FDA Grants Priority Review to Zanubrutinib Regimen in Frontline MCL

The FDA has accepted and granted priority review to the supplemental new drug application (sNDA) for zanubrutinib (Brukinsa) in combination with rituximab (Rituxan) for the treatment of adult patients with previously untreated mantle cell lymphoma (MCL), according to a news release from the developer, BeOne Medicines.¹ If approved, zanubrutinib plus rituximab would be the first and only chemotherapy-free, Bruton tyrosine kinase (BTK) inhibitor–based regimen for adults with previously untreated MCL.

What did the FDA action entail?

The FDA granted priority review to the sNDA evaluating the chemotherapy-free regimen of zanubrutinib plus rituximab in the first-line MCL setting. The application is supported by data from the pivotal phase 3 MANGROVE trial (NCT04002297), in which the regimen significantly reduced the risk of disease progression or death compared with standard chemoimmunotherapy. A supplemental application for zanubrutinib in MCL has also been submitted to the European Medicines Agency and accepted by the Center for Drug Evaluation of China’s National Medical Products Administration.

What MANGROVE data supported the application?

In the MANGROVE trial, zanubrutinib plus rituximab reduced the risk of progression or death by 43% vs bendamustine (Treanda) plus rituximab (BR), meeting the trial’s primary end point of progression-free survival (PFS) as assessed by an independent review committee (HR, 0.57; 95% CI, 0.43-0.76; P <.0001). The safety profile of zanubrutinib plus rituximab was consistent with the known safety profiles of both agents, with no new safety signals identified. Full results from MANGROVE are scheduled to be presented at the 2026 American Society of Hematology (ASH) Annual Meeting.

“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,” said Amit Agarwal, MD, PhD, chief medical officer of hematology at BeOne Medicines, in a news release.¹ “[Zanubrutinib’s] ability to drive deeper, more powerful responses is what makes a chemotherapy-free approach now possible. We look forward to working closely with the FDA to make our foundational BTK inhibitor available to patients as quickly as possible.”

What was the MANGROVE trial design?

MANGROVE is a global, randomized, open-label phase 3 trial evaluating zanubrutinib plus rituximab vs BR in adult patients with previously untreated MCL. It is the first phase 3 trial to evaluate a chemotherapy-free, BTK inhibitor–based regimen against standard chemoimmunotherapy with BR in the frontline setting.

The trial enrolled 510 patients across 157 active sites worldwide. In the experimental arm, patients received zanubrutinib at 160 mg orally twice daily plus rituximab during the initial treatment period, followed by zanubrutinib monotherapy until disease progression or intolerance. In the control arm, patients received BR for 6 cycles.

The primary end point was PFS by independent central review.² Secondary end points included overall survival, investigator-assessed PFS, overall response rate, duration of response, patient-reported outcomes, and safety.

What is the current context for zanubrutinib?

Zanubrutinib is a next-generation BTK inhibitor designed to deliver complete and sustained BTK inhibition. It is currently approved in the US for adult patients with relapsed or refractory MCL, as well as for chronic lymphocytic leukemia/small lymphocytic lymphoma, Waldenström macroglobulinemia, relapsed or refractory marginal zone lymphoma, and relapsed or refractory follicular lymphoma. According to the developers, the agent has been used to treat more than 310,000 patients worldwide across its approved indications.

References

1. US FDA grants priority review to BeOne Medicines’ Brukinsa combination in first-line mantle cell lymphoma. News release. BeOne Medicines Ltd. November 4, 2026. Accessed November 5, 2026. https://tinyurl.com/3xd3uzjd
2. 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 (MANGROVE). ClinicalTrials.gov. Updated September 30, 2026. Accessed November 5, 2026. https://tinyurl.com/48c2pck5