Topline Data Show Zanubrutinib Plus Rituximab Cut Risk of Progression or Death 43% Over BR in Frontline Treatment of MCL

The Bruton tyrosine kinase (BTK) inhibitor zanubrutinib (Brukinsa; BeOne Medicines) reduced the risk of disease progression or death 43% when used with rituximab to treat patients newly diagnosed with mantle cell lymphoma (MCL), compared with a classic regimen of bendamustine plus rituximab (BR).

Topline data from MANGROVE trial, which showed the study met its primary end point of progression-free survival, were shared early today by BeOne, with full data to be presented at a forthcoming medical meeting, the company said in a statement.¹ Regulatory submissions with global authorities are planned for the second half of 2026, the company said in an email.

MANGROVE (NCT04002297) is the first phase 3 trial to evaluate a new chemotherapy-free standard in frontline MCL, a rare form of non-Hodgkin lymphoma that has had poor prognosis and comparatively few treatment options. The regimen offers practice-changing potential, Amit Agarwal, MD, PhD, chief medical officer for hematology at BeOne Medicines, said in the company’s statement.¹

“For patients with newly diagnosed MCL, chemotherapy is currently the default. MANGROVE demonstrates for the first time that [zanubrutinib] plus rituximab, a chemotherapy-free regimen, can deliver unprecedented improvements in progression-free survival, potentially redefining the treatment paradigm globally.”

According to the statement, for this prespecified interim analysis, MANGROVE met its primary end point of PFS with a highly statistically significant and clinically meaningful improvement for the combination of oral zanubrutinib and rituximab versus BR, as assessed by an independent review committee, HR = 0.57 (95% CI, 0.43, 0.76) P < .0001).

The trial is the first phase 3 study designed with both a chemotherapy-free regimen and without intravenous (IV) rituximab maintenance, thus eliminating 2 years of infusions for patients.¹

A Chance to Limit Toxicity in Frontline Treatment

Writing in The Hematologist, Tycel Phillips, MD, of City of Hope, offered background and rationale for MANGROVE in August 2025. Phillips addressed both the potential of BTK inhibitors in frontline treatment of MCL as well as the opportunity to avoid the toxicity of chemoimmunotherapy.²

“The treatment landscape for MCL has evolved in the last several years, much of it fueled by the introduction of covalent Bruton tyrosine kinase inhibitors,” he wrote. “The introduction of these agents in relapsed/refractory (R/R) MCL has significantly improved the outcomes of this patient population. Given the efficacy and tolerance of these medications, there has been a push to evaluate [covalent BTK inhibitors] in earlier lines of therapy.”

Phillips highlighted randomized studies that had shown the benefit of combining a BTK inhibitor with a chemoimmunotherapy regimen, “based on eligibility for autologous stem cell transplant.” He noted that FDA had approved the BTK inhibitor acalabrutinib “together with BR,” but that “there is some controversy as to whether the combination is better than sequential use of the agents, given concern for increased toxicity of the combination as well as improvement in long-term remission.”²

More importantly, he wrote, is the question of whether chemoimmunotherapy is needed in frontline MCL, given strong results from other studies and the concern about long-term adverse effects.²

The MANGROVE Regimen vs Standard of Care

Phillips outlined the protocol for the study: patients in the BR arm received bendamustine on days 1 and 2 of 6 monthly cycles, while the rituximab is given on day 1 of each cycle. In the zanubrutinib arm, patients would receive zanubrutinib at 160 mg (2 capsules) twice daily and rituximab on day 1 of cycles 1 to 6; after that, zanubrutinib is given until disease progression or intolerance.²

Besides the primary end point of PFS, key secondary end points include overall response rate, overall survival, duration of response, duration of complete response, time to response, and quality of life measures.²

In their statement, BeOne Medicines officials said that the safety profile of the zanubrutinib-rituximab combination was consistent with the known safety profile of both medicines, with no new safety signals seen. OS was immature but a trend favoring the zanubrutinib arm was observed.

At present, zanubrutinib is approved by FDA to treat 5 types of adult B-cell malignancies: chronic lymphocytic leukemia/small lymphocytic lymphoma, Waldenström’s macroglobulinemia; MCL for patients treated with at least 1 therapy, marginal zone lymphoma for patients treated with 1 prior anti-CD20 therapy, and follicular lymphoma, in combination for patients treated with at least 2 lines of therapy.

References

1. BeOne Medicines announces positive phase 3 results for BRUKINSA in frontline mantle cell lymphoma. News release. BusinessWire. June 30, 2026. Accessed June 30, 2026. https://www.businesswire.com/news/home/20260630413578/en/BeOne-Medicines-Announces-Positive-Phase-3-Results-for-BRUKINSA-in-Frontline-Mantle-Cell-Lymphom

2. Phillips T. Bending the needle: Phase III MANGROVE study in first-line mantle cell lymphoma. The Hematologist. 2025;22(5): https://doi.org/10.1182/hem.V22.5.2025512