Phase 1 study of zanubrutinib plus lenalidomide for patients with relapsed/refractory diffuse large B-cell lymphoma

Clinical Snapshot

Key Findings

• P Value: Not reported for primary endpoint

• Effect Size: Complete response rate 42%, median time to response 2.8 months

• Primary Outcome: Overall response rate 58% at recommended phase 2 dose (zanubrutinib 160mg BID + lenalidomide 25mg daily)

• Nnt Or Sensitivity: Median duration of response 14.9 months; 12-month event-free rate 34% (95% CI: 21-48%)

• Confidence Interval: Median PFS 5.5 months (95% CI: 2.9-11.1)

Clinical Application

Both agents available in Australia; requires haematology expertise for toxicity management, particularly neutropenia monitoring Zanubrutinib PBS-listed for other B-cell malignancies; lenalidomide available through Special Access Scheme. Fits treatment gap between standard salvage and palliative care Patients with R/R DLBCL after ≥1 prior therapy, particularly those ineligible for or having failed CAR-T or stem cell transplant

Abstract

Patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) typically have a poor prognosis. In preclinical studies, lenalidomide and a Bruton tyrosine kinase (BTK) inhibitor demonstrated synergistic antitumor effects. Zanubrutinib, a next-generation BTK inhibitor, has greater selectivity to minimize off-target binding. BGB-3111-110 was a phase 1 multicenter dose-escalation/-expansion study. Patients with R/R DLBCL received zanubrutinib 160 mg twice daily plus lenalidomide (15, 20, or 25 mg once daily) until progression or unacceptable toxicity. Primary end points were safety, recommended phase 2 dose (RP2D), and overall response rate (ORR; Lugano 2014 criteria). Sixty-six patients were enrolled and treated. Patients had a median of 2 previous therapies, 83% had stage III/IV disease, and ∼67% had non-geminal center B-cell-like or activated B-cell-like DLBCL. No dose-limiting toxicities occurred; the lenalidomide RP2D was 25 mg once daily when combined with zanubrutinib 160 mg twice daily. Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 74%; the most common (>20%) grade ≥3 TEAEs were decreased neutrophil count (58%) and decreased white blood cell count (29%). TEAEs led to 7 treatment discontinuations (11%) and 2 deaths (3%). At the RP2D, ORR and complete response rate were 58% and 42%, respectively; median time to response was 2.8 months. Median duration of response was 14.9 months. Median progression-free survival was 5.5 months (95% confidence interval [CI], 2.9-11.1); the 12-month event-free rate was 34% (95% CI, 21-48). Zanubrutinib plus lenalidomide demonstrated acceptable tolerability and antitumor activity in patients with R/R DLBCL. This trial was registered at www.clinicaltrials.gov as NCT04436107.

References

1. 1.Song, Z., Cheng, Y., Yang, H., Zhang, L., Zou, L., Guo, Y., Cao, J., Huang, H., Wang, Z., Huang, S., Fang, Y., Lyu, J., Zhang, Y., Liu, Y., Zhou, K., & Zhang, H. (2026). Phase 1 study of zanubrutinib plus lenalidomide for patients with relapsed/refractory diffuse large B-cell lymphoma. Blood Advances. https://doi.org/10.1182/bloodadvances.2025018482