Abstract
Mantle cell lymphoma (MCL) is a rare lymphoma with a median age at diagnosis of 60-70 years. Front line therapy has traditionally been bendamustine-rituximab (BR) in older patients and then Bruton Tyrosine kinase inhibitors (BTKi) for relapsed disease. Due to their efficacy, BTKi are now being combined with chemotherapy as induction treatment. The TRIANGLE trial of R-CHOP/R-DHAP +/- ibrutinib +/- transplant showed the benefit of adding a BTKi in young patients (Dreyling M, 2022). The SHINE trial, a phase III trial of BR +/- ibrutinib in patients >65 years, showed a significant improvement in median PFS (81 months vs. 53 months) (Wang M, 2022). However, this came with an increase in toxicity with more treatment related deaths in the ibrutinib arm (11% vs. 6%) and no difference in overall survival. Therefore, a better tolerated approach is still needed in older patients.
A phase II study of rituximab + indefinite ibrutinib in 50 patients >65 years demonstrated efficacy of frontline BTKi with a 96% ORR and 71% CR (Jain P, 2021). However, a disadvantage of BTKi therapy is continuous treatment until disease progression or intolerance. In this study half of patients required dose reductions and almost a third of patients stopped treatment due to drug toxicity, most frequently atrial fibrillation or bleeding. If front line intermittent BTKi therapy is as effective as continuous therapy, it could minimize cumulative toxicity.
A052101 (NCT05976763), an Alliance for Clinical Trials in Oncology trial, is a randomized phase 3 multicenter trial of upfront zanubrutinib that asks the question “in older patients with previously untreated MCL who obtain a CR with zanubrutinib-rituximab, is it safe and equally effective to stop treatment and restart it upon disease progression rather than continuing indefinitely?”
The A052101 trial is enrolling pts with previously untreated MCL who are either >70 years old or 60-69 years old but are not transplant candidates due to cardiac ejection fraction <45%, DLCO <60% of predicted, creatinine clearance <70, Eastern Cooperative Oncology Group (ECOG) performance status of >2, or a Cumulative Illness Rating Scales score of >6. Key exclusion criteria include: history of a severe bleeding disorder or clinically significant cardiac arrhythmias.
Patients will take zanubrutinib 320 mg daily and rituximab/rituximab biosimilar once monthly for 6 cycles. Patients with less than partial response after 6 cycles will go off study treatment. Patients with a complete remission will be randomized in a 1:1 manner to intermittent treatment versus continuous treatment. Randomization will be stratified by age (60-69 years vs ≥70 years) and MIPI score. Those randomized to the continuous arm will receive zanubrutinib until intolerance or disease progression. Those randomized to the intermittent arm will stop all study drugs after those initial 6 cycles and will restart zanubrutinib at first disease progression and continue it until intolerance or second disease progression. In order to make the study results generalizable to clinical practice, disease progression will be defined by clinical parameters rather than minimal residual disease testing.
The primary objective of this study is to compare time from randomization to first progression or death (PFS1) in the continuous treatment arm to the time to second progression or death (PFS2) in the intermittent treatment arm. The primary evaluation will be to determine whether, for patients in a CR, active monitoring followed by retreatment with zanubrutinib therapy upon disease progression will result in non-inferior clinical outcomes compared to indefinite zanubrutinib.
Serial quality of life testing and adverse event monitoring will be performed throughout the study to gain a full understanding of the impact of continuous vs intermittent zanubrutinib on patients' lives.
A052101 has the potential to change management of older patients with previously untreated MCL. If our study demonstrates that the time to second progression/death when using the stop and retreat strategy is non-inferior to time to first progression/death when using continuous BTK therapy, then it might lead to a new standard of care in this patient population. This could result in decreased health care costs, decreased toxicity and improved quality of life for older patients with mantle cell lymphoma.
Support: U10CA180821, U10CA180882; https://acknowledgments.alliancefound.org
Beaven:Vittoria Biotherapeutics: Membership on an entity's Board of Directors or advisory committees; F. Hoffman-LaRoche LTD: Research Funding. Cohen:Nurix: Research Funding; Astra Zeneca: Consultancy, Research Funding; Hutchmed: Consultancy, Research Funding; Takeda: Research Funding; Kite/Gilead: Consultancy; Janssen: Consultancy; Genentech: Research Funding; Lilly: Consultancy, Research Funding; Beigene: Consultancy. Phillips:Merck: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Genmab: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Eli Lilly and Company: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; ADCT: Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy; Xencor: Membership on an entity's Board of Directors or advisory committees. Pophali:Marker Therapeutics: Research Funding; Fate Therapeutics: Research Funding; SeaGen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Thanarajasingam:SeaGen: Other: Advisory Board (one time - completed, no personal remuneration); Novartis: Other: Advisory Board (one time - completed, no personal remuneration). Alencar:Abbvie: Consultancy; TG therapeutics: Consultancy; Loxo/Lilly: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Beigene: Consultancy, Research Funding; Amgen: Consultancy; Kite: Consultancy; SeaGen: Consultancy; Epizyme: Consultancy; Janssen: Consultancy. Dinner:Pfizer: Consultancy; Rigel: Consultancy; Kite: Consultancy. Hsi:Abcon Therapeutics: Current holder of stock options in a privately-held company; Eli Lilly: Other: sponsored research. Welliver:Eli Lilly: Membership on an entity's Board of Directors or advisory committees. Kahl:Roche: Consultancy, Research Funding; ADCT: Consultancy; Genentech: Consultancy; Novartis: Consultancy; Merck: Consultancy; AbbVie: Consultancy; AstraZeneca: Consultancy, Research Funding; Kite: Consultancy; Bristol Myers Squibb: Consultancy; Lilly: Consultancy; BeiGene: Consultancy, Research Funding. Bartlett:AbbVie: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Foresight Diagnostics: Membership on an entity's Board of Directors or advisory committees; Genmab: Membership on an entity's Board of Directors or advisory committees, Research Funding; Autolus: Research Funding; Celegne: Research Funding; Forty Seven: Research Funding; Gilead: Research Funding; Washington University School of Medicine: Current Employment; ADC Therapeutics: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Research Funding; Pharmacyclics: Research Funding; Millennium: Research Funding; Janssen: Research Funding; Kite Pharm: Membership on an entity's Board of Directors or advisory committees, Research Funding. Leonard:AbbVie, AstraZeneca, Astellas, Bayer, BeiGene,BMS, Calithera, Constellation, Eisai, Epizyme,GenMab, Grail, Incyte, Janssen, Karyopharm, Lilly,Merck, Mustang Bio, Pfi zer, Roche/Genentech,Seagen, Second Genome, Sutro: Consultancy.
Zanubrutinib is a bruton tyrosine kinase inhibitor that is FDA approved for treatment of rel/ref mantle cell lymphoma. The trial discussed here is studying it as part of first line therapy.