MAHOGANY: Will it Establish Zanbrutinib, a Second-generation Bruton Tyrosine Kinase Inhibitor, as a Preferred Targeted Therapy for Relapsed/Refractory Follicular and Marginal Zone Lymphomas?

STUDY TITLE: A Phase 3 Randomized, Open-label, Multi-center Study of Zanubrutinib Plus Rituximab or Obinutuzumab versus Lenalidomide Plus Rituximab in Patients with Relapsed/Refractory Follicular and Marginal Zone Lymphoma

CLINICAL TRIALS.GOV IDENTIFIER: NCT05100862

PARTICIPATING CENTERS: Approximately 300 study sites in 25 countries

ACCRUAL GOAL: 750 patients

STUDY DESIGN: This randomized, open-label, multicenter phase III trial aims to compare the safety and efficacy of zanubrutinib combined with an anti-CD20 antibody versus lenalidomide plus rituximab in patients with relapsed/refractory (r/r) follicular or marginal zone lymphoma (MZL). To confirm the clinical benefit observed in ROSEWOOD,¹  600 eligible patients with follicular lymphoma ([FL]; grades 1-3a; at least one prior line of chemoimmunotherapy; in need of therapy; and no prior Bruton tyrosine kinase inhibitor [BTKi] treatment) will be randomized 1:1 to receive zanubrutinib (160 mg BID or 320 mg daily until progression or intolerance) in combination with obinutuzumab (1,000 mg on days 1, 8, and 15 of cycle 1 and day 1 of cycles 2-6) versus rituximab plus lenalidomide ([R²], dose and schedule based on the AUGMENT study).²  Approximately 150 patients with r/r MZL will be randomized 1:1 to receive zanubrutinib (160 mg BID or 320 mg daily until progression or intolerance) in combination with rituximab (375 mg/m² on days 1, 8, 15, and 22 of cycle 1 and day 1 of cycles 2-5) versus R². The primary endpoint for both cohorts is progression-free survival (PFS) as assessed by an independent review committee. The investigators aim to examine the hypothesis that zanubrutinib in combination with an anti-CD20 antibody (obinutuzumab in the FL cohort; rituximab in the MZL cohort) will result in superior PFS when compared with that observed for R² in r/r FL or MZL. This study is currently recruiting, with approximately 300 study sites in 25 countries planned, and enrollment is underway in the United States and Australia.

STUDY SUMMARY: Although FL and MZL are biologically distinct, they share common clinical features. Most patients with these indolent lymphoma subtypes will experience multiple relapses over the projected two-decade disease course. Therefore, well-tolerated and effective treatment options are needed, particularly in the relapsed setting. Targeting the B-cell receptor signaling pathway using BTKis has proven an effective therapeutic strategy for several B-cell lymphomas. Zanubrutinib, a second generation BTKi, has demonstrated promising safety and efficacy in both patients with FL and MZL. In the single-arm, phase II MAGNOLIA trial, zanubrutinib monotherapy led to an objective response rate (ORR) of 68% and PFS estimate of 83% at 15 months.³  Based on the results of this pivotal single-arm study, zanubrutinib has been approved for r/r MZL. The randomized, phase II ROSEWOOD trial subsequently examined zanubrutinib combined with obinutuzumab in patients with r/r FL, which resulted in an ORR of 69% vs. 46% and a significantly longer median PFS of 28 months vs. 10 months when compared with obinutuzumab alone.¹  Despite these favorable outcomes, a randomized phase III study is necessary to confirm whether zanubrutinib leads to a clinical benefit in r/r FL or MZL.

RATIONALE: BTK inhibitors have shown promising efficacy across a number of B-cell malignancies and have had a major impact on the treatment landscape for chronic lymphocytic leukemia, Waldenstrom’s macroglobulinemia, and mantle cell lymphoma. The ROSEWOOD trial was an interesting study, as it suggested that zanubrutinib contributes to the efficacy achieved when combined with obinutuzumab, achieving results superior to those observed for obinutuzumab alone. However, obinutuzumab monotherapy is not an acceptable standard-of-care option among the vast treatment options available for r/r FL. Therefore, the MAHOGANY study aims to explore whether zanubrutinib plus obinutuzumab is superior to R², an appropriate choice for a control arm.

COMMENT: The single-arm MAGNOLIA study is intriguing based on the durable responses observed for single-agent zanubrutinib in the context of r/r MZL, highlighting the need for a phase III study to explore whether this is better than other standard-of-care options such as single-agent rituximab, chemoimmunotherapy, and R². The notable difference in this study of FL and MZL is the addition of rituximab to zanubrutinib in the experimental arm — an attempt to examine the contribution of the BTKi to the effects of the anti-CD20 antibody present in both arms. However, whether FL is as heavily dependent as MZL on the B-cell receptor signaling pathway for survival remains to be determined.

If zanubrutinib is a more effective, well-tolerated BTKi, the MAHOGANY trial will confirm its clinical benefit in r/r MZL and lead to the approval of the first BTKi for r/r FL. The choice of PFS as the primary endpoint and the provision of ongoing therapy for the experimental arm in each cohort may seem like a winning strategy from the onset given the fixed duration of treatment in the control arm. However, the SELENE study, which set out to explore the addition of continuous ibrutinib combined with fixed-duration chemoimmunotherapy versus chemoimmunotherapy alone in r/r FL and MZL, was a negative trial.⁴