Zanubrutinib (Brukinsa) in combination with R-CHOP (rituximab [Rituxan], cyclophosphamide, doxorubicin, vincristine, and prednisone) displayed preliminary activity in patients with treatment-naive diffuse large B-cell lymphoma (DLBCL) with activation of the BCR signaling pathway and certain genetic mutations, according to data from a phase 2 study (NCT05290337) presented during the 2025 ASH Annual Meeting & Exposition.1
Efficacy-evaluable patients who received the combination (n = 58) achieved an overall response rate (ORR) of 91.4%, including a complete response (CR) rate of 79.3%. The estimated 3-year progression-free survival (PFS) and overall survival (OS) rates were 80.3% (95% CI, 70.5%-91.5%) and 89.1% (95% CI, 81.2%-97.8%), respectively.
Phase 2 Study of Zanubrutinib Plus R-CHOP in Untreated DLBCL With Specific Gene Expression: Key Takeaways
- Efficacy-evaluable patients who received zanubrutinib plus R-CHOP (n = 58) achieved an ORR of 91.4%, with a CR rate of 79.3%.
- The estimated 3-year PFS and OS rates were 80.3% (95% CI, 70.5%-91.5%) and 89.1% (95% CI, 81.2%-97.8%), respectively.
- The most common any-grade AEs included infection (61.0%), leukopenia (54.2%), and neutropenia (52.5%).
“Previous studies indicated that for those with specific gene mutations, R-CHOP demonstrated limited efficacy,” Qunling Zhang, MD, of the Department of Medical Oncology at Fudan University Shanghai Cancer Center in Shanghai, China, and colleagues noted in the presentation. “However, promising response rates with BTK inhibitors suggest the potential for combined therapeutic regimens within this patient cohort.”
How was the phase 2 study designed?
The phase 2 trial enrolled patients who were 18 to 75 years old with newly diagnosed DLBCL with activation of the BCR signaling pathway whose disease harbored a mutation in MYD88, CD79B, NOTCH1, or TP53, or carried a MYC gene translocation, at a single center in China.1,2 Other key eligibility criteria included an ECOG performance status of 0 to 1, a life expectancy of over 3 months, at least 1 measurable target lesion, a left ventricular ejection fraction of at least 50%, and normal hematological, hepatic and renal function.2
Patients received 1 cycle of R-CHOP followed by 5 cycles of zanubrutinib in combination with R-CHOP.1The primary end point was the 3-year PFS rate. Secondary end points included ORR, event-free survival, OS, and safety.
At baseline, the mean age in the overall population (n = 59) was 53.9 years (SD, 12.2). Most patients were male (62.7%), had disease that originated from non-Germinal center B-cell like cells (55.9%), and presented with stage III to IV disease (52.5%). The baseline IPI scores were 0 (30.5%), 1 (22.0%), 2 (22.0%), 3 (16.9%), and 4 (8.5%).
Among the 58 patients who completed treatment and underwent tumor assessment, genetic alterations were found in MCD (42.4%), A53 (27.1%), BN2 (8.5%), MYC (rearrangement, 8.5%), N1 (5.1%), other (5.1%), and ST2 (3.4%).
What were the subgroup and safety data?
Additional findings from the phase 2 trial revealed that efficacy-evaluable patients with MCD mutations (n = 25) achieved a CR rate of 84%. The 3-year PFS rate was 96.0% (95% CI, 88.6%-100.0%) among these patients and the 3-year OS rate was 100%.
Efficacy-evaluable patients with the A53/MYC/other subtype (n = 30) achieved a 3-year PFS rate of 71.6% (95% CI, 56.7%-90.5%). Patients with N1 disease (n = 3) had a 3-year PFS rate that was not reached; the 2-year PFS rate in this subgroup was 33.3%. The 2-year OS rates in the A53/MYC/other and N1 subgroups were 85.4% (95% CI, 73.0%-99.8%) and 33.3% (95% CI, 6.7%-100%), respectively.
In terms of safety, any-grade adverse effects included infection (61.0%), leukopenia (54.2%), neutropenia (52.5%), alopecia (40.7%), thrombocytopenia (28.8%), anorexia or poor appetite (25.4%), nausea (20.3%), weight loss (16.9%), febrile neutropenia (15.3%), and elevated alanine aminotransferase levels (10.2%). Grade 3 to 4 AEs consisted of neutropenia (45.8%), leukopenia (42.4%), infection (27.1%), thrombocytopenia (20.3%), and febrile neutropenia (15.3%).
Disclosures: Zhang listed no relevant financial relationships.
References
- Zhang Q, Jiang S, Liu Y, et al. The phase II study of zanubrutinib combined with R-CHOP in previously untreated diffuse large B-cell lymphoma (DLBCL) patients with specific gene-expression. Blood. 2025;146(suppl 1):57. doi:10.1182/blood-2025-57
- ZR-CHOP in DLBCL with specific gene abnormality. ClinicalTrials.gov. Updated March 22, 2022. Accessed December 6, 2025. https://clinicaltrials.gov/study/NCT05290337
