FDA Grants Zanubrutinib Breakthrough Designation for Mantle Cell Lymphoma


The FDA has granted the investigational BTK inhibitor zanubrutinib a breakthrough therapy designation for the treatment of adult patients with mantle cell lymphoma who have previously received at least 1 prior therapy.

Jane Huang, MD

The FDA has granted the investigational BTK inhibitor zanubrutinib (BGB-3111) a breakthrough therapy designation for the treatment of adult patients with mantle cell lymphoma (MCL) who have previously received at least 1 prior therapy, according to BeiGene, the company manufacturing the agent.1

“We are very excited to receive the breakthrough therapy designation from the FDA,” said Jane Huang, MD, chief medical officer, Hematology, of BeiGene, in a press release. “Zanubrutinib has been designed to maximize BTK occupancy and minimize off-target effects. We believe that the breakthrough therapy designation underscores the potential of zanubrutinib as a meaningful treatment for patients with MCL who have received at least 1 prior therapy. More than 1300 patients worldwide have been treated with zanubrutinib, and it’s being developed in a broad clinical program that currently includes 7 phase III or pivotal trials conducted globally or in China.”

The designation is based on reported activity with zanubrutinib in MCL, which includes phase II data that were presented at the 2018 ASH Annual Meeting (NCT03206970). Results of a single-arm, open-label, multicenter Chinese trial demonstrated that the overall response rate (ORR) with the next-generation small molecule BTK inhibitor was 83.5%.2 Additionally, responses appeared to be durable. These data were also incorporated into a new drug application (NDA) in China for zanubrutinib in patients with relapsed/refractory MCL.

The 1-year progression-free survival (PFS) rate in patients who received zanubrutinib was 90% and the 2-year PFS was 82%. At a median follow-up of 35.9 weeks, the median PFS had not yet been reached.

In the study, 86 adult patients with MCL who had received 1 to 4 prior treatment regimens were treated with 160 mg twice daily of zanubrutinib until disease progression or unacceptable toxicity. The primary endpoint was ORR by an independent review committee using PET-based imaging, according to the Lugano classification.

Regarding patient characteristics, the median patient age was 60.5 years, and the disease status was refractory in 52.3% and relapsed in 47.7%. Seventy-eight patients (90.7%) had stage III/IV disease and 72 (83.7%) were intermediate or high risk by the Mantle Cell Lymphoma International Prognostic Index Combined Biologic Index. Moreover, 7 patients (8.1%) had bulky disease >10 cm and 37 (43%) had disease >5 cm, and 12 patients (14%) had the blastoid variant of MCL. The median number of prior therapies was 2.

At the time of the data cutoff on March 27, 2018, 21 patients were off treatment, 13 of which were due to progressive disease and 6 because of adverse events (AEs). One patient discontinued treatment at the investigator’s discretion 1 month after starting zanubrutinib and 1 patient who achieved a complete response (CR) withdrew consent.

Eighty-five patients were evaluable for efficacy, and of the 71 patients with an ORR, the best ORR was a CR in 50 patients (58.8%), a partial response (PR) in 21 (24.7%), and stable disease in 2 patients (2.4%). Five patients discontinued treatment prior to the first disease assessment and 1 had no evidence of measurable disease at baseline.

The benefit with zanubrutinib was found to be consistent across subgroups, including patients with and without the blastoid variant form of MCL, those with and without bulky disease, and those who had <3 or 3 or more prior lines of therapy. The ORR among patients with the blastoid variant subtype was 75%.

A total of 28 patients (32.6%) had a grade 3 treatment-emergent adverse event (TEAE) regardless of causality; 6 patients (7.0%) discontinued zanubrutinib because of a TEAE. There were 4 deaths; 1 in the setting of infection, 1 due to pneumonia, 1 due to cerebral hemorrhage, and 1 because of a traffic accident. TEAEs of special interest included diarrhea (10.5%), hypertension (8.1%), and petechiae/purpura/contusion (4.7%).

The most frequent TEAEs included decreased neutrophil count (31.4%), upper respiratory tract infection (29.1%), rash (29.1%), decreased platelet count (22.1%), and decreased white blood cell (WBC) count (17.4%). Grade ≥3 TEAEs reported in at least 2 patients included decreased neutrophil count (11.6%), lung infection (5.8%), anemia (4.7%), and decreased WBC count (3.5%).

With respect to the performance of BTK inhibitors as a whole, investigators noted that distinctive AEs were observed in this trial: diarrhea was observed in 9 patients (10.5%), which were all grade 1/2 events. A major hemorrhage was observed in 1 patient (1.2%) with a blastoid variant of MCL who had intra-parenchymal central nervous system bleeding.

Updated findings of an open-label trial of single-agent zanubrutinib in patients with numerous B-cell malignancies, including MCL, were also presented at the 2018 ASH Annual Meeting.3 In the study, as of July 24, 2018, 48 patients with MCL with treatment-naïve (n = 9) or relapsed/refractory disease (n = 39) had been enrolled with a median follow-up time of 12.7 months. A total 45 patients, including 6 with treatment-naïve MCL and 39 with relapsed/refractory MCL were evaluable for efficacy; 26 patients remained on study treatment at the time of the data cutoff.

By investigator assessment, the ORR was 88.9%; the CR rate was 26.7% and the PR rate was 62.2%. Additionally, the median duration of response was 16.2 months and the median PFS for relapsed/refractory patients was 18.0 months.

The safety profile was zanubrutinib was overall consistent with prior studies of the agent in patients with B-cell malignancies; the majority of AEs were grade 1/2 in severity. The most frequent AEs of any attribution were petechia/purpura/contusion (33.3%), diarrhea (33.3%), upper respiratory tract infection (29.2%), fatigue (25.0%), and constipation (18.8%). Grade 3/5 AEs occurred in 56.3% of patients; those reported in >3 patients included anemia (8.3%), major hemorrhage (6.3%), cellulitis (6.3%), myalgia (6.3%), neutropenia (6.3%), pneumonia (6.3%), and thrombocytopenia (6.3%).

A total 18.8% of patients discontinued treatment with zanubrutinib due to AEs; 4 deaths occurred due to AEs but were unrelated to zanubrutinib.

Zanubrutinib is currently being evaluated in clinical trials as a single agent and in combination with other therapies to treat other hematologic malignancies, including Waldenström macroglobulinemia, chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), and follicular lymphoma.

Zanubrutinib was previously granted a fast track designation by the FDA for the treatment of patients with WM. In China, new drug applications for zanubrutinib in relapsed/refractory MCL and relapsed/refractory CLL/SLL have been accepted by the China National Medical Products Administration and have been granted priority review.


  1. BeiGene Receives U.S. FDA Breakthrough Therapy Designation for Zanubrutinib in Mantle Cell Lymphoma. BeiGene. Published January 14, 2019." . Accessed January 14, 2019.
  2. Song Y, Zhou K, Zou D, et al. Safety and activity of the investigational Bruton tyrosine kinase inhibitor zanubrutinib (BGB-3111) in patients with mantle cell lymphoma from a phase 2 trial. In: Proceedings from the 2018 ASH Annual Meeting; December 1-4, 2018; San Diego, CA. Abstract 148.
  3. Tam CS, Wang M, Simpson D, et al. Updated Safety and Activity of the Investigational Bruton Tyrosine Kinase Inhibitor Zanubrutinib (BGB-3111) in Patients with Mantle Cell Lymphoma. In: Proceedings from the 2018 ASH Annual Meeting; December 1-4, 2018; San Diego, CA. Abstract 1592.
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