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2422 BRUIN MCL-321: A Phase 3 Open-Label, Randomized Study of Pirtobrutinib Versus Investigator Choice of BTK Inhibitor in Patients with Previously Treated, BTK Inhibitor Naïve Mantle Cell Lymphoma (Trial in Progress)

Program: Oral and Poster Abstracts
Session: 623. Mantle Cell, Follicular, and Other Indolent B Cell Lymphomas: Clinical and Epidemiological: Poster II
Hematology Disease Topics & Pathways:
Clinical Trials, Lymphomas, Clinical Research, Diseases, Lymphoid Malignancies
Sunday, December 12, 2021, 6:00 PM-8:00 PM

Toby A. Eyre1*, Nirav N. Shah, MD2, Steven Le Gouill3, Martin H. Dreyling, MD, PhD4, Elisabeth Vandenberghe, MD, PhD5, Wojciech Jurczak, MD, PhD6*, Yucai Wang, MD, PhD7, Chan Yoon Cheah8, Mitul D. Gandhi, MD9, Christopher H. Chay, MD10*, Jeff P. Sharman, MD11, David Jacob Andorsky, MD12, Ming Yin13*, Minna Balbas13*, Jennifer Kherani13* and Michael L. Wang, MD14

1Oxford University Hospitals NHS Foundation Trust, Churchill Cancer Center, Oxford, United Kingdom
2Medical College of Wisconsin, Milwaukee, WI
3Service d’hématologie clinique du CHU de Nantes, INSERM CRCINA Nantes-Angers, NeXT Université de Nantes, Nantes, France
4Department of Internal Medicine III, LMU Hospital, Munich, Germany
5Hope Directorate St. James Hospital, Dublin, Ireland
6Maria Sklodowska-Curie National Research Institute of Oncology, Kraków, Poland
7Division of Hematology, Mayo Clinic, Rochester, MN
8Linear Clinical Research and Sir Charles Gairdner Hospital, Perth, Australia
9Virginia Cancer Specialists, Fairfax, VA
10Messino Cancer Centers, Asheville, NC
11Willamette Valley Cancer Institute and Research Center, US Oncology Research, Eugene, OR
12Rocky Mountain Cancer Centers, US Oncology Research, Boulder, CO
13Loxo Oncology at Lilly, Stamford, CT
14University of Texas MD Anderson Cancer Center, Houston, TX

Background: Covalent Bruton’s Tyrosine Kinase (BTK) inhibitors (BTKi) have transformed the management of relapsed mantle cell lymphoma (MCL), but these treatments are not curative and the majority of patients will require additional treatment. Covalent BTKi share pharmacologic liabilities (e.g. low oral bioavailability, short half-life) that collectively may lead to suboptimal BTK target coverage especially in rapidly proliferating tumors with high BTK protein turnover such as MCL. To address these limitations, pirtobrutinib, a highly selective, non-covalent BTKi that inhibits both wild type (WT) and C481-mutated BTK with equal low nM potency was developed. In the phase 1/2 BRUIN study, pirtobrutinib achieved pharmacokinetic exposures that exceeded its BTK IC96 at trough, was well tolerated, and demonstrated promising efficacy in heavily pretreated, poor-prognosis MCL patients, most of whom had prior treatment with a covalent BTKi (Mato et al. Lancet 2021;397,10277:892-901). The purpose of this randomized study is to demonstrate the superiority of pirtobrutinib compared to investigator’s choice of covalent BTKi in patients with previously treated MCL.

Study Design and Methods: BRUIN MCL-321 is a randomized, open-label, global phase 3 study comparing pirtobrutinib monotherapy versus investigator’s choice of covalent BTKi monotherapy (ibrutinib, acalabrutinib, or zanubrutinib) in patients with previously treated, BTKi naïve MCL. Approximately 500 patients will be randomized 1:1. Randomization will be stratified by sMIPI risk (low/intermediate vs high), comparator BTKi (ibrutinib vs acalabrutinib/ zanubrutinib), and number of prior lines of therapy (1 vs ≥ 2).

Eligible patients are adults aged ≥18 years with a confirmed diagnosis of MCL (cyclin D1 overexpression, and ≥ 1 B-cell marker) who have received ≥ 1 prior line of systemic therapy for MCL that did not include a prior BTKi. Patients must have measurable disease per Lugano criteria and must have progressed on or relapsed following the most recent line of therapy prior to study enrollment. Key exclusion criteria include a history of current or prior CNS involvement, significant cardiovascular disease, stroke, or intracranial hemorrhage within 6 months of randomization, and allogeneic stem cell transplant (SCT), autologous SCT or chimeric antigen receptor (CAR) T-cell therapy within 60 days of randomization.

