FDA Accepts sNDA for Zanubrutinib for MZL

The FDA has accepted a supplemental new drug application (sNDA) for zanubrutinib (Brukinsa) for the treatment of adult patients with marginal zone lymphoma (MZL) who have recived 1 prior anti-CD20-based therapy. The agent was also granted priority review, with a Prescription Drug User Fee Act (PDUFA) target action date of September 19, 2021, according to a press release by BeiGene, Ltd.

Zanubrutinib is a Bruton’s tyrosine kinase (BTK) inhibitor that is being developed to treat multiple B-cell malignancies. Zanubrutinib is meant to optimize bioavailability, half-life, and selectivity. Currently, it holds indications in mantle cell lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, and Waldenströms macroglobulinemia. 

The sNBA is mainly based on the phase 2 MAGNOLIA Trial (NCT03846427) with supportive data from a global phase 1/2 trial (NCT02343120) of the agent in B-cell malignancies. A pooled analysis from 7 separate trials totaling 847 patients was also included in the submission.

The MAGNOLIA study had an actual enrollment of 68 patients. The primary outcome of the study was overall response rate (ORR) up to 3 years. Secondary outcomes included progression-free survival (PFS), time to response (TTR), participant-reported outcomes (PROs), and occurrence and severity of treatment-emergent adverse events (AEs).

The study was composed of a single arm. Patients received 160mg of zanubrutinib twice a day. 

In order to participate, patients must be at least 18 years old or older, have histologically confirmed MZL, have previously received 1 or more lines of therapy including at least one CD20-direct regimen, a current need for systemic MZL therapy, measurable disease, an ECOG score of 0-2, a life expectancy of 6 months or more, and adequate organ and bone marrow function.

The median patient age was 70 years old (range, 37-95). The median number of prior therapies was 2 (range, 1-6). At the median follow-up of 6.8 months, the ORR was 60% (CR 15%, PR 45%, stable disease 27%) and was observed in all MZL subtypes, 58% in extranodal, 64% in nodal, 58% in splenic, and 50% in unknown subtypes. Median DOR and PFS were not reached. Of the initial 68 patients, 21 had discontinued study treatment. Treatment discontinuation was mainly due to disease progression (23.5%), 1 withdrew consent, and 2 patients required prohibited mediation. An additional 2 withdrew due to AEs, 1 from pyrexia and 1 from myocardial infraction. The most common AEs were diarrhea (19.1%), bruising (17.6%), and constipation (13.2%).2

The phase 1/2 supportive data enrolled 397 participants. The primary outcome of the study was the number of participants with AEs. Secondary outcomes included area under the plasma concentration-time curve from o to the time of the last measurable concentration, maximum plasma concertation, time to reach maximum plasma concentration, terminal elimination, BTK inhibition activity, and tumor response.

During the single-arm study, dose-levels were escalated following a modified 3+3 dose escalation scheme.

In order to participate, patients must have been 18 years old or older, have a confirmed B-lymphoid malignancy, required treatment, have relapsed or refractory disease, and an ECOG score of 0-2. Patients with prior BTK inhibitor treatment or allogeneic stem cell transplantation were not eligible to participate.

“This is our first regulatory submission in MZL, a serious disease diagnosed in more than 2,000 patients every year in the U.S., with no clear standard of care. In clinical trials, BRUKINSA has demonstrated promising efficacy and tolerability in MZL and presents a potential new option for MZL patients,” said Jane Huang, M.D., Chief Medical Officer, Hematology at BeiGene. “We look forward to continuing our communications with the FDA in the coming months as we work on advancing the broad global development program for our potentially best-in-class BTK inhibitor.”

_REFERENCES:

_{1.BeiGene announces U.S. FDA acceptance and priority review of supplemental new drug application for BRUKINSA® (Zanubrutinib) in marginal zone lymphoma. News release. BeiGene. May 19, 2021. Accessed May 19, 2021. https://bit.ly/3hDIj92.}

_{2.Opat S, Tedeschi A, Linton K, et al. Efficacy and safety of zanubrutinib in patients with relapsed/Rrfractory marginal zone lymphoma: initial results of the MAGNOLIA (BGB-3111-214) trial. Blood 2020; 136 (Supplement 1): 28–30. doi: https://doi.org/10.1182/blood-2020-134611}