A New BTK Inhibitor on the Block: Zanubrutinib Demonstrates High Activity in Aggressive Non-Hodgkin Lymphomas

Zanubrutinib (BGB-3111) is a potent, highly specific, and irreversible Bruton tyrosine kinase (BTK) inhibitor that is effective in treating aggressive B-cell malignancies, according to results from a phase IB, first-in-human trial presented at the 2017 ASH Annual Meeting.

The agent demonstrated “durable responses across a variety of [lymphoma] histologies,” with an overall response rate (ORR) of 60 percent, reported lead author Constantine S. Tam, MD, from Peter MacCallum Cancer Centre and St. Vincent’s Hospital in Melbourne, Australia. Zanubrutinib was particularly effective in patients with aggressive mantle cell lymphoma (MCL; ORR=88%).

In this open-label, multicenter, phase Ib study, the researchers assessed safety and efficacy of zanubrutinib (160 mg twice-daily or 320 mg once-daily) in 99 patients with non-Hodgkin lymphoma (NHL; excluding those with Waldenström macroglobulinemia or chronic lymphocytic leukemia/small lymphocytic lymphoma).

Sixty-five patients had aggressive lymphoma (38 patients with MCL and 27 with diffuse large B-cell lymphoma [DLBCL]) and 34 had indolent lymphoma (24 patients with follicular lymphoma and 10 with marginal zone lymphoma).

With the exception of one patient with treatment-naïve MCL, all patients had relapsed/refractory disease. The median number of prior lines of therapy was two (range = 0-10 therapies).

The median follow-up time was 5.6 months (range = 0.3-22.3 months) and 5.1 months (range = 0.1-31.9 months) for indolent and aggressive lymphoma, respectively.

By September 15, 2017 (data cutoff), the most frequent adverse events (AEs) in both the indolent and aggressive cohorts were petechiae/purpura/contusion (24% and 25%, respectively) and upper respiratory tract infection (21% and 18%). The most frequently reported grade ≥3 AEs included anemia (9% and 11%) and neutropenia (9% and 9%). Other common grade ≥3 AEs in the indolent cohort included urinary tract infection (6%) and abdominal pain (6%), while common grade ≥3 AEs in the aggressive cohort included thrombocytopenia (9%) and pneumonia (6%).

Thirty-seven patients reported serious AEs: 11 (32%) in the indolent cohort and 26 (40%) in the aggressive cohort. Seven of these were considered related to zanubrutinib, including nausea, urinary tract infection, diarrhea, and creatinine increase in the indolent cohort and peripheral edema, pneumonia, and pneumonitis in the aggressive cohort.

No cases of atrial fibrillation (a complication associated with BTK inhibitors) were reported at the time of presentation.

The investigators assessed activity in 84 patients who had at least 12 weeks of follow-up. The overall ORR in this group was 60 percent (n=50).

During the presentation, Dr. Tam highlighted the response rates seen in the cohort with aggressive disease, including 26 patients with DLBCL and 32 patients with MCL (see TABLE). Response was not evaluable in three patients, but after a median follow-up of 5.6 months (range = 0.1-31.9 months), the ORR was 62 percent (n=36). This included 12 patients with complete response (CR; 21%) and 24 patients with partial response (PR; 41%). Five patients (9%) had stable disease and 14 (24%) had progressive disease.

More patients in the MCL group experienced a CR or PR, and response rates appeared to be lower in patients with DLBCL.

Zanubrutinib showed promising activity as a monotherapy in multiple NHL subtypes, Dr. Tam concluded, adding that ongoing phase II trials are evaluating zanubrutinib as single therapy and in combination with other agents.

The findings of this early-phase study are limited by its small patient population, short duration of follow-up, and lack of a comparator arm.

The authors report financial relationships with BeiGene, the manufacturer of BGB-3111.


Reference

Tam CS, Simpson D, Opat S, et al. Safety and activity of the highly specific BTK inhibitor BGB-3111 in patients with indolent and aggressive non Hodgkin’s lymphoma. Abstract #152. Presented at the 2017 American Society of Hematology Annual Meeting, December 9, 2017; Atlanta, GA.

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