Phase 1 Study of Zanubrutinib Plus Lenalidomide in Patients With Relapsed/Refractory Diffuse Large B-Cell Lymphoma.

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 + lenalidomide (15, 20, or 25 mg once daily) until progression or unacceptable toxicity. Primary endpoints 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 prior therapies, 83% had stage III/IV disease, and approximately 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 AEs (TEAEs) occurred in 74%; the most common (>20%) grade ≥3 TEAEs were neutrophil count decreased (58%) and white blood cell count decreased (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% CI, 2.9-11.1 months); the 12-month event-free rate was 34% (95% CI, 21%-48%). Zanubrutinib + lenalidomide demonstrated acceptable tolerability and antitumor activity in patients with R/R DLBCL. This trial was registered at ClinicalTrials.gov as #NCT04436107.