Chemo-Free Zanubrutinib Combo Bests Bendamustine in Frontline MCL

Topline data from the phase 3 MANGROVE trial (NCT04002297) indicate that zanubrutinib (Brukinsa) plus rituximab (Rituxan) significantly improved progression-free survival (PFS) compared with bendamustine plus rituximab in adults with previously untreated mantle cell lymphoma (MCL).¹

The chemotherapy-free regimen met the trial’s primary end point of PFS as assessed by an independent review committee, with a HR of 0.57 (95% CI, 0.43-0.76; P <.0001) equating to a 43% reduction in the risk of progression or death.

Overall survival (OS), a key secondary end point, remained immature at the time of this interim analysis, though investigators observed a trend favoring the zanubrutinib-based arm. OS will be formally tested at the trial’s final analysis.

Regarding safety, the safety profile of zanubrutinib plus rituximab was consistent with the known safety profiles of both agents, and no new safety signals were identified.

“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,” Amit Agarwal, MD, PhD, chief medical officer of hematology at BeOne Medicines, stated in a news release.¹ “We believe it would be very meaningful for patients to be free from the burden of frequent infusions.”

MANGROVE Rationale and Trial Design

Chemoimmunotherapy carries recognized burdens, including myelosuppression, prolonged immune suppression, elevated infection risk, and cumulative toxicity that can be particularly difficult for older patients to tolerate. Prior efforts to improve frontline outcomes in MCL with Bruton tyrosine kinase (BTK) inhibitors have generally focused on adding these agents to chemotherapy rather than replacing it. MANGROVE instead tested whether a chemotherapy-free regimen could maintain durable disease control while sparing patients the toxicity associated with upfront chemotherapy.

MANGROVE enrolled 510 adult patients with previously untreated MCL across 176 sites worldwide.² Patients were randomly assigned to receive zanubrutinib at 160 mg orally twice daily plus rituximab during the initial treatment period, followed by zanubrutinib monotherapy until disease progression or intolerance, or to receive bendamustine plus rituximab for 6 cycles.

Secondary end points beyond OS included investigator-assessed PFS, overall response rate, duration of response, patient-reported outcomes, and safety.

Next Steps

Full efficacy and safety results from MANGROVE are expected to be presented at an upcoming medical meeting. Additionally, the sponsor has reported to be in discussions with global regulatory authorities, with submissions planned for the second half of 2026.

Zanubrutinib is currently approved in more than 80 markets globally and has been used to treat more than 290,000 patients worldwide across its approved indications in B-cell malignancies. In November 2019, the FDA granted accelerated approval to zanubrutinib as a single agent for treatment of adult patients with MCL who have received at least 1 prior therapy.

If global regulatory submissions for this frontline MCL indication are cleared, the chemotherapy-free regimen could expand the drug’s existing footprint in this disease setting.

REFERENCES

1. BeOne Medicines Announces Positive Phase 3 Results for BRUKINSA in Frontline Mantle Cell Lymphoma. News release. BeOne Medicines. June 30, 2026. Accessed June 30, 2026. https://tinyurl.com/mu4n359w

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 May 18, 2026. Accessed June 30, 2026. https://clinicaltrials.gov/study/NCT04002297