EHA 2023 | Phase Ib/IIa study of AZD4573 + acalabrutinib in R/R DLBCL

AZD4573 is an intravenous CDK9 inhibitor. CDK9 is a transcription factor which is crucial for the pathophysiology and survival of B-cell lymphoma, but also other types of lymphoma, including T-cell, non-Hodgkin lymphoma, and Hodgkin lymphoma. There’s been in Europe a Phase I study a few years ago using AZD4573 as a single agent. There was a lot of activity, so much that actually one concern was tumor lysis syndrome, with even patients unfortunately passing away from TLS. But the duration of response was limited. So, there’s been a lot of translational work trying to understand how we can improve CDK9 inhibition. As you know, it’s very relevant also to apoptotic pathway, and some preclinical studies have shown that, by using acalabrutinib, this can increase the expression of pro-apoptotic proteins and the combination with AZD4573 can be synergistic, with very significant preclinical activity.

So this has brought to the Phase I/II of AZD4573 plus acalabrutinib in patients with relapsed/refractory large B-cell Lymphoma. And there are also ongoing trials looking into the same agent in the two lymphoma subtypes that I mentioned before, so Hodgkin lymphoma and T-cell lymphoma. We have already presented some early data at ASH last year and updated data being presented at EHA this year and ICML next week. We’re very excited. First of all, during the dose escalation there was no DLT, and we were able to easily achieve the maximum tolerated dose. When it comes to toxicity as expected because CDK9 is also very relevant to hematopoiesis, we saw some myelosuppression, but it was very easily manageable to growth factors. One thing that we observed, that was also reported in the original Phase I trial with single agent AZD4573, was LFT elevation, but we were able to further look into the biological mechanism of this, and it really ended up to be a transcriptional event where CDK9 inhibition downregulated the expression of channels relevant to hepatocytes but necessary for the transportation of AST and ALT enzymes, but it was really no liver injury. So the treatment was very well tolerated. Was overall a weekly infusion until progression or unacceptable toxicity.

In terms of efficacy, we also have seen very encouraging results despite still being an early study. First of all, we’ve seen overall, close to 40 to 50% response rates, with 30 to 40% CR rates, which is quite impressive in light of the very difficult to treat population included in this study. This, by definition, where patients with aggressive B-cell lymphoma, who had already relapsed or progressed after all standard treatment options. So one thing that I want to emphasize is that A, we had a lot of patients with large B-cell lymphoma where relapsed after CAR-T, and also we included a lot of patients that T-cell rich histocyte large B-cell lymphoma. So both of these are highly unmet needs currently in our community. As you all know, there’s currently no standard treatment for patients with large B-cell lymphoma relapsed after CAR-T and unfortunately, life expectancy tends to be quite short for these patients. But several patients on this trial, thanks to AZT4573 plus acalabrutinib were able to achieve either CR or PR and then eventually were consolidated with stem cell transplant in many months or two years later and are still disease-free. As for T-cell rich histiocyte large B-cell lymphoma, there are now increasing data that chemotherapy, transplant and, more recently, CAR-T don’t work due to also lack of CD19 expression. But virtually all patients with T-cell rich included in this study responded to AZD4573. So there’s a lot of excitement around this combination and hopefully new studies will come out in the near future.