The objective of this analysis was to report the safety and efficacy of the investigational combination of sonrotoclax plus zanubrutinib in patients with relapsed or refractory mantle cell lymphoma, with a median follow–up of approximately two years.
BGB–11417–101 was an ongoing, open–label, phase 1/1b dose–escalation and expansion study in adults with relapsed or refractory MCL who had received ≥1 prior therapy. Treatment began with a zanubrutinib lead–in administered at either 320 mg once daily or 160 mg twice daily for 8–12 weeks. Sonrotoclax was then added using a ramp–up schedule to a target dose of 80 mg, 160 mg, 320 mg, or 640 mg once daily to mitigate the risk of tumor lysis syndrome. Combination therapy continued until progressive disease, unacceptable toxicity, or elective discontinuation after 96 weeks. The primary endpoint was safety, including tumor lysis syndrome assessed by Howard criteria. Secondary endpoints included overall response rate (ORR), defined as partial response or better per Lugano 2014 criteria.
As of December 6, 2025, 51 patients were enrolled across sonrotoclax dose cohorts (80mg [n=6], 160 mg [n=13], 320 mg [n=27], and 640 mg [n=5]); 46 initiated combination therapy, and 49.0% remained on treatment at data cutoff. Median age was 68 years, and 70.6% of patients were male. Patients had received a median of 1 prior therapy (range, 1–4), with a median duration of last treatment of 6.0 months (range, 0.1-65.6). Prior therapies included stem cell transplant (n=15), CAR–T therapy (n=1), and Bruton tyrosine kinase (BTK) inhibitors (n=4).
The most common any–grade adverse events were diarrhea (37.3%), neutropenia (33.3%), and COVID–19 (33.3%). Grade ≥3 treatment–emergent adverse events (TEAE) occurred in 66.7% of patients, with neutropenia being the most common (21.6%). Serious TEAEs were reported in 41.2% of patients, with pneumonia being the most common (15.7%). Twenty-one patients (41.2%) discontinued sonrotoclax plus zanubrutinib and 6 (11.8%) discontinued zanubrutinib only. TEAEs led to discontinuation of sonrotoclax plus zanubrutinib in 4 patients (7.8%) and led to discontinuation of zanubrutinib only in 2 patients (3.9%) due to diarrhea and cryptococcal meningoencephalitis; no adverse events led to discontinuation of sonrotoclax alone. TEAEs led to death in 2 patients (3.9%), due to pneumonia and abdominal sepsis. No laboratory or clinical tumor lysis syndrome was reported. In the sonrotoclax 320–mg plus zanubrutinib cohort, the most common any–grade TEAE was diarrhea (51.9%, mostly grade 1–2), and the most common grade ≥3 TEAE was neutropenia (22.2%).
Across all 51 patients, the ORR was 80.4%, and the complete response (CR) rate was 60.8%. Median time to CR was 6.4 months (range, 1.5-32.5). With a median follow–up of 25.5 months (range, 0.7-51.6), 80.6% of patients who achieved CR remained in CR. In the sonrotoclax 320–mg cohort (median follow-up, 21.3 months), the ORR was 81.5%, with a CR rate of 59.3%, and the 30–month duration–of–response rate was 77.7% (95% CI, 50.2%-91.2%). Among 4 patients previously treated with a BTK inhibitor, 2 achieved partial response. All 6 patients who electively discontinued treatment achieved CR and remained in complete remission (median time off treatment, 9.6 months [range, 2.9-12.1]).
