The objective of this analysis was to report updated safety and efficacy results for the investigational combination of sonrotoclax plus zanubrutinib in patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), including patients with del(17p)/TP53, enrolled in the global, phase 1/1b BGB–11417–101 study.
BGB–11417–101 was a global, phase 1/1b study in patients with relapsed or refractory CLL/SLL who had received ≥1 prior therapy and had no progressive disease on a prior Bruton tyrosine kinase (BTK) inhibitor. Patients received zanubrutinib at either 320 mg once daily or 160 mg twice daily for an initial 8–12–week lead–in period, after which sonrotoclax was added using a dose ramp–up to a target dose of 40 mg, 80 mg, 160 mg, 320 mg, or 640 mg once daily. Treatment continued until progressive disease, unacceptable toxicity, or protocol–defined elective discontinuation after 96 weeks. The primary endpoint was safety and tolerability. Secondary and exploratory endpoints included overall response rate (ORR; defined as partial response with lymphocytosis or better per iwCLL 2018 criteria) and peripheral blood undetectable minimal residual disease at 10⁻⁴ by flow cytometry.
As of December 6, 2025, 47 patients were enrolled, including 22 assigned to the sonrotoclax 320–mg cohort. Median age was 65 years (range, 36–76). TP53 mutation or del(17p) was reported in 37% of patients, and unmutated IGHV in 77% of patients. Patients had received a median of 1 prior therapy (range, 1–3), with a median duration of last systemic therapy of 5.0 months (range, 0.1-86.6). Seven patients had received a BTK inhibitor as their most recent prior therapy. Overall, median study follow–up was 37.8 months (range, 10.2–57.8). Out of 47 patients, 34% remained on treatment, while 66% had discontinued the investigational combination, most commonly due to protocol–defined elective discontinuation (51%); 2.0% discontinued due to progressive disease.
Grade ≥3 treatment–emergent adverse events (TEAE) occurred in 72% of patients, most commonly neutropenia (28%), hypertension (11%), and pneumonia (11%). Serious TEAEs occurred in 47%, with pneumonia (11%), cellulitis (9%), and pyrexia (4%) reported in more than 1 patient. TEAEs led to discontinuation of the combination in 8% of patients (arthralgia, myelodysplastic syndrome, meningococcal sepsis, and multiple myeloma) and to discontinuation of zanubrutinib alone in 2% (intracranial hemorrhage). No tumor lysis syndrome occurred, and no TEAEs led to death.
Among 46 efficacy–evaluable patients, the ORR was 98%, and the complete response (CR) rate was 54%. Median time to response was 2.6 months (range, 1.5–24.6). The 36–month progression–free survival rate was 95% (95% CI, 83%–99%). In the sonrotoclax 320–mg cohort (n=21 efficacy–evaluable), the ORR was 100%, with a CR rate of 52% and a median time to response of 2.5 months (range, 1.6–6.9). Among 3 evaluable patients previously treated with a BTK inhibitor, all achieved a partial response. The 24–month progression–free survival rate in this cohort was 94% (95% CI, 67%–99%), with one progression event reported in a patient with TP53 mutation/del(17p)/mutated IGHV, at a median follow-up of 28.7 months (range, 20.1-48.9). In 21 MRD–evaluable patients in the sonrotoclax 320–mg cohort, the best peripheral blood undetectable minimal residual disease rate at the 10⁻⁴ level (uMRD4) was 86%. Median time from reaching target dose to undetectable minimal residual disease was 5.3 months (range, 2.5–16.3). Best uMRD4 rates by weeks 24, 48, and 96 were 52%, 81%, and 82%, respectively, and no patient reverted to MRD–positive status.
