The all-oral combination of sonrotoclax (Beqalzi) and zanubrutinib (Brukinsa) elicited undetectable minimal residual disease (MRD) rates exceeding 90% in patients with treatment-naive (TN) chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), including those with high-risk cytogenetics, such as 17p deletions (del(17p)) and TP53 mutations, according to updated data from the phase 1/1b BGB-11417-101 trial (NCT04277637) presented at the
Findings showed that efficacy-evaluable patients (n = 135) achieved an overall response rate (ORR) of 100%, including complete response (CR) rates of 51.0% in the 160-mg sonrotoclax cohort (n = 51) and 59.5% in the 320-mg cohort (n = 84). In the 320-mg cohort (n = 56), undetectable MRD rates at a 10-4 sensitivity (MRD4) reached 98.2% by week 96, and the rates of undetectable MRD at a 10-5 sensitivity (MRD5), as measured by next-generation sequencing (NGS), were 87.3% across both cohorts (n = 79). Responses were consistent regardless of IGHV mutational status or del(17p)/TP53 mutation status.
“The depths and kinetics of undetectable MRD achieved with sonrotoclax plus zanubrutinib highlight the improved potency and differentiated profile of this combination vs available combination therapies in first-line CLL,” presenting study author Mazyar Shadman, MD, MPH, and colleagues wrote in a poster presentation of the data.
Shadman is a professor in the Clinical Research Division, deputy chief medical officer, medical director of Cellular Immunotherapy, and the Innovators Network Endowed Chair at Fred Hutchinson Cancer Center in Seattle, Washington.
Although sonrotoclax is not currently approved by the FDA in any CLL/SLL indications, the agent
BGB-11417-101 is a global phase 1/1b study evaluating sonrotoclax, a next-generation, highly selective BCL-2 inhibitor, as monotherapy or in combination with zanubrutinib and/or obinutuzumab (Gazyva) in patients with B-cell malignancies. Updated data presented at ASCO 2026 focused specifically on patients with treatment-naive CLL/SLL treated with sonrotoclax plus zanubrutinib.
Patients in the previously untreated CLL/SLL cohorts started treatment with zanubrutinib alone as lead-in dosing for 8 to 12 weeks, with the BTK inhibitor administered at 320 mg once daily or 160 mg twice daily; patients continued to receive these dose levels for the duration of treatment. After 8 to 12 weeks, sonrotoclax was initiated with ramp-up dosing to target doses of 160 mg or 320 mg once daily. Patients continued treatment until disease progression, intolerance, or elective discontinuation at 96 weeks.
The trial’s primary end points were to determine the recommended phase 2 dose of sonrotoclax, along with safety and tolerability. ORR was a secondary end point, and undetectable MRD4 rate was an exploratory end point.
At baseline, patients in the CLL/SLL cohorts (n = 137) had a median age of 62.0 years (range, 32-84), and 71.5% were male. Most patients had CLL (94.9%). Additionally, 59.9% of patients had unmutated IGHV, 13.1% of patients had confirmed del(17p) and/or TP53 mutations, and 28.5% of patients had high tumor burden. The median follow-up at data cutoff was 33.6 months (range, 13.1-48.8).
Data also showed that the combination produced deep and rapid responses, with a median time to first response of 2.6 months (range, 1.3-10.8). At a median follow-up of 30.7 months, no disease progression events were observed among patients treated with sonrotoclax at 320 mg, including 35 patients who electively discontinued zanubrutinib or sonrotoclax after completing combination treatment, with a median treatment-free duration of 9.8 months (range, 2.7-15.5).
Across all cohorts, undetectable MRD4 rates by week 96 were consistent regardless of IGHV mutation status or del(17p)/TP53 status. In the 320-mg cohort, the median time to undetectable MRD4 from the start of combination therapy was 4.5 months in patients with IGHV mutations (n = 32) and 5.2 months in patients with IGHV-unmutated disease (n = 46).
Treatment-emergent adverse effects (TEAEs) occurred in 99.3% of evaluable patients across both cohorts (n = 137), with 63.5% of patients experiencing grade 3 or higher TEAEs. Serious TEAEs were reported in 34.3% of patients; however, no TEAEs led to death.
TEAEs led to treatment discontinuation of zanubrutninib and sonrotoclax in 5.8% and 3.6% of patients, respectively. The relative dose intensity of sonrotoclax was 99.0%, and the median duration of exposure was 26.7 months (range, 0.8-48.8).
