ASH 2023 | Sonrotoclax plus zanubrutinib combination shows promise in treatment-naïve CLL/SLL

That’s a follow-on from the ibrutinib/venetoclax discussion. So in mantle cell lymphoma we showed it was active, and of course, the IV combination is now widely used in CLL, including in multiple frontline studies. And while IV works pretty well, we felt that it can be improved, you know, there were safety issues with IV and it’s not 100% reliable in inducing minimal residual disease negativity. 

So what the presentation at the ASH represented this year is a second generation combination. So we replace the first generation ibrutinib with zanubrutinib, which is safer and more effective, and then we replace venetoclax with sonrotoclax. And what sonrotoclax is, is another BCL2 inhibitor that is approximately ten times stronger than venetoclax. And the hope is that we will have a regimen that will have hopefully less side effects than ibrutinib and venetoclax, and yet be more effective. 

So, obviously, it’s a single-arm study. It’s 107 patients treated in the first line for CLL. But what we saw was that the combination was really tolerable. So of the 107 patients that we treated, only one patient had to stop the drugs due to a drug interaction and the other 106 patients stayed on the treatment regimen as intended, and we’ve had a response rate of 100% so far and no progression on the PFS curve, so the PSF curve is absolutely flat. But to me, what’s really exciting is actually the minimal residual disease kinetics, because we wanted to know if this combination may be more efficient than ibrutinib with venetoclax. And what we saw at six months is that we had a 78% clearance of MRD. Now this is a small number, but the same number for ibrutinib/venetoclax is typically around 40 to 50%. 

So we think that this is a really exciting combination. Based on our Phase II single-arm data, it looks to be just as safe, if not safer than ibrutinib without venetoclax, and certainly, it looks like it’s going to clear the disease faster and cause deeper remissions. So we’re now taking that combination into a Phase III study, which is a global registration study in firstline CLL, and I really think it has the potential to be the best combination that we have ever developed for CLL.