results

This ASH, we enjoyed a very good production of projects with great data. So one of the data I presented is on the novel BCL2 inhibitor. We all know that targeted therapies are small molecules. They are strange that they can reduce a big tumor very quickly, and they are not that expensive to make. The shortcoming is that they don’t last as long as we want it to be, and some of the responses are not that durable, but the thing is that we could combine the different target therapies. And in order to combine, we never combine drugs attacking the same target. We combine, like the most current combination is rituximab against CD20 on the surface of lymphoma cells, B-cell lymphoma cells, and the BTK inhibitor is in the cytosol of the B-cell lymphoma cells, and at the same time we also target BCL2. BCL2, the most common drug currently is called venetoclax, CD20 many antibodies, BTK inhibitors, four generations of BTK inhibitors, many choices. But we only have one choice of venetoclax that has a low response rate, and that’s quite sometimes toxic in terms of decreasing blood counts. So we very much need another generation of improved BCL2 inhibitor. And that is the abstract I presented on sonrotoclax. 

Sonrotoclax is a next generation BCL2 inhibitor that has 14-fold higher enzymatic activity in the test tube compared with venetoclax. It is not only more potent, but it is more specific. It is six times more selective than venetoclax. And venetoclax class half-life is 26 hours, so a lot of times venetoclax reaction side effects can last very long. For example, one of the new side effects famous for venetoclax is tumor lysis syndrome, we call it TLS. And so we have to monitor TLS because the half-life is so long and there’s a lot of accumulation of the drug in the human system. However, the new sonrotoclax has a half-life for only five hours. So there’s lack of human system accumulation, therefore, the need to monitor TLS is much less and maybe the side effect could be improved. 

So this study is a phase one, two study. The phase one part is we started with low dose, 160, but the actual dose we enrolled on the expansion cohort 2 is 320 milligrams once a day. This dosage we treated at 103 patients. And so this 103 patients are evaluable for efficacy. First of all, the efficacy was higher than the historic control, than venetoclax for example. The overall response was 52%, with a CR about 16% and therefore, the primary endpoint of the trial is met. And the population was heavily pretreated with three other therapies for the lymphoma, and sonrotoclax being the number four. But if we only count those patients who receive the two prior lines of therapy and the response rate is higher at 61%, of course, if you move to only one prior line, it’s going to be higher and if you use in the front line, probably it’s going to be even higher over 80s, according to my academic personal knowledge. 

So the side effect is similar as with venetoclax, but better, in my opinion. First of all, there are cytopenias. There’s decreased blood neutrophils, decreased red blood cells, decreased thrombocytes, but all mild, not very heavy. And there’s also infections as a class infections increase. And there’s also some electrolyte disturbances. Everything was manageable, transient, and reversible. 

So we think that also even the high degrees of prognostic factors, if the patient have high Ki-67 or TP53 mutation, or blastoid morphology, their response rate are similar across the class. In my opinion, this is one of the most exciting agents presented at this ASH for mantle cell lymphoma, in the mantle cell lymphoma field. And I anticipate the FDA, I think in my opinion, FDA should approve this drug. And this drug is not only for good for mantle cell lymphoma, they also have good data for CLL and others. And it will change the landscape again for the treatment of mantle cell lymphoma and other B-cell malignancies. So I really think this is, if I had to choose, this is one of the top abstracts.

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