EHA 2025 | Updated Phase I results of sonrotoclax plus zanubrutinib in R/R CLL/SLL

So, sonrotoclax is a novel BCL2 inhibitor. It’s more potent than venetoclax and we presented update results at this meeting of a Phase I/Ib study involving sonrotoclax and a number of other agents including zanubrutinib and obinutuzumab in patients with a range of B-cell malignancies. 

So at this meeting in particular we updated the follow-up on the cohort of patients with relapsed and refractory CLL/SLL. It was about 47 patients and the patients were previously treated. There were a couple of patients who’d had a prior BTK inhibitor therapy but discontinued because of intolerance. Essentially patients received a lead-in treatment with zanubrutinib and then step-up dosing with sonrotoclax. These are both oral therapies which is very convenient and there was an option for patients to discontinue treatment after they’d been on both therapies for 96 weeks. So a dual oral BCL2-BTK inhibitor therapy for patients with relapsed disease. 

Among the patients treated this was a dose-finding study. Doses ranged from 40 to 640 and we didn’t find an MTD. The recommended Phase II dose was 320 milligrams. The patient cohort was enriched for high risk characteristics with about a third with TP53 and about three-quarters with IGHV unmutated subtypes. So the safety profile was very manageable, there was no TLS, there were no major grade 3 infections, AF wasn’t a problem. The most common side effects that we saw were COVID-19, it was done during the pandemic but it was mostly mild, no grade 5 events, diarrhea only mostly grade 1 and mild and a bit of bruising but probably less than you’d expect from for for instance, I plus V. 

And the efficacy was pretty remarkable. The complete response rate was 45%, about 55%, or close to 55% partial responses, such that the overall response rate was close to 100%. And probably more impressive was the MRD negativity rates. And we did this by Eric Flow cytometry on this study. And at the 320 milligram cohort, the patients had pretty frequently achieved UMRD4. In fact, they achieved UMRD4 overall, the best overall MRD negative rate was about 85% on the study, and we saw it increase the longer that patients had been on drugs. So, I mean, that was very encouraging. We also had about 14 patients discontinue therapy after the 96-week mark electively, and all those patients remain well and off treatment and in remission. The PFS now looks highly encouraging with the median follow-up of close to 34 months. We are now seeing a 30 month PFS rate of 94.7%, which is really pretty impressive in this population. Both events occurred in patients with TP53 mutations. So, I mean, I think this is a really encouraging all oral doublet therapy for patients with relapsed and refractory CLL.

This transcript is AI-generated. While we strive for accuracy, please verify this copy with the video.