Authored by Ann Liu, PhD
Medically Reviewed by Brian Koffman, MDCM (retired), MSEd
The Bottom Line:
The combination of sonrotoclax and zanubrutinib was well-tolerated and produced high rates of undetectable disease in patients with treatment-naïve CLL.
Who Performed the Research and Where Was it Presented:
Dr. Jacob Soumerai from Massachusetts General Hospital Cancer Center and colleagues presented the results at the American Society for Hematology (ASH) Annual Meeting 2024.
Background:
One of the combination treatments for chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL) that people are excited about is combining a BTK inhibitor with a BCL2 inhibitor. Previous clinical trials have shown that the combination of ibrutinib and venetoclax was very effective for treating CLL. Still, there were concerns about some of its toxicities, and it has not been approved in the US, although it is approved in Europe and Canada. This study combined sonrotoclax, an experimental BCL2 inhibitor, with zanubrutinib, an approved BTK inhibitor. Combination treatments like this aim to get patients into deep remissions with undetectable measurable residual disease (uMRD).
Methods and Participants:
This study was part of a larger phase 1 clinical trial testing sonrotoclax in various B cell cancers. This particular part focused on the combination of sonrotoclax plus zanubrutinib for patients with treatment-naïve CLL. Patients started on zanubrutinib for 8-12 weeks, and then sonrotoclax was gradually ramped up to one of two dose levels (160 mg or 320 mg per day). Patients were on treatment for 2 years and then had the option to stop.
Results:
- In total, 112 patients with treatment-naïve CLL were enrolled in the study.
- The median follow-up was a little over 18 months.
- No tumor lysis syndrome was observed, so starting zanubrutinib to lower the tumor burden and gradually ramping up sonrotoclax worked to prevent this type of reaction.
- Combination treatments can cause low neutrophil (infection-fighting white blood cells) counts (neutropenia). Severely (≥grade 3) low neutrophil counts were seen in 26% of patients on sonrotoclax plus zanubrutinib, which is relatively low for a combination treatment.
- Two patients had grade 3 febrile neutropenia (serious low neutrophil count associated with fever).
- No patients had to stop treatment due to low neutrophil counts (or increased infection risk).
- The most common adverse events were low neutrophil counts (41%), bruising (38%), COVID-19 (30%), and diarrhea (29%).
- Most gastrointestinal side effects, such as diarrhea and nausea, were mild.
- Out of 108 patients who could be evaluated for a response, the overall response rate was 100%, and the complete response rate appeared to increase over time.
- The median time to response was 2.6 months, and median time to complete response was 8.4 months.
- At 6 months, 78% of patients had reached uMRD in the blood. At 48 weeks (almost 1 year), 91% of patients had reached uRMD.
- Both dose levels tested were equally safe, but the higher dose level looks to be more effective.
Conclusions:
In this phase 1 clinical trial, the combination of sonrotoclax plus zanubrutinib was well-tolerated with no unexpected side effects of concern. Low neutrophils were noted in 41% of patients. Almost four out of five patients at six months and nine out of ten at eleven months were uMRD, suggesting impressively fast and deep responses that improved over time.
A phase 3 clinical trial of sonrotoclax plus zanubrutinib is already ongoing. If you are interested in participating, more information can be found here: Study of Sonrotoclax (BGB-11417) Plus Zanubrutinib (BGB-3111) Compared With Venetoclax Plus Obinutuzumab in Participants With Chronic Lymphocytic Leukemia (CLL)
Links and Resources:
Watch the interview on the abstract here:
You can read the ASH abstract here: Sonrotoclax and Zanubrutinib as Frontline Treatment for CLL Demonstrates High MRD Clearance Rates with Good Tolerability: Data from an Ongoing Phase 1/1b Study BGB-11417-101
For more up to date data presented at the ASH 2024 conference and discussed in our interview, please view the study presentation slides.