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

The FDA accepted and granted priority review to the supplemental new drug application for zanubrutinib (Brukinsa; BeOne Medicines) in combination with rituximab (Rituxan; Genentech) for the treatment of adult patients with previously untreated mantle cell lymphoma (MCL). If approved, the regimen would be the first and only chemotherapy-free, Bruton tyrosine kinase (BTK) inhibitor–based option for this population.¹

“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, said 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.”¹

An Unmet Need in Frontline MCL

MCL is a rare, incurable lymphoma that accounts for approximately 5% to 6% of non-Hodgkin lymphoma cases in the US and western Europe.³ It is typically aggressive and predominantly affects older adults, who often have comorbidities that can influence treatment decisions and tolerability to therapies. Frontline care has long relied on chemoimmunotherapy such as bendamustine and rituximab (BR), which carries well-documented burdens, including myelosuppression, prolonged immune suppression, increased infection risk, and cumulative toxicity that can be especially difficult for older patients.²

Covalent BTK inhibitors have substantially improved outcomes in relapsed or refractory MCL, prompting interest in moving them into earlier lines of therapy.² To date, those efforts have largely focused on adding BTK inhibitors to chemotherapy rather than replacing it. For patients who are ineligible for autologous stem cell transplant, the ECHO trial (NCT02972840) established acalabrutinib (Calquence; AstraZeneca) plus BR, a regimen the FDA has approved; however, questions remain about whether the combination outperforms sequential use of the agents, given concerns about added toxicity.²

The MANGROVE Trial

The application is supported by the phase 3 MANGROVE trial (NCT04002297)⁴, a global, randomized, open-label phase 3 trial that enrolled 510 adults with previously untreated MCL who were not eligible for stem cell transplant.^1-4 It is the first phase 3 trial to compare a chemotherapy-free, BTK inhibitor–based regimen with BR in the frontline setting.¹

In the experimental arm, patients received zanubrutinib 160 mg orally twice daily plus rituximab on day 1 of cycles 1 to 6, followed by zanubrutinib monotherapy until disease progression or intolerance. In the control arm, patients received bendamustine on days 1 and 2 and rituximab on day 1 of 6 monthly cycles.³

The primary end point is progression-free survival (PFS) assessed by an independent review committee (IRC). Overall survival (OS) is a key secondary end point; other secondary end points include investigator-assessed PFS, overall response rate, duration of response, duration of complete response, time to response, patient-reported outcomes and quality of life, and safety.^1,3

Results and Building on Earlier Evidence

According to released data, zanubrutinib plus rituximab reduced the risk of disease progression or death by approximately 43% compared with BR.¹ Additionally, at a prespecified interim analysis, MANGROVE met its primary end point, with the zanubrutinib regimen significantly improving IRC-assessed PFS compared with BR (HR, 0.57; 95% CI, 0.43-0.76; P < .0001).³ The safety profile was consistent with the known profiles of both agents, and there were no new safety signals identified. OS data were immature at the time of the analysis, although a strong trend favoring the zanubrutinib combination was observed. The investigators noted that OS will be formally tested at the final analysis.³

Because the regimen does not include rituximab maintenance, BeOne noted that it could spare patients approximately 2 years of infusions.³ Additionally, full results are expected to be presented during the Plenary Scientific Session at the 68th American Society of Hematology Annual Meeting on December 13, 2026.¹

MANGROVE builds on the ENRICH trial, which was the first study to compare a BTK inhibitor with chemoimmunotherapy in frontline MCL. That trial, which was only conducted in the UK, randomly assigned patients to the first-generation BTK inhibitor ibrutinib (Imbruvica; Pharmacyclics LLC, Janssen Biotech, Inc) or to BR or R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).^1,2 MANGROVE compares only against BR, which has outperformed R-CHOP in 2 randomized studies, and uses a second-generation agent. This distinction matters because ibrutinib no longer carries a US indication for MCL and has long-term toxicity concerns that are less frequent with second-generation BTK inhibitors.^1,2

One noted limitation is that the BR arm does not include rituximab maintenance, which is considered important for prolonging remission in frontline MCL, whereas zanubrutinib is continued indefinitely.²

Regulatory Status and Safety of Zanubrutinib Regimen

Applications for zanubrutinib in MCL have also been submitted to the European Medicines Agency and accepted by the Center for Drug Evaluation of China’s National Medical Products Administration.¹ In the US, zanubrutinib is currently approved for adults with relapsed or refractory MCL, chronic lymphocytic leukemia/small lymphocytic lymphoma, Waldenström macroglobulinemia, relapsed or refractory marginal zone lymphoma, and relapsed or refractory follicular lymphoma.¹

Serious adverse events (AEs), including fatal events, have occurred with zanubrutinib, including hemorrhage, infections, cytopenias, second primary malignancies, cardiac arrhythmias, and hepatotoxicity. In a pooled safety population (N = 1729), the most common AEs; ≥ 30%) were decreased neutrophil count (51%), decreased platelet count (41%), upper respiratory tract infection (38%), hemorrhage (32%), and musculoskeletal pain (31%).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 5, 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. Phillips T. Bending the needle: Phase III MANGROVE study in first-line mantle cell lymphoma. The Hematologist. 2025;22(5). doi:10.1182/hem.V22.5.2025512

3. BeOne Medicines announces positive phase 3 results for BRUKINSA in frontline mantle cell lymphoma. News release. BeOne Medicines. June 30, 2026. Accessed November 5, 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

4. 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 identifier: NCT04002297. Accessed November 5, 2026. https://clinicaltrials.gov/study/NCT04002297