This Phase 1/1b study evaluated the safety and efficacy of the investigational combination of zanubrutinib plus sonrotoclax in patients with treatment-naive chronic lymphocytic leukemia or small lymphocytic lymphoma, including those with del(17p)/TP53 mutations.

This was a single-arm study in which patients received zanubrutinib 320 mg once daily for an 8–12-week lead-in period followed by combination treatment with sonrotoclax with dose ramp-up to a target dose of 320 mg once daily. Treatment continued until disease progression, unacceptable toxicity, or protocol-defined elective discontinuation after 96 weeks of combination therapy at the target dose. The primary endpoint was safety, assessed using NCI-CTCAE version 5.0. Secondary endpoints included overall response rate, and exploratory endpoints included undetectable minimal residual disease rates (uMRD4) assessed by flow cytometry and next-generation sequencing.

After a median follow-up of 30.9 months (range, 3.1-41.9), the most common any-grade treatment-emergent adverse events among 86 patients were neutropenia (38%), contusion (38%), COVID-19 (33%), and upper respiratory tract infection (30%). Neutropenia was the most common grade ≥3 adverse event, reported in 29% of patients. No cases of tumor lysis syndrome were observed, and no adverse events leading to death were reported.

In 84 efficacy-evaluable patients, the overall response rate was 100%, with complete responses reported in 55%. The median time to response was 2.6 months (range, 1.5-9.1). No disease progression was reported in the 320 mg cohort, and the estimated 30-month progression-free survival was 100%. The best uMRD4 rate assessed by flow cytometry was 99% (83/84) and 100% (10/10) in patients with del(17p)/TP53 mutations. Median time from reaching sonrotoclax target dose to uMRD was 3.0 months (range, 2.3-27.4), and the best uMRD4 rates by weeks 24, 48 and 96 were 81% (69/85), 91% (63/69), and 98% (55/56), respectively. No patient with uMRD4 reverted to MRD4+.