Sonrotoclax Plus Zanubrutinib Produces Deep MRD Responses in Treatment-Naive CLL

Updated findings from a phase 1/1b study suggest that the investigational combination of sonrotoclax (Beqalzi; BeOne Medicines USA, Inc) and zanubrutinib (Brukinsa; BeOne Medicines USA, Inc) may produce exceptionally deep responses in patients with previously untreated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma, including those with high-risk disease features.

The data, presented at the 2026 European Hematology Association Congress, showed high rates of undetectable minimal residual disease (uMRD) and durable disease control with the all-oral regimen, supporting ongoing phase 3 evaluation of the combination.

Current frontline fixed-duration regimens that combine a Bruton tyrosine kinase (BTK) inhibitor with a BCL2 inhibitor have demonstrated efficacy in CLL. However, investigators noted that rates of uMRD remain suboptimal, even with second-generation BTK inhibitors. Sonrotoclax, a next-generation BCL2 inhibitor reported to have approximately 14-fold greater pharmacologic potency than venetoclax (Venclexta; AbbVie Inc), is being evaluated as a strategy to deepen responses.

Investigating Sonrotoclax Plus Zanubrutinib

The study enrolled 86 patients who received 320 mg of zanubrutinib once daily for 8 to 12 weeks, followed by sonrotoclax with a ramp-up to the target daily dose of 320 mg. Patients remained on treatment until disease progression, unacceptable toxicity, or protocol-defined elective discontinuation after 96 weeks of combination therapy at the target dose. At a median follow-up of 30.9 months, 45 patients (52%) remained on treatment while 40 patients (47%) had discontinued sonrotoclax. Most discontinuations were due to protocol-defined elective treatment completion rather than toxicity.

The regimen demonstrated a manageable safety profile. The most common treatment-emergent adverse events of any grade were neutropenia (38%), contusion (38%), COVID-19 infection (33%), and upper respiratory tract infection (30%). Grade 3 or higher neutropenia occurred in 29% of patients. Importantly, no cases of tumor lysis syndrome were reported, and no adverse events resulted in death.

Among 84 efficacy-evaluable patients, the overall response rate was 100%, with 55% achieving a complete response. Responses occurred rapidly, with a median time to response of 2.6 months. No patient in the 320-mg cohort experienced disease progression, resulting in an estimated 30-month progression-free survival rate of 100%.

Investigators Report Meaningful MRD Data

The most notable findings were observed in MRD analyses. The best uMRD4 rate (ie, the percentage who achieved a uMRD below a threshold of 10⁻⁴), defined as fewer than 1 CLL cell per 10,000 leukocytes by flow cytometry, was 99% overall. Among patients with TP53 mutations or 17p deletions, a subgroup historically associated with poorer outcomes, the uMRD4 rate was 100%.

Responses deepened over time. By weeks 24, 48, and 96, uMRD4 rates were 81%, 91%, and 98%, respectively. The median time from reaching the target sonrotoclax dose to achieving uMRD was 3 months. Notably, no patient who achieved uMRD4 subsequently lost MRD negativity during the follow-up period.

In next-generation sequencing analyses, 86% of evaluable patients achieved uMRD5, indicating even deeper levels of disease clearance, with fewer than 1 malignant cell per 100,000 leukocytes.

Improving Outcomes in CLL

Investigators concluded that sonrotoclax plus zanubrutinib was well tolerated and produced uMRD rates exceeding 90%, including among patients with high-risk cytogenetic abnormalities. They noted that both the depth and speed of MRD responses suggest a differentiated profile compared with currently available frontline combination therapies.

The regimen is currently being further evaluated in 2 phase 3 clinical trials (NCT06073821, NCT07277231), which will help determine whether these promising early findings translate into improved long-term outcomes for patients with CLL.

REFERENCE

Cheah CY, Opat S, Lasica M, et al. 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: 2026 European Hematology Association Congress; June 11-14, 2026; Stockholm, Sweden. Abstract S145.