BTK Inhibitor Zanubrutinib Leads to Modest Results Against Some DLBCL Malignancies

Brukinsa (zanubrutinib) monotherapy led to modest responses in patients with non–germinal center diffuse large B-cell lymphoma (non-GCB DLBCL) and may be a meaningful treatment option for some patients based on biomarker screening, according to a new study.

The report, published in Blood Advances, was based on a single-arm multicenter phase 2 study of 41 patients with relapsed or refractory non-GCB DLBCL.

The authors wrote that recent advances in the study of DLBCL indicate that the cancer type is actually a group of disorders, rather than a single disease. Phenotypes include germinal center B-cell–like lymphomas and non–germinal center lymphomas. Immunotherapy with rituximab (Rituxan), cyclophosphamide, doxorubicin (Adriamycin), and prednisolone is generally the first-line treatment for patients with DLBCL; however, many patients are refractory to therapy or experience relapse, often leading to poor outcomes.

Zanubrutinib is an oral Bruton’s tyrosine kinase (BTK) inhibitor that has been shown to have a favorable safety profile and positive results in several B-cell malignancies. Based on the therapy’s success in other B-cell cancers, the authors wanted to know whether the therapy might be effective in non-GCB DLBCL.

The investigators enrolled 41 patients in their phase 2 study, with the goal of seeing if these patients with relapsed or refractory disease would benefit from 2 daily oral doses of 160 mg of zanubrutinib. Their primary end point was overall response rate (ORR), with progression-free survival (PFS) and duration of response (DOR) as secondary end points. Overall survival (OS) was an exploratory end point.

After a median follow-up of 6.8 months, the investigators said 29.3% of patients had responded to the therapy, with a complete response (CR) rate of 17.1%. The median DOR was 4.5 months, PFS was 2.8 months, and OS was 8.4 months, they added.

At data cutoff, only 4 of 37 patients were continuing to take the drug. Nearly half of the patients (48.8%) experienced grade 3 or higher adverse events (AEs), but only 4 patients discontinued the drug due to AEs. No patients experienced major hemorrhage, atrial fibrillation, and/or flutter. Among the most common treatment-associated AEs were decreased neutrophil count (9 patients), hypokalemia (7 patients), and decreased platelet count (5 patients). Twenty-four patients died, most (19) from progressive disease.

The investigators retrospectively conducted biomarker testing on the patients in the study. They found that patients with both CD79B and MYD88 mutations appeared to have antitumor activity. This patient group was also found to do poorly with standard immunochemotherapy.

“Our genetic analysis results also suggested the potential activity of zanubrutinib in these subsets of DLBCL (ORR, 50%; 3/6),” the authors reported. “An improved biomarker strategy beyond the GCB vs non-GCB classification may aid in targeting DLBCL more precisely.”

They noted several limitations to their findings, including the small sample size and the small representation of patients with previous autologous stem cell transplantation (4 patients).

“Notwithstanding these limitations, the overall activity of zanubrutinib in R/R DLBCL appears similar to that of the other BTK inhibitors, but with a suggestion of improved tolerability compared with ibrutinib,” they wrote.

They concluded that zanubrutinib is worthy of further study in this patient group, with a particular focus on developing mechanism-based treatment combinations and biomarker-driven patient selection.

Reference

Yang H, Xiang B, Song Y, et al. Zanubrutinib monotherapy for relapsed or refractory non-germinal center diffuse large B-cell lymphoma. Blood Adv. 2022;6(6):1629-1636. doi:10.1182/bloodadvances.2020003698