FDA Grants Zanubrutinib Priority Review for Relapsed/Refractory Mantle Cell Lymphoma


The FDA has granted a priority review designation to a new drug application for zanubrutinib for the treatment of patients with mantle cell lymphoma who have received ≥1 prior therapy.

The FDA has granted a priority review designation to a new drug application (NDA) for zanubrutinib (BGB-3111) for the treatment of patients with mantle cell lymphoma (MCL) who have received ≥1 prior therapy.1

The application is based on data from an international phase I/II trial (NCT02343120) in patients with B-cell lymphomas, a group of patients with relapsed/refractory MCL in China in a phase II trial (NCT03206970), pooled safety data from 5 clinical trials, and nonclinical data, stated BeiGene, the developer of the investigational BTK inhibitor.

Under the Prescription Drug User Fee Act, the FDA must make a decision on the NDA by February 27, 2020.

"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," Jane Huang, MD, chief medical officer, Hematology, at BeiGene, stated 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."

Zanubrutinib is an investigational small molecule BTK inhibitor that is currently being investigated as a single agent and in combination with other agents to treat patients with a wide range of B-cell malignancies.

In the phase I/II trial, 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, as of July 24, 2018. Forty-five 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 objective response rate (ORR) with zanubrutinib was 88.9%; the complete response (CR) rate was 26.7% and the partial response (PR) rate was 62.2%.2 Additionally, the median duration of response (DOR) was 16.2 months and the median progression-free survival (PFS) was 18.0 months.

The safety profile was zanubrutinib was consistent with prior studies of the agent in patients with B-cell malignancies; the majority of adverse events (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.

The single-arm, open-label, multicenter, phase II Chinese trial, preliminary results of which were presented at the 2018 ASH Annual Meeting, comprised 86 adult patients with MCL who had received 1 to 4 prior treatment regimens who 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 age was 60.5 years, and the disease status was refractory in 52.3% and relapsed in 47.7% of patients. 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 AEs. One patient discontinued treatment at the investigator’s discretion 1 month after starting zanubrutinib and 1 patient who achieved a CR withdrew consent.

Of the 85 patients who were evaluable for efficacy, results demonstrated that the ORR with the zanubrutinib was 83.5%, and responses appeared to be durable.3 The 1-year 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.

The benefit 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%.

Updated findings, which were presented at the 15th International Conference on Malignant Lymphoma, showed that at a median 13.9 months of follow-up, the median PFS was 16.7 months and the median DOR was 14.0 months (range, 2.32-14.0).4 The updated ORR was 84.7% (95% CI, 75.3%-91.6%), which comprised a 76.5% CR rate and a 8.2% PR rate. One patient had stable disease.

The updated safety data showed that treatment-emergent AEs (TEAEs) were observed in 96.5% of patients, with grade ≥3 AEs noted in 39.5%. Treatment was discontinued in 29 (33.7%) patients due to disease progression and AEs, which were mainly decreased white blood cell count, upper respiratory infection, decreased platelet county, diarrhea, and hypokalemia.

"We are conducting a broad global clinical development program for zanubrutinib that currently consists of eight phase 3 or potentially registration-enabling trials, including two head-to-head comparative trials, with approximately 1500 patients treated across all programs," Huang added in the press release.


  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. BeiGene, Ltd. Published August 21, 2019. https://bit.ly/2z9Liyz. Accessed August 21, 2019.
  2. 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.
  3. 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.
  4. Song Y, Zhou K, Zou D et al. Zanubrutinib in Patients with Relapsed/Refractory Mantle Cell Lymphoma. Presented at: 15th International Conference on Malignant Lymphoma Palazzo dei Congressi; June 18-22, 2019; Lugano, Switzerland.
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