The FDA has granted priority review to a supplemental new drug application (sNDA) for zanubrutinib (Brukinsa) plus rituximab (Rituxan) for adults with previously untreated mantle cell lymphoma (MCL).¹ If approved, the combination would offer a chemotherapy-free, Bruton tyrosine kinase (BTK) inhibitor–based treatment option in the frontline setting.

The FDA's priority review designation shortens the target review timeline for the application. The application is supported by findings from the phase 3 MANGROVE trial, which demonstrated a 43% reduction in the risk of disease progression or death with zanubrutinib plus rituximab compared with bendamustine plus rituximab. The trial met its primary end point of progression-free survival (PFS), as assessed by an independent review committee (IRC; HR, 0.57; 95% CI, 0.43-0.76; P < .0001). The safety profile of the zanubrutinib combination was consistent with the established safety profiles of the individual agents, with no new safety signals identified.

“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, hematology, at BeOne Medicines, stated in a news release. “[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.”

MANGROVE Trial Background

MANGROVE (NCT04002297) is a global, randomized, open-label phase 3 study comparing zanubrutinib plus rituximab with bendamustine plus rituximab in adults with previously untreated MCL who were ineligible for stem cell transplantation.² The trial enrolled 510 patients across 157 active sites worldwide.

Patients in the experimental arm received zanubrutinib 160 mg orally twice daily in combination with rituximab during the initial treatment period, followed by zanubrutinib monotherapy until disease progression or intolerance. Patients in the control arm received bendamustine plus rituximab for 6 cycles.

The primary end point was PFS assessed by IRC. Secondary end points included investigator-assessed PFS, overall response rate, duration of response, overall survival (OS), patient-reported outcomes, and safety. OS was designated as a key secondary end point.

A Potential Chemotherapy-Free Option

Zanubrutinib is currently FDA-approved for adults with relapsed or refractory MCL, as well as several other B-cell malignancies. The newly submitted application seeks to expand its use as combination therapy into the previously untreated MCL setting.

The potential addition of zanubrutinib plus rituximab to frontline treatment would provide an alternative to chemotherapy-based regimens. However, additional data will be important for understanding the magnitude of clinical benefit, including response rates, duration of response, and OS outcomes. Presentation of the complete MANGROVE findings at the 2026 ASH Annual Meeting is expected to provide a more detailed assessment of the regimen's efficacy and safety. These data, along with the FDA's regulatory review, will help determine the role of zanubrutinib plus rituximab in the frontline treatment landscape for patients with MCL.

FAQs

What did the FDA announce for zanubrutinib plus rituximab in mantle cell lymphoma?

The FDA granted priority review to a supplemental new drug application (sNDA) for zanubrutinib (Brukinsa) plus rituximab (Rituxan) in adults with previously untreated MCL. If approved, the combination would be a chemotherapy-free, Bruton tyrosine kinase (BTK) inhibitor–based option in the frontline setting.¹

What does priority review mean?

A priority review designation means the FDA’s goal is to act on an application within 6 months, compared with 10 months under standard review.³ It shortens the review timeline but does not change the standard for approval.

Is zanubrutinib plus rituximab approved for first-line MCL yet?

No. The application is under FDA review, and approval has not been granted.¹

What data support the application?

The application is supported by the phase 3 MANGROVE trial. Zanubrutinib plus rituximab reduced the risk of disease progression or death by 43% compared with bendamustine plus rituximab. The trial met its primary end point of independent review committee–assessed progression-free survival (HR, 0.57; 95% CI, 0.43-0.76; P < .0001).

Who was enrolled in the MANGROVE trial, and how was treatment given?

MANGROVE (NCT04002297) is a global, randomized, open-label phase 3 study of 510 adults with previously untreated MCL who were ineligible for stem cell transplantation. Patients in the experimental arm received zanubrutinib 160 mg orally twice daily plus rituximab, followed by zanubrutinib monotherapy until disease progression or intolerance. The control arm received bendamustine plus rituximab for 6 cycles.²

Was the safety profile of zanubrutinib plus rituximab different from known profiles?

No. The safety profile was consistent with the established profiles of the individual agents, and no new safety signals were identified.¹

What does “chemotherapy-free” mean for patients with MCL?

It means treatment with a targeted BTK inhibitor plus the antibody rituximab instead of a chemoimmunotherapy regimen. Chemoimmunotherapy remains a mainstay of frontline MCL treatment despite its toxicity burden.

What is a BTK inhibitor, and how does it work in MCL?

BTK inhibitors interfere with the B-cell receptor signaling pathway. When that pathway is overactive, B cells can multiply uncontrollably and lead to lymphoma.⁴

What is mantle cell lymphoma?

MCL is a rare, aggressive subtype of non-Hodgkin lymphoma that primarily affects older adults. It often responds to initial chemoimmunotherapy, but relapse is frequent.⁵

What is zanubrutinib currently approved to treat?

Zanubrutinib is FDA approved for adults with relapsed or refractory MCL and for several other B-cell malignancies.¹ These include Waldenström macroglobulinemia, marginal zone lymphoma, chronic lymphocytic leukemia or small lymphocytic lymphoma, and relapsed or refractory follicular lymphoma in combination with obinutuzumab.⁶

When will more MANGROVE data be available?

Presentation of the complete MANGROVE findings is expected at the 2026 ASH Annual Meeting. Those data should clarify response rates, duration of response, and overall survival, which was a key secondary end point.^1,2

REFERENCES

1. U.S. FDA Grants Priority Review to BeOne Medicines’ BRUKINSA Combination in First-Line Mantle Cell Lymphoma. News release. BeOne Medicines. November 4, 2026. Accessed November 4, 2026. https://tinyurl.com/jrb7vy67

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 4, 2026. https://clinicaltrials.gov/study/NCT04002297

3. Priority review. US Food and Drug Administration. Updated January 4, 2018. Accessed November 4, 2026. https://tinyurl.com/5ycv74rv

4. How BTK inhibitors treat mantle cell lymphoma. MD Anderson Cancer Center. March 20, 2023. Accessed November 4, 2026. https://tinyurl.com/2mfwvsj4

5. Bruton tyrosine kinase inhibitors in mantle cell lymphoma: what are the current options? Eur J Haematol. 2025;115(6):599-609. doi:10.1111/ejh.70036

6. Brukinsa FDA approval history. Drugs.com. Updated June 13, 2025. Accessed November 4, 2026. https://www.drugs.com/history/brukinsa.html