FDA Grants Priority Review to Zanubrutinib Plus Rituximab for Previously Untreated MCL

The FDA has granted priority review to a supplemental new drug application (sNDA) for zanubrutinib (Brukinsa) plus rituximab (Rituxan) for the treatment of adult patients with previously untreated mantle cell lymphoma (MCL).¹ Notably, the priority review designation shortens the agency's review timeline and a Prescription Drug User Fee Act target action date was not disclosed.

The sNDA is supported by data from the phase 3 MANGROVE trial (NCT04002297), in which zanubrutinib plus rituximab reduced the risk of progression or death by 43% vs bendamustine (Treanda) plus rituximab (BR).^1,2 At a prespecified interim analysis, the regimen met the primary end point of progression-free survival (PFS) assessed by an independent review committee (IRC), (HR, 0.57; 95% CI, 0.43-0.76; P < .0001).² Overall survival (OS), a key secondary end point, was immature at the time of the analysis, and a trend in favor of zanubrutinib plus rituximab was observed.

“In newly diagnosed MCL, chemoimmunotherapy remains a mainstay of frontline treatment despite the toxicity burden it carries. The FDA’s acceptance of our application brings us closer to a chemotherapy-free, zanubrutinib-based option that significantly reduces the risk of disease progression or death,” Amit Agarwal, MD, PhD, chief medical officer of hematology at BeOne Medicines, said in a news release.¹ "Zanubrutinib’s ability to drive deeper, more powerful responses is what makes a chemotherapy-free approach now possible."

How was the MANGROVE trial designed?

The global, randomized, and open-label phase 3 trial enrolled 510 patients with previously untreated and histlogically confirmedMCL.^2,3 Eligible patients needed to be at least 70 years of age, or at least 60 and younger than 70 years of age with comorbidities precluding autologous stem cell transplantation.³ Patients were also required to have measurable disease by CT or MRI, no prior systemic therapy for MCL, and an ECOG performance status of 0 to 2.

Key exclusion criteria included known central nervous system involvement by lymphoma, clinically significant cardiovascular disease, a history of a severe bleeding disorder, and a need for ongoing treatment with a strong CYP3A inhibitor or inducer.³

Patients were randomly assigned to receive zanubrutinib at 160 mg orally twice daily plus intravenous rituximab at 375 mg/m² during the initial treatment period, followed by zanubrutinib monotherapy until IRC-confirmed disease progression/intolerance or 6 cycles of BR.^1,3

IRC-assessed PFS served as the primary end point. Secondary end points include investigator-assessed PFS, OS, overall response rate, duration of response, time to response, complete response rate, and safety.³

What is the safety profile of zanubrutinib?

The safety profile of zanubrutinib plus rituximab in MANGROVE was consistent with the known profiles of each agent, and no new safety signals were identified.^1,2

In a pooled safety population of 1729 patients who received zanubrutinib, the most common adverse effects that occurred in at least 30% of patients were decreased neutrophil count (51%), decreased platelet count (41%), upper respiratory tract infection (38%), hemorrhage (32%), and musculoskeletal pain (31%).²

What are the next steps for zanubrutinib in MCL?

Full efficacy and safety results from MANGROVE are scheduled to be presented during the Plenary Scientific Session of the ASH Annual Meeting on December 13, 2026.¹ Additionally, OS will be formally tested at the final analysis.²

Applications for zanubrutinib plus rituximab in previously untreated MCL have also been submitted to the European Medicines Agency and accepted by China's Center for Drug Evaluation of the National Medical Products Administration.¹

References

1. U.S. FDA grants priority review to BeOne Medicines' Brukinsa combination in first-line mantle cell lymphoma. News release. BeOne Medicines. November 3, 2026. Accessed November 4, 2026. https://www.businesswire.com/news/home/20261103605806/en/U.S.-FDA-Grants-Priority-Review-to-BeOne-Medicines-BRUKINSA-Combination-in-First-Line-Mantle-Cell-Lymphoma
2. BeOne Medicines announces positive phase 3 results for Brukinsa in frontline mantle cell lymphoma. News release. BeOne Medicines. June 30, 2026. Accessed November 4, 2026. https://ir.beonemedicines.com/news/beone-medicines-announces-positive-phase-3-results-for-brukinsa-in-frontline-mantle-cell-lymphoma/44597eac-a44b-451f-a021-48d345cdb85e
3. A study to investigate the efficacy of zanubrutinib plus rituximab compared with bendamustine plus rituximab in adults with previously untreated mantle cell lymphoma who are ineligible for stem cell transplantation. ClinicalTrials.gov. Updated September 30, 2026. Accessed November 4, 2026. https://clinicaltrials.gov/study/NCT04002297