MAHOGANY: A PHASE 3 TRIAL OF ZANUBRUTINIB PLUS ANTI‐CD20 VERSUS LENALIDOMIDE PLUS RITUXIMAB IN PATIENTS WITH RELAPSED/REFRACTORY FOLLICULAR OR MARGINAL ZONE LYMPHOMA
Bibliographic record
Abstract
Introduction: Inhibition of Bruton tyrosine kinase (BTK) has emerged as a strategy for treatment of patients (pts) with B-cell malignancies including indolent non-Hodgkin lymphomas. Zanubrutinib is a second-generation, potent, and specific BTK inhibitor and has shown to be more effective and better tolerated than first-generation BTK inhibitors in several diseases including chronic lymphocytic leukemia/small lymphocytic lymphoma and Waldenström macroglobulinemia. Zanubrutinib is approved in >15 countries, including the United States and European Union, for pts with relapsed/refractory (R/R) marginal zone lymphoma (MZL) who received ≥1 anti-CD20–based regimen, based on the single-arm MAGNOLIA trial (Opat et al. Clin Cancer Res 2021). In R/R follicular lymphoma (FL), ROSEWOOD, a phase 2 randomized study of zanubrutinib plus obinutuzumab versus obinutuzumab, met its primary endpoint of increased overall response rate (ORR) at primary analysis (Zinzani et al. J Clin Oncol 2022). In this trial, zanubrutinib plus obinutuzumab in pts with R/R FL demonstrated deep and durable responses with a favorable safety profile. Methods: MAHOGANY (BGB-3111-308, NCT05100862) is a phase 3 randomized, open-label trial that compares efficacy and safety of a combination of zanubrutinib plus anti-CD20 monoclonal antibody versus lenalidomide plus rituximab in 2 independent cohorts, for pts with either R/R FL or MZL. Key eligibility criteria include histologically confirmed FL (grades 1–3A) or MZL, previously treated with ≥1 anti-CD20-based regimen, relapsed after or refractory to the most recent systemic therapy, in need of treatment, no prior BTK inhibitor exposure, and no prior resistance to a lenalidomide-based regimen. In the FL cohort, pts will be randomized 1:1 to zanubrutinib plus obinutuzumab (N = 300) and lenalidomide plus rituximab (N = 300). Randomization is stratified by age (≥60 vs. <60 years), number of prior lines of therapy (1–2 vs. >2), and rituximab-refractory status (yes vs. no). The primary endpoint is progression-free survival (PFS) assessed by an independent review committee (IRC) according to Lugano 2014 criteria. Key secondary endpoints are ORR by IRC assessment and overall survival. In the MZL cohort, pts will be randomized 1:1 to zanubrutinib plus rituximab (N = 75) and lenalidomide plus rituximab (N = 75). Randomization is stratified by age (≥60 vs. <60 years) and number of prior lines of therapy (1–2 vs. >2). The primary endpoint is PFS assessed by IRC according to Lugano 2014 criteria. The key secondary endpoint is ORR by IRC assessment. Zanubrutinib is given at 160 mg twice daily or 320 mg once daily according to investigator, until progression or unacceptable toxicity. Obinutuzumab or rituximab are given for up to 8 infusions. Lenalidomide is given according to approved label for up to 12 cycles. Recruitment is ongoing. Encore Abstract—previously submitted to ASCO 2023 and EHA 2023 The research was funded by: BeiGene Keywords: aggressive B-cell non-Hodgkin lymphoma, combination therapies Conflicts of interests pertinent to the abstract L. Sehn Consultant or advisory role AbbVie, Seattle Genetics, Janssen, Amgen, Roche/Genentech, Gilead Sciences, Kite, a Gilead Company, Merck, Teva, TG Therapeutics, AstraZeneca, Incyte, Sandoz-Novartis, Genmab, Celgene/BMS, BeiGene Honoraria: Amgen, AbbVie, Gilead Sciences, Janssen-ORtho, Kite, a Gilead Company, Merck, Roche/Genentech, Seattle Genetics, Teva, AstraZeneca, Incyte, Sandoz-Novartis, Genmab, Celgene/BMS, BeiGene Research funding: Roche/Genentech, Teva C. Sarkozy Consultant or advisory role Janssen, GSK, Incyte, BMS Honoraria: AbbVie Research funding: Roche Educational grants: Roche, Incyte Other remuneration: Incyte A. Salar Consultant or advisory role BeiGene, Roche Research funding: Roche, AbbVie Other remuneration: Kite, a Gilead Company, Janssen J. Trotman Consultant or advisory role BeiGene WM Advisory Board 2022 (uncompensated) Research funding: BeiGene, Janssen, Pharmacyclics, Roche, Celgene/BMS, Selectar P. L. Zinzani Consultant or advisory role Celltrion, Gilead Sciences, Janssen-Cilag, BMS, Servier, Sandoz, MSD, Roche, EUSA Pharma, Kyowa Kirin, Takeda, Secura Bio, TG Therapeutics, Novartis, ADC Therapeutics, Incyte, BeiGene, Novartis J. Zhang Employment or leadership position: BeiGene Stock ownership: BeiGene P. Fustier Employment or leadership position: BeiGene Stock ownership: BeiGene R. Delarue Employment or leadership position: Celgene/BMS, BeiGene Stock ownership: Celgene/BMS, BeiGene L. Nastoupil Consultant or advisory role Sirpant, Iterus Bios Honoraria: Gilead Sciences, Novartis, Janssen Oncology, TG Therapeutics, BMS, ADC Therapeutics, Morphosys, Epizyme, Genmab, Takeda, Genentech/Roche, Caribou Biosciences Research funding: Janssen Biotech, Genentech/Roche, Epizyme, Novartis, IgM Biosciences, Gilead Sciences, Allogene Therapeutics, Takeda, BMS/Celgene Educational grants: Genentech/Roche
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".