ASH 2025 | Zanubrutinib, obinutuzumab, and sonrotoclax in patients with treatment-naive CLL

I presented our abstract entitled zanubrutinib and obinutuzumab and sonrotoclax in patients with treatment naive CLL. This was a triplet cohort from our ongoing phase 1b study called BGB-11417-101. And so we know that in relapsed/refractory CLL, zanubrutinib has demonstrated superior progression-free survival and safety outcomes when compared with the first-generation covalent BTK inhibitor ibrutinib, including fewer cardiac adverse events. Sonrotoclax is a next-generation BCL2 inhibitor, which is more selective and pharmacologically potent when compared with venetoclax and has a short half-life without drug accumulation. And so this BGB-11417-101 is an ongoing phase 1, 1B dose escalation expansion study for patients with various B-cell malignancies. And this poster really highlighted the initial results of combination therapy with the zanubrutinib, obinutuzumab, sonrotoclax triplet in treatment naive CLL. 

And so in this study, patients initiated oral zanubrutinib in cycle one at the current approved dose, either at 160 milligrams twice daily or 320 milligrams daily. Intravenous obinutuzumab was also initiated in cycle one and continued for six cycles, so through cycle six. In oral, sonrotoclax was initiated on cycle two, day one, and initiated per a ramp-up schedule to the recommended phase two dose of 320 milligrams daily, which has been defined for CLL in other cohorts of this phase one study. After cycle 15, patients who achieved peripheral blood uMRD4 by next-generation sequencing were permitted to discontinue therapy, and others had the option of continuing on therapy until progression or unacceptable toxicity. And so the main study endpoints of this were safety and tolerability, overall response, and blood uMRD4. 

And so this study included a total of 15 patients with treatment-naive CLL or SLL who were enrolled and received at least one cycle of therapy. At the data cutoff in late August of this year, 10 patients had reached the cycle 15 MRD time point and discontinued therapy after achieving uMRD4 per NGS. The other five patients have yet to reach this cycle 15 time point and so remain on therapy. This was a fairly representative cohort of patients. And we presented both safety and efficacy data from this cohort. 

So we did not see any tumor lysis syndrome, either laboratory or clinical TLS during the sonrotoclax ramp up. One patient did experience laboratory TLS, this occurred during the obinutuzumab infusion prior to receiving sonrotoclax. We observed infections in 73% of patients. 13% had grade three or four infections. There were no fatal events on this study. Neutropenia was generally transient and did not lead to higher rates of grade 3 or worse infections, and additional safety data can be seen on the poster presentation. 

In terms of efficacy, all patients achieved an objective response. So at the data cutoff, all MRD-evaluable patients who had reached the cycle 15 time point had achieved uMRD5 per next-generation sequencing, discontinued therapy, and remained in an ongoing remission as of the last data cutoff. The median time off treatment is 5.5 months, and no PFS events have been observed, all patients remaining in a remission, including the 10 patients who discontinued therapy in a uMRD4 response. 

And so in summary, this combination of zanubrutinib, obinutuzumab, and sonrotoclax at the 320 milligram sonrotoclax dose level was well-tolerated in treatment-naive CLL. No deaths or discontinuations of any study drug due to a treatment emergent adverse event occurred. No laboratory or clinical TLS occurred during the venetoclax ramp-up. We observed substantial efficacy with all patients achieving a response. All patients who reached the cycle 15 peripheral blood MRD assessment achieved uMRD5 and discontinued treatment per protocol, all also remaining in an ongoing remission with a median time off therapy of five and a half months. And again, with a median follow-up of 18 months, no PFS events have occurred, suggesting the potential for this triplet regimen to achieve deep and very durable remissions in treatment-naive CLL. And I just highlight that this combination is being further evaluated – we are leading a phase two multi-center investigator-initiated trial of zanubrutinib, obinutuzumab, and sonrotoclax, or BOSON, incorporating an MRD kinetics guided treatment duration strategy at the Mass General Brigham Cancer Institute in the Memorial Sloan Kettering Cancer Center, which is currently still open to accrual.

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