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Long-Term Efficacy and Safety Data From Phase II Trial Reported for Zanubrutinib in R/R MCL

June 27, 2022

July 2022

Anna Azvolinsky, PhD

Anna Azvolinsky, PhD, is a freelance medical and science journalist based in New York City.

Monotherapy with the Bruton tyrosine kinase (BTK) inhibitor zanubrutinib resulted in durable responses and an acceptable safety profile in patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL) at a median follow up of almost three years. Results from the multi-center, open-label, phase II BGB-3111-206 trial were published in Blood.

Zanubrutinib received accelerated approval by the U.S. Food and Drug Administration in November 2019 for adult patients with MCL who have received at least one prior therapy, based on 18.4 months of follow-up data. Subsequently, the therapy was also approved in the U.S. for Waldenström macroglobulinemia and received accelerated approval for adult patients with relapsed or refractory marginal zone lymphoma who have received at least one anti-CD20-based regimen.

Study authors, led by Yuqin Song, MD, PhD, of Peking University Cancer Hospital and Institute in China, evaluated 86 patients who received 160 mg of zanubrutinib twice daily in the single-arm, open-label, phase II trial. Median patient age was 61 (range = 34-75), 78% were men, and 84.7% had intermediate- or high-risk disease as determined by the combined MCL International Prognostic Index (MIPI-b). Stage 3-4 patients comprised 90.7% of all patients, 70.9% had extranodal disease, and 45.3% had bone marrow involvement.

The primary end point was overall response rate (ORR), assessed per Lugano 2014. After median follow-up of 35.3 months, the ORR was 83.7% (95% CI 74.2-90.8), with 77.9% achieving complete response (CR) and 5.8% achieving partial response. The median duration of response was not reached. All patients who exhibited a response did so by 12 weeks after initiating zanubrutinib therapy. The median time to response was 2.7 months.

After a median follow up of 35.3 months, 39 patients (45.3%) continued treatment, and the median treatment duration was 27.6 months (range = 0.2-41.6).

Twenty-one patients died by the data cutoff: 12 as a result of disease progression, seven from an adverse event (AE), and two for unknown reasons and subsequent to receiving additional lines of therapy. Of the patients who discontinued treatment, the reasons were progressive disease (43%), AEs (9.3%), physician’s decision (1.2%), and withdrawal of consent after achieving CR (1.2%).

Median progression-free survival (PFS) was 33.0 months (95% CI 19.4-NE). The 36-month PFS and overall survival rates were 47.6% (95% CI 36.2-58.1) and 74.8% (95% CI 63.7-83.0), respectively. For those patients who achieved a CR, the median PFS had not yet been achieved, whereas the patients who had a partial response or no response had a median PFS of 16.6 months (95% CI, 5.3-not yet reached) and 2.6 months (95% CI 0.8-2.9 months), respectively.

The median overall survival (OS) had not yet been achieved at the time of the study’s publication. Among the 37 patients who discontinued zanubrutinib, the median OS was 15.7 months (95% CI 9.6-not yet reached) with a median follow-up of 11.3 months.

The analysis showed no response variability by patient subgroup, including those patients who were characterized as having a poor prognosis. The authors noted that those patients who had a low- or intermediate-risk MIPI-b score, Ki67 index at or below 30%, fewer lines of therapy, and TP53 wild-type disease had prolonged duration of response and PFS.

The study limitation listed by the authors was its small sample size.

Most AEs occurred during the early stage of zanubrutinib therapy, and no new safety signals were observed with longer term follow up. Grade ≥3 AEs occurred in 50.0% of patients and included decreased neutrophil count (18.6%), pneumonia (12.8%), decreased platelet count, decreased white blood cell count (7.0%), and anemia (5.8%).

“This phase II study with extended 35.3-month follow-up data continued to demonstrate a favorable benefit-risk profile of zanubrutinib monotherapy in R/R MCL,” the authors concluded.

Any conflicts of interest declared by the authors can be found in the original article.

Reference

Song Y, Zhou K, Zou D-H, et al. Zanubrutinib in relapsed/refractory mantle cell lymphoma: long-term efficacy and safety results from a phase 2 study [published online ahead of print, 2022 Mar 18]. Blood. doi: 10.1182/blood.2021014162.

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