Sonrotoclax Plus Zanubrutinib Achieves >90% uMRD in Treatment-Naive CLL/SLL

The all-oral combination of sonrotoclax (BGB-11417) and zanubrutinib (Brukinsa) produced undetectable minimal residual disease (uMRD) rates exceeding 90% in patients with treatment-naive chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), with no disease progression observed in the recommended phase 2 dose (RP2D) cohort at a median follow-up of more than 34 months, according to updated results from the phase 1/1b BGB-11417-101 trial (NCT04277637) presented at the European Hematology Association (EHA) 2026 Congress in Stockholm, Sweden.¹

Chan Y. Cheah, MBBS, FRACP, FRCPA, of Sir Charles Gairdner Hospital and the University of Western Australia, Nedlands, Australia, presented updated data from the TN CLL/SLL cohort of BGB-11417-101, a global phase 1/1b dose-escalation and expansion study evaluating sonrotoclax as monotherapy or in combination with zanubrutinib and/or obinutuzumab (Gazyva) in patients with B-cell malignancies. The primary objective was to determine the RP2D of sonrotoclax and evaluate safety and tolerability. The regimen consists of an 8- to 12-week zanubrutinib lead-in of 320 mg once daily or 160 mg twice daily, followed by sonrotoclax ramp-up to target doses of either 160 mg or 320 mg daily, with elective discontinuation of sonrotoclax permitted after 96 weeks at target dose.

Key Efficacy Data: Response Rates and MRD Negativity

Among 135 efficacy-evaluable patients, the overall response rate (ORR) was 100%, with a median time to first response of 2.6 months (range, 1.5–10.8 months). Complete response (CR) rates were 51.0% in the 160-mg cohort and 59.5% in the 320-mg RP2D cohort, for an overall CR rate of 56.3% across all efficacy-evaluable patients.

MRD negativity rates in the 320-mg cohort increased progressively over time. In peripheral blood, best uMRD4 rates, defined as less than 1 CLL cell per 10,000 leukocytes were 81.2% at week 24 (n = 85), 91.8% at week 48 (n = 85), and 98.2% at week 96 (n = 56). At the deeper uMRD5 threshold of less than 1 CLL cell per 100,000 leukocytes, the best blood uMRD5 rate in the 320-mg cohort was 87.3% (n = 79). Critically, no conversion from uMRD4 to detectable MRD occurred as of the data cutoff.

In subgroup analyses by molecular risk status, uMRD4 rates at week 96 across all cohorts were consistent regardless of IGHV mutational status, including 91.7% in the IGHV-mutated group (n = 36) vs 96.8% in IGHV-unmutated group (n = 63). A similar trend was noted for TP53 status: 92.9% among those with TP53 mutation/del(17p) (n = 14) vs 97.7% in those with no TP53 mutation/del(17p) (n = 86). Time to uMRD4 in the 320-mg cohort was rapid regardless of IGHV status: median 4.5 months from sonrotoclax initiation in patients who were IGHV-mutated (n = 32) and 5.2 months in those who were IGHV-unmutated (n = 46).

No disease progression events were observed in the 320-mg RP2D cohort, yielding a 24-month progression-free survival (PFS) rate of 100%. In the 160-mg cohort, one patient with Richter transformation experienced progressive disease. Among the 69 patients who electively discontinued sonrotoclax, the median time off treatment was 9.2 months (range, 0.6–21.6), with no progression events observed off treatment in the 320-mg cohort.

Trial Design and Patient Population

A total of 137 patients with TN CLL/SLL were enrolled across two cohorts: sonrotoclax 160 mg plus zanubrutinib (n = 51) and sonrotoclax 320 mg plus zanubrutinib (n = 86), the latter representing the RP2D cohort. Sixty-nine patients electively discontinued sonrotoclax after 96 weeks at target dose. Baseline characteristics were balanced across cohorts. Median age was 62.0 years (range, 32–84) across all patients, with 40.1% aged 65 years or older and 71.5% male. Disease type at enrollment was CLL in 94.9% of patients and SLL in 5.1%. High-risk molecular features were present in a meaningful proportion of patients: 13.1% carried a del(17p) or TP53 mutation, 15.3% had del(11q), and 59.9% had unmutated immunoglobulin heavy chain variable (uIGHV) gene status. High tumor burden at baseline was recorded in 28.5% of all patients. The median study follow-up was 33.6 months (range, 3.1–48.8) across all patients and 34.1 months (range, 3.1–45.2) in the RP2D cohort.

Adverse Event Data and Safety Profile

The combination was generally well tolerated, with most treatment-emergent adverse events (TEAEs) occurring at grades 1 and 2 and described by investigators as transient. Across all 137 patients, any-grade TEAEs were reported in 99.3% of patients; grade 3 or higher TEAEs occurred in 63.5%. Serious TEAEs were reported in 34.3% of patients.

No TEAE led to death and no clinical or laboratory tumor lysis syndrome (TLS) was observed. Only 5 patients (3.6%) discontinued sonrotoclax due to a TEAE. Median relative dose intensity for sonrotoclax was 99%, and the median duration of exposure was 26.7 months (range, 0.8–48.8) across all patients.

The most common any-grade TEAEs occurring in at least 15% of patients in either cohort included neutropenia, COVID-19, contusion, diarrhea, upper respiratory tract infection, nausea, headache, fatigue, rash, arthralgia, cough, and back pain. In the 320-mg cohort, neutropenia of any grade was observed in 39% of patients. –– 31% grade 3 events –– and COVID-19 in 33%. The favorable tolerability profile, combined with the absence of TLS events is consistent with sonrotoclax's optimized pharmacokinetic profile, which features a shorter half-life and minimal drug accumulation compared with venetoclax (Venclexta). Sonrotoclax recently received FDA approval in relapsed/refractory mantle cell lymphoma, broadening its approved indications.²

Limitations and Next Steps

As a phase 1/1b study without a randomized comparator arm, BGB-11417-101 does not provide head-to-head efficacy data against existing standard-of-care regimens. The absence of a formal comparator limits conclusions about the relative benefit of sonrotoclax over venetoclax-based doublets with a BTK inhibitor. The MRD data, while high, are limited to peripheral blood; confirmatory bone marrow MRD assessments were not presented.

References

1. Cheah CY, Opat SS, 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: European Hematology Association 2026 Congress; June 11–14, 2026; Stockholm, Sweden. Abstract S145. Data originally presented at: 2026 ASCO Annual Meeting; May 29–June 2, 2026; Chicago, IL. Abstract 7043.
2. FDA grants accelerated approval to sonrotoclax for relapsed or refractory mantle cell lymphoma. News release. FDA. May 13, 2026. Accessed June 14, 2026. https://tinyurl.com/3jbzuu75