FDA Grants Priority Review to Zanubrutinib for Previously Treated Mantle Cell Lymphoma

The FDA has granted a New Drug Application for zanubrutinib a priority review for the treatment of patients with mantle cell lymphoma who have previously received at least 1 prior treatment.

Jane Huang, MD

The FDA has granted a priority review to a New Drug Application for zanubrutinib for the treatment of patients with mantle cell lymphoma (MCL) who have previously received at least 1 prior treatment.1

The FDA has set a target action date of February 27, 2020 for a decision on the approval.

“Zanubrutinib, a potent and selective BTK inhibitor designed to maximize BTK occupancy and minimize off-target effects, has shown promise as a potential treatment for a number of B-cell malignancies,” said Jane Huang, MD, chief medical officer of hematology at BeiGene, the company developing the Bruton tyrosine kinase inhibitor, in a press release. “We are proud to have submitted our first NDA in the United States, which has now been accepted and designated for Priority Review by the FDA for the treatment of patients with relapsed/refractory mantle cell lymphoma, an aggressive form of lymphoma. We are conducting a broad global clinical development program for zanubrutinib that currently consists of 8 phase III or potentially registration-enabling trials, including 2 head-to-head comparative trials, with approximately 1500 patients treated across all programs.”

Data supporting the NDA includes findings from a global phase I/II trial of zanubrutinib in patients with B-cell lymphomas, data from a multicenter phase II trial of zanubrutinib in patients with relapsed or refractory MCL that was conducted in China, and safety data from 641 patients across 5 clinical trials.

Findings from the multicenter Chinese phase II trial were presented at the 2018 ASH Annual Meeting demonstrating a 2-year progression-free survival (PFS) rate of 82%.2

The trial enrolled 86 adult patients with MCL who had previously received 1 to 4 prior treatments. Patients were given 160 mg zanubrutinib twice daily until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) by an independent review committee using PET-based imaging, according to the Lugano classification.

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.

Among the 85 patients evaluable for efficacy, the ORR was 83.5% with a complete response rate of 58.8% as the best response and partial responses in 24.7%. Patients with blastoid variant had an ORR of 75%.

The median PFS was not met as of the data cutoff after a median follow-up of 35.9 weeks. As of data cutoff, 21 patients had discontinued treatment, 13 due to progressive disease and 6 due to adverse events (AEs).

The most frequent treatment-emergent AEs (TEAEs) were 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%).

There were 4 deaths in the trial; 1 due to 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%).

Findings from the phase I/II trial of zanubrutinib in patients with B-cell malignancies were also presented at the ASH meeting.3

The study included 48 patients with MCL, 9 of whom were treatment-naïve and 39 who had relapsed or refractory disease; 45 of these patients were evaluable for efficacy. At data cutoff, 26 patients were still on treatment.

The ORR by investigator assessment was 88.9% with complete responses in 26.7% and partial responses in 62.2%. The median PFS was 18.0 months in the relapsed/refractory patients and the median duration of response was 16.2 months.

The phase I/II trial showed a similar safety profile across patients with B-cell malignancies that was consistent with prior studies. Most of the 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 they were considered unrelated to zanubrutinib.

The FDA had also granted a breakthrough drug designation to the BTK inhibitor earlier in the year in the same setting.


  1. BeiGene Announces U.S. FDA Acceptance and Grant of Priority Review for its New Drug Application of Zanubrutinib in Patients with Relapsed/Refractory Mantle Cell Lymphoma [press release]. Cambridge, MA and Beijing, China: BeiGene, Ltd; August 21, 2019. https://bit.ly/2z9Liyz. Accessed August 22, 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.