Authored by Ann Liu, PhD
The Bottom Line:
In an early-stage clinical trial, zanubrutinib-sonrotoclax-obinutuzumab was tolerated, and all patients with CLL / SLL responded to treatment.
Who Performed the Research and Where Was it Presented:
Dr. Jacob Soumerai from Massachusetts General Hospital Cancer Center and Harvard Medical School and colleagues presented the results at the American Society for Hematology (ASH) Annual Meeting in 2025.
Background:
Venetoclax was the first B-cell lymphoma 2 inhibitor (BCL2i) approved to treat chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL). It kills cancer cells rapidly, and it is often used in combination with anti-CD20 monoclonal antibodies and/or BTK inhibitors. Sonrotoclax is a second-generation BCL2i that is more selective and more potent than venetoclax. Researchers have already reported promising results from studies testing the doublet combinations of sonrotoclax plus zanubrutinib and sonrotoclax plus obinutuzumab for treatment-naïve CLL. In this study, researchers tested the safety of the triple combination of sonrotoclax, zanubrutinib, and obinutuzumab in patients with treatment-naïve CLL / SLL.
Methods and Participants:
This is a phase 1 clinical trial evaluating the safety of the combination of zanubrutinib, sonrotoclax, and obinutuzumab in patients with B-cell cancers. Researchers were also determining the best dose level to give to patients in the future.
Results:
- Fifteen patients with treatment-naïve CLL / SLL had enrolled in the study by May 2025.
- Half of the patients were under 62 years old and most had unmutated IGHV.
- The most common side effects were low neutrophil counts (80%), nausea (47%), infusion-related reaction (40%), low platelet counts (40%), fatigue (33%), headache (33%), and insomnia (33%). The rate of infections, a problem in prior trials of similar triple-drug therapy, were not reported.
- No patients experienced tumor lysis syndrome during sonrotoclax ramp-up.
- No patients discontinued treatment due to side effects.
- At the time of data cutoff, six patients remained on treatment, and nine patients had discontinued treatment due to reaching undetectable measurable residual disease status.
- Among 10 patients who could be evaluated for efficacy, all patients had their CLL / SLL measurably improve, and 6 of those 10 had eradication of CLL in the blood, most within 3 months, allowing discontinuation of the sonrotoclax.
- While only half of patients have been followed for more than 14 months, no deaths or relapses have occurred.
Conclusions:
This early-stage clinical trial provided additional evidence that sonrotoclax as part of combination therapy can be tolerated, although almost everyone had at least one side effect when combined with zanubrutinib andobinutuzumab. In this small sample, many patients achieved remission as quickly as 4 months. Given that sonrotoclax is now FDA approved for a rarer form of blood cancer and has theoretical advantages over venetoclax, we should expect to see more studies of this drug in CLL / SLL. We still do not know which types of patients have enough extra benefits with three-drug versus two-drug protocols to justify the additional likelihood of side effects.
Links and Resources:
You can read the actual ASH abstract here: Zanubrutinib + obinutuzumab + sonrotoclax in patients with treatment-naive chronic lymphocytic leukemia/small lymphocytic lymphoma (TN CLL / SLL): Initial results from an ongoing phase 1/1b study, BGB-11417-101
Take care of yourself first.
Ann Liu, PhD
