Zanubrutinib Gains Accelerated Approval in R/R Marginal Zone Lymphoma

Zanubrutinib, a second-generation selective inhibitor of Bruton's tyrosine kinase (BTK), received accelerated approval today for adult patients with relapsed or refractory (R/R) marginal zone lymphoma (MZL) who have received at least 1 anti-CD20–based treatment.

This is the third approval for zanubrutinib, which is sold as Brukinsa by BeiGene.

The FDA’s action is based on overall response rate (ORR), as seen in updated phase 2 results for the MAGNOLIA trial, which were presented in June during the virtual meeting of the European Hematology Association (EHA). Continued approval will depend on zanubrutinib’s performance in a phase 3 trial.

BeiGene officials announced the approval today in a statement.

“We are excited about the FDA’s approval for [zanubrutinib] in patients with previously treated marginal zone lymphoma, a significant milestone that was made possible by the diligent BeiGene team, the dedicated investigators, and the participating patients and their families,” said Jane Huang, MD, chief medical officer for hematology at BeiGene.

“The MAGNOLIA trial results provided additional evidence that the selective design of Brukinsa can be translated to improved treatment outcomes for these patients.”

Stephen Opat, FRACP, FRCPA, MBBS, director of Clinical Hematology at Monash University and lead principal investigator for MAGNOLIA, explained that BTK plays a critical role in B-cell receptor signaling, which drives the development of MZL. In the trial, zanubrutinib was well tolerated, he said, with a low rate of discontinuation due to adverse events (AEs).

Updated MAGNOLIA Results Presented During EHA

MAGNOLIA is a single-arm, multicenter phase 2 study of adults with relapsed/refractory MZL who were treated with at least 1 prior line of therapy, including at least 1 CD20-directed regimen.

Patients were treated with 160 mg of zanubrutinib twice daily until disease progression or unacceptable toxicity. Use of long-term antiplatelet and anticoagulation agents was permitted. The primary end point was an ORR as determined by an independent review committee. Secondary end points include ORR by investigator assessment, duration of response (DOR), progression-free survival (PFS), and safety.

Results through August 2020 presented at the American Society of Hematology annual meeting in December 2020 showed that patients taking zanubrutinib tolerated it better than earlier-generation BTK inhibitors, allowing for longer courses of treatment. The new round of results presented at EHA, which include data through January 11, 2021, included 68 patients enrolled and treated, with a median age of 70, including 28% who were at least 75 years old.

MZL subtypes seen in the study included 38% of patients with extranodal MZL, 38% nodal, 18% splenic, and 6% indeterminate MZL. Patients in the study had received a median of 2 prior therapies, and 32% had disease that was refractory to their last therapy.

Results presented at EHA showed:

• Patients were exposed to the drug for a median of 59.1 (range, 3.7-84.1) weeks; 66 patients could be evaluated for the drug’s efficacy
• At a median follow-up of 15.5 (range, 1.6-21.7) months, investigator-assessed ORR, including complete response (CR) and partial response (PR), was 74%; this included 24 CRs, 50% PRs, and 17% with stable disease
• Responses were observed in all subtypes, with an ORR of 68% in extranodal, 84% in nodal, 75% in splenic, and 50% in indeterminate subtypes; he CR rate was 36% for extranodal MZL, 20% for nodal, 8% for splenic, and 25% for indeterminate subtype
• Median DOR and PFS were not reached; at 15 months, PFS was 68% and the 12-month DOR was 81%.
  
  

Adverse events. Of the 66 patients who could be evaluated, 28 (41%) stopped treatments, including 20 due to disease progression, 1 who withdrew consent, and 3 who required prohibited medications. Four stopped treatment due to AEs, including 2 who had COVID-19 pneumonia, 1 patient who had a heart attack, and 1 with due to pyrexia attributed to disease transformation.

The most common (≥10%) treatment-emergent AEs reported were diarrhea (22%), bruising (21%), constipation (15%), pyrexia (13%), abdominal pain (12%), upper respiratory tract infection (12%), back pain (10%), and nausea (10%). Most AEs were grade 1 or 2.