ASH 2023 | BCL2 and BTK dual-inhibition with sonrotoclax + zanubrutinib in previously untreated CLL and SLL

So sonrotoclax is a next-generation BCL2 inhibitor, so same class as venetoclax. It’s been shown both in vivo and in vitro to be more potent than venetoclax in terms of BCL2 inhibition, and has less off-target BCL2 family protein inhibition as well. So last year I presented the data for the dose-escalation and dose-expansion phase in both relapsed and refractory and previously untreated CLL/SLL and there’s a follow-up presentation with more follow-up and more patients treated this year.

The number of patients now that we’re presenting on is 107, and roughly half of these have been treated at the 160mg dose and the other half at the 320mg dose. So the majority of patients are treatment-naive. And these two cohorts for dose expansion are really looking at the combination with zanubrutinib, which as you know, is a covalent BTK inhibitor. The combination is actually reasonably well-tolerated. The number of adverse events seen is as you would expect for the combination, so no unexpected safety signals here. The most common things that you see are those that you’d expect in patients treated with zanubrutinib, such as contusion being the most common one, neutropenia, which also is a zanubrutinib and sonrotoclax side effect, seen in a number of patients. And in fact, neutropenia is the highest grade three or higher adverse event being seen in about 25% of people treated with 320mg and 18% of people treated at 160mg. Other than that, the other adverse events are reasonably manageable and mostly low-grade things like headache, diarrhea, fatigue, nausea, and cough. In terms of things like tumor lysis syndrome, there is a ramp-up schedule. Both the weekly and a daily ramp-up schedule have been explored with this combination for the sonrotoclax, and there’s been no clinical or laboratory TLS seen in this particular cohort. GR toxicity was pretty uncommon. Diarrhea was mostly grade one, and there’s been no atrial fibrillation observed so far in the study. We know that Zanubrutinib causes less atrial fibrillation than ibrutinib for instance, we saw that in ALPINE. So the rates of infections were reasonably low-grade, three or higher only 8% and no deaths due to infection.

We think about the the overall response rates seen on this study. They’ve been fairly high, as you would imagine and expect for a patient population with treatment-naive CLL. We see universal responses. In fact, the overall response rate to this combination is 100%. The best response by week 24 is, we see in fact, some complete responses, 16 and 25% at week 24 in the 160 and 320mg cohort, respectively, and 42 and 33% in the 48-week response assessments, respectively, although these are relatively immature because the median follow-up on this study is relatively short. We are also seeing high rates of MRD negativity on this study, using flow cytometry criteria, we’re seeing substantial rates of MRD negativity. So I think it’s clear that the combination of sonrotoclax and zanubrutinib is a potent treatment combination, a potent non-chemotherapy treatment regimen, which is well-tolerated for patients with CLL and in fact is being taken forward into the 301 Phase III study where the combination is being randomized against venetoclax obinutuzumab in previously untreated patients. At a median follow up of 9.7 months, the PFS is 100%. So there are no patients with disease progression or death at any sonrotoclax dose level, although, you know, follow-ups are quite short.