Sonrotoclax Plus Zanubrutinib Achieves Undetectable MRD Rates Above 90% in Frontline CLL/SLL

Emerging data presented at the European Hematology Association 2026 Congress demonstrated that the oral combination of sonrotoclax (Beqalzi, BeOne Medicines USA, Inc) and zanubrutinib (Brukinsa, BeOne Medicines USA, Inc) achieved undetectable minimal residual disease (uMRD) rates exceeding 90% in patients with previously untreated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), including those with high-risk del(17p) or TP53 abnormalities.¹

In a phase 1/1b trial (NCT04277637) that evaluated frontline treatment with sonrotoclax and zanubrutinib, researchers of the trial reported a best uMRD4 rate of 99% among efficacy-evaluable patients and 100% among patients harboring TP53 mutations or del(17p), highlighting the potential of the regimen to induce exceptionally deep remissions in a population that commonly experiences poorer outcomes.¹

Pursuing Deeper Remissions in Frontline CLL

The introduction of Bruton tyrosine kinase (BTK) inhibitors and BCL2 inhibitors have evolved the treatment landscape for CLL, allowing many patients to avoid traditional chemotherapy while achieving durable disease control.²

Fixed-duration combinations incorporating BTK and BCL2 inhibition have more recently emerged as attractive treatment strategies because they offer the potential for deep remissions while limiting treatment duration. However, currently available regimens have produced lower rates of undetectable minimal residual disease than investigators would ideally like to achieve.¹

Sonrotoclax is a next-generation BCL2 inhibitor designed to deliver greater potency than currently available BCL2-targeted therapies. According to the data, sonrotoclax demonstrates an approximate 14-fold greater pharmacologic potency than venetoclax, providing a rationale for combining the agent with zanubrutinib in hopes of achieving deeper responses.¹ Zanubrutinib is a second-generation BTK inhibitor with established efficacy in CLL and other B-cell malignancies.³

Study Design

The trial evaluated sonrotoclax plus zanubrutinib in treatment-naive patients with CLL/SLL enrolled in a phase 1/1b study (NCT04277637).¹

Patients initially received zanubrutinib monotherapy at 320 mg once daily for 8 to 12 weeks before the addition of sonrotoclax, which was gradually escalated to a target dose of 320 mg daily. Treatment continued until disease progression, unacceptable toxicity, or protocol-defined elective discontinuation following 96 weeks of combination therapy.¹

The primary end point was safety, while secondary end points included overall response rate (ORR). Exploratory analyses evaluated rates of uMRD in peripheral blood using both flow cytometry and next-generation sequencing techniques.¹

At the time of data cutoff, 86 patients were enrolled in the 320-mg sonrotoclax cohort. The median follow-up was about 30.9 months.¹

High Rates of Deep Molecular Responses

Among 84 efficacy-evaluable patients, the ORR reached 100%, with 55% of patients achieving a complete response. The median time to response was about 2.6 months. Notably, there were no patients who experienced disease progression, resulting in an estimated 30-month progression-free survival rate of 100%.¹

The best uMRD4 rate assessed by flow cytometry reached 99% overall, while all evaluable patients with TP53 mutations or del(17p) achieved uMRD4. Deep responses occurred rapidly following initiation of sonrotoclax. The median time from reaching the target sonrotoclax dose to achieving uMRD was 3 months.¹

Best uMRD4 rates continued to improve over time, reaching approximately 81% at week 24, 91% at week 48, and 98% at week 96. Importantly, investigators reported that no patient who achieved uMRD4 subsequently reverted to MRD positivity. Among patients evaluable by next-generation sequencing, the best uMRD5 rate was 86%, demonstrating deep molecular responses even at more sensitive thresholds.¹

Safety Findings Support Continued Development

The combination was generally well tolerated, with no new safety concerns identified during the study. The most common treatment-emergent adverse events (AEs) observed included neutropenia (38%), contusion (38%), COVID-19 infection (33%), and upper respiratory tract infection (30%), and neutropenia was the most common grade 3 or higher AE (29%).¹

Importantly, no cases of tumor lysis syndrome were observed, and no AEs resulted in death. Forty patients discontinued sonrotoclax treatment, most of whom did so because of protocol-defined elective discontinuation, rather than toxicity or disease progression.¹

The exceptionally high uMRD rates observed with sonrotoclax and zanubrutinib—particularly among patients with high-risk del(17p) and TP53 abnormalities—suggest that next-generation BCL2 inhibition may further improve outcomes beyond those achieved with currently available BTK inhibitor–BCL2 inhibitor combinations.¹

The authors note that the regimen is currently being evaluated in 2 ongoing phase 3 clinical trials, which will help determine whether these promising early findings translate into improved long-term outcomes and establish a future role for the combination in frontline CLL management.¹

REFERENCES

1. First-line treatment of CLL/SLL with the all-oral combination of sonrotoclax and zanubrutinib achieves undetectable minimal residual disease rates of >90%, including in patients with del(17p)/TP53. Presented at the European Hematology Association 2026 Congress. Abstract S145. https://library.ehaweb.org/eha/2026/eha-2026/4206699/chan.y.cheah.first-line.treatment.of.cll.sll.with.the.all-oral.combination.of.html

2. Chronic lymphocytic leukemia treatment (PDQ®)–Health Professional Version. National Cancer Institute. Updated April 25, 2025. Accessed June 18, 2026. https://www.cancer.gov/types/leukemia/hp/cll-treatment-pdq

3. Brukinsa (zanubrutinib) prescribing information. BeOne Medicines. Accessed June 18, 2026. https://brukinsahcp.com/wp-content/uploads/brukinsa-prescribing-information.pdf