Bending the Needle: Phase III MANGROVE Study in First-Line Mantle Cell Lymphoma Free

STUDY TITLE: 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

PARTICIPATING CENTERS: 176 locations worldwide

SPONSOR: BeOne

ACCRUAL GOAL: 510 randomized participants between two arms

STUDY DESIGN: The goal of this open-label, randomized, phase III study is to evaluate the efficacy and safety of zanubrutinib plus rituximab (ZR) versus bendamustine plus rituximab (BR) in previously untreated participants with mantle cell lymphoma (MCL) who are not eligible for stem cell transplantation. Patients in the BR arm are given bendamustine on days 1 and 2 of six monthly cycles, while rituximab is given on day 1 of each cycle. In the ZR arm, patients receive zanubrutinib at 160 mg (two capsules) twice daily and rituximab on day 1 of cycles 1 to 6; after the sixth cycle, zanubrutinib is given until intolerance or disease progression. The primary endpoint of the study is progression-free survival (PFS), defined as from randomization to the first occurrence of disease progression or relapse, or death due to any cause, whichever occurs first during the predefined period of approximately seven years (96 months). Important secondary endpoints include investigator-assessed PFS, overall response rate (ORR), overall survival, duration of response (DOR), duration of complete response, time to response, and quality-of-life assessments.

RATIONALE: MCL is a rare, incurable lymphoma that accounts for 5% to 6% of cases of non-Hodgkin lymphoma in the U.S. and western Europe.¹  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 (cBTKis). The introduction of these agents in relapsed/refractory (R/R) MCL has significantly improved the outcomes of this patient population.^2-4  Given the efficacy and tolerance of these medications, there has been a push to evaluate cBTKis in earlier lines of therapy. In the last 24 months, we have seen three randomized studies indicate benefit of the combination of a cBTKi and a chemoimmunotherapy (CIT) regimen in two groups of patients, based on eligibility for autologous stem cell transplant (ASCT).^5-7  For those ineligible for ASCT, the recent ECHO⁷  study has established the role of the cBTKi acalabrutinib together with BR. While the U.S. Food and Drug Administration has approved this regimen, 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. Additionally, and more important to this study, is the question of whether CIT is needed in front-line (1L) MCL. Several smaller, early-phase studies have demonstrated impressive ORR, complete response rates, and DOR with regimens devoid of CIT.^8-11  Given concern about tolerance and long-term side effects, as well as the ineffectiveness of CIT in patients with certain high-risk features, this study seeks to evaluate the comparative efficacy of each of the treatments in an unselected patient population.

COMMENT: Improving tolerance and efficacy in 1L MCL has taken on greater significance with the introduction of several novel agents in the R/R setting. This started with the immunomodulatory drug lenalidomide but has taken on greater urgency with the introduction of cBTKis. These oral medications have opened the window to greater exploration of alternative treatments in the 1L space. The unanswered question is how these drugs compare alone to standard CIT. While the ENRICH¹²  study was the first to compare a cBTKi to CIT, the study was conducted only in the U.K. and randomized patients to the first-generation BTKi ibrutinib versus BR or R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). MANGROVE improves upon the earlier study design in two very important, fundamental aspects: it randomizes patients to only BR, which has shown in two randomized studies to be more effective than R-CHOP^13-14  (R-CHOP was also shown to be less effective than ibrutinib in ENRICH), as well as uses a second-generation cBTKi. The latter is important, as ibrutinib no longer has an indication for MCL in the U.S. and is known to have long-term toxicity concerns that are less frequent in the second-generation cBTKi. One major drawback to the MANGROVE study is the lack of rituximab maintenance in the BR arm, while zanubrutinib is continued indefinitely. This is a key point, as rituximab maintenance is considered important to prolong remission in 1L MCL. We will await the results of this study, which is active but has completed accrual, as it will add to the growing literature of CIT-free regimens in 1L MCL.