FDA Approves Zanubrutinib for Relapsed/Refractory MCL


The FDA has granted an accelerated approval to zanubrutinib capsules for the treatment of adult patients with mantle cell lymphoma who have received ≥1 prior therapy.

The FDA has granted an accelerated approval to zanubrutinib (Brukinsa) capsules for the treatment of adult patients with mantle cell lymphoma (MCL) who have received ≥1 prior therapy.1

The approval, which occurred more than 3 months ahead of the FDA's action date, is based on findings from two single-arm studies, in which zanubrutinib elicited an overall response rate (ORR) of 84% in patients with MCL who received ≥1 prior treatment.2

"Mantle cell lymphoma usually responds well to initial treatment, but eventually returns or stops responding, and the cancer cells continue to grow. This is a life-threatening condition," Richard Pazdur, MD, director of the FDA's Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA's Center for Drug Evaluation and Research, stated in a press release. "Clinical trials showed that 84% of patients saw tumor shrinkage with this therapy. For patients whose disease relapses or becomes refractory, secondary therapies may be successful in providing another remission, and today's approval will provide patients with another treatment option."

Zanubrutinib is a small molecule BTK inhibitor that has been investigated as a single agent and in combination with other agents to treat patients with a wide range of B-cell malignancies. Continued approval for zanubrutinib in this indication may be contingent upon the findings of a confirmatory trial.

The recommended dose of oral zanubrutinib is 320 mg, taken either 160 mg twice daily or 320 mg once daily, with or without food. The dose can be adjusted for adverse events (AEs), and can be reduced for patients with severe hepatic impairment and certain drug interactions, stated BeiGene, the developer of the BTK inhibitor, in a press release.

In the single-arm, open-label, multicenter, phase II Chinese BGB-3111-206 (NCT03206970) trial, 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.3 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 (range, 34-75), 78% of patients were male, 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 58%, 29%, and 13% were low, intermediate, and high risk, respectively, 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; 71% of patients had extranodal disease. The median number of prior therapies was 2; the most common prior regimens included CHOP-based (91%) and rituximab (Rituxan)-based (74%).

Updated results showed that the ORR was 84% (95% CI, 74%-91%), which included a 59% complete response (CR) rate and a 24% partial response (PR) rate at a median follow-up of 18.4 months. The median duration of response (DOR) was 19.5 months (95% CI, 16.6—not estimated [NE]).

Secondly, in the international, phase I/ll BGB-3111-AU-003 (NCT02343120) trial, 32 previously treated patients with MCL were treated with zanubrutinib at the 160 mg twice daily or 320 mg daily dose.4 The median age was 70 years (range, 42-86), and 38% of patients were ≥75 years old. Additionally, 69% of patients were male and 78% were Caucasian. The MIPI score was low in 28%, intermediate in 41%, and high risk in 31% of patients.

Updated results showed that the ORR was 84% (95% CI, 67%-95%), which included a 22% CR rate and a 62% PR rate. At a median follow-up of 18.8 months, the median DOR was 18.5 months (95% CI, 12.6—NE).

Regarding safety, the most common adverse events (AEs; >10%) with zanubrutinib were decreased neutrophil count, decreased platelet count, upper respiratory tract infection, decreased white blood cell count, decreased hemoglobin, rash, bruising, diarrhea, cough, musculoskeletal pain, pneumonia, urinary tract infection, hematuria, fatigue, constipation, and hemorrhage. The most frequent serious AEs were pneumonia (11%) and hemorrhage (5%). BeiGene stated in the press release that of the 118 patients with MCL who were treated with zanubrutinib, 8 (7%) patients discontinued treatment due to AEs across the trials. The most frequent AE that led to treatment discontinuation was pneumonia (3.4%), and 1 (0.8%) patient experienced an AE, hepatitis B, that led to dose reduction.

"BTK inhibition is an established mode of treatment for patients with MCL, but many patients treated with previously approved BTK inhibitors do not fully respond to BTK therapy or are forced to discontinue treatment early due to side effects," study investigator Luhua (Michael) Wang, MD, professor, Department of Lymphoma and Myeloma, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, stated in the press release. "Today we have a new option for our adult patients who have received one prior systemic or targeted therapy and are living with MCL, an aggressive blood cancer that's often diagnosed at a more advanced stage."


  1. FDA approves therapy to treat patients with relapsed and refractory mantle cell lymphoma supported by clinical trial results showing high response rate of tumor shrinkage. FDA. Published November 14, 2019. https://bit.ly/375KElo. Accessed November 14, 2019.
  2. U.S. FDA Grants BeiGene’s BRUKINSATM (zanubrutinib) Accelerated Approval to Treat Adult Patients with Mantle Cell Lymphoma Who Received at Least One Prior Therapy. BeiGene. Published November 14, 2019. https://bit.ly/2NLovB7. Accessed November 14, 2019.
  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. 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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