The primary endpoint is progression-free survival (PFS) per Lugano criteria assessed by an independent review committee (IRC), with the goal of demonstrating superiority of pirtobrutinib over investigator’s choice of covalent BTKi. Secondary endpoints include overall response rate (ORR), duration of response (DoR), investigator-assessed PFS per Lugano criteria, overall survival (OS), event-free survival (EFS), time to treatment failure (TTF), time to next treatment (TTNT), time from randomization to disease progression on next line of treatment or death from any cause (PFS2), safety and tolerability, and patient reported outcomes. This global study is currently enrolling patients (NCT04662255).

Disclosures: Eyre: Secura Bio: Consultancy, Honoraria; Beigene: Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Other: Travel to conferences; Gilead/KITE: Honoraria, Other: Travel support for conferences, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria; Incyte: Consultancy; AstraZeneca: Honoraria, Research Funding; Loxo Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria. Shah: Miltenyi Biotec: Consultancy, Honoraria, Research Funding; Kite: Consultancy; Epizyme: Consultancy; Umoja: Consultancy; Legend: Consultancy; Incyte: Consultancy; Lily: Consultancy, Honoraria, Research Funding. Dreyling: Novartis: Consultancy, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy, Research Funding, Speakers Bureau; Astra Zeneca: Consultancy, Speakers Bureau; BeiGene: Consultancy; Celgene: Consultancy, Research Funding, Speakers Bureau; Amgen: Speakers Bureau; Genmab: Consultancy; Bayer HealthCare Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau; Gilead/Kite: Consultancy, Research Funding, Speakers Bureau; Abbvie: Research Funding; Incyte: Consultancy, Speakers Bureau. Vandenberghe: Jansnens: Honoraria; Abbvie: Honoraria. Jurczak: Abbvie, AstraZeneca, BeiGene, Celtrion, Celgene, Debbiopharm, Epizyme, Incyte, Janssen, Loxo Oncology, Merck, Mei Pharma, Morphosys, Novo Nordisk, Roche, Sandoz, Takeda, TG Therapeutics: Research Funding; Astra Zeneca, BeiGene, Janssen, Loxo Oncology, Sandoz, Roche,: Membership on an entity's Board of Directors or advisory committees. Wang: Genentech: Research Funding; Eli Lilly: Membership on an entity's Board of Directors or advisory committees; MorphoSys: Research Funding; LOXO Oncology: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; InnoCare: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees. Cheah: Loxo/Lilly: Consultancy, Honoraria, Other: advisory; Janssen: Consultancy, Honoraria, Other: advisory; Roche: Consultancy, Honoraria, Other: advisory and travel expenses, Research Funding; TG Therapeutics: Consultancy, Honoraria, Other: advisory; AstraZeneca: Consultancy, Honoraria, Other: advisory; Celgene: Research Funding; AbbVie: Research Funding; Beigene: Consultancy, Honoraria, Other: advisory; Ascentage pharma: Consultancy, Honoraria, Other: advisory; Gilead: Consultancy, Honoraria, Other: advisory; MSD: Consultancy, Honoraria, Other: advisory, Research Funding. Gandhi: Karyopharm Therapeutics: Honoraria; TG Therapeutics: Honoraria; GlaxoSmithKline: Honoraria. Sharman: Lilly: Consultancy; AbbVie: Consultancy; Bristol-Myers Squibb: Consultancy; TG Therapeutics: Consultancy; Centessa: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics LLC, an AbbVie Company: Consultancy; BeiGene: Consultancy; AstraZeneca: Consultancy; Genentech, Inc.: Consultancy; Velos: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees. Andorsky: Abbvie: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; Epizyme: Research Funding. Yin: Loxo Oncology at Lilly: Current Employment; AstraZeneca: Ended employment in the past 24 months. Balbas: Nektar Therapeutics: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Loxo Oncology at Lilly: Current Employment, Current equity holder in publicly-traded company. Kherani: Loxo Oncology at Lilly: Current Employment, Current equity holder in publicly-traded company. Wang: AstraZeneca, Bayer Healthcare, BeiGene, CSTone, DTRM Biopharma (Cayman) Limited, Epizyme, Genentech, InnoCare, Janssen, Juno, Kite Pharma, Loxo Oncology, Miltenyi Biomedicine GmbH, Oncternal, Pharmacyclics, VelosBio: Consultancy; Acerta Pharma, AstraZeneca, BeiGene, BioInvent, Celgene, Innocare, Janssen, Juno, Kite, Pharma, Lilly, Loxo Oncology, Molecular Templates, Oncternal, Pharmacyclics, VelosBio: Research Funding; Acerta Pharma, Anticancer Association, AstraZeneca, BeiGene, CAHON, Chinese Medical Association, Clinical Care Options, Dava Oncology, Epizyme, Hebei Cancer Prevention Federation, Imbruvica, Imedex, Janssen, Kite Pharma, Miltenyi Biomedicine GmbH, Moffit : Honoraria.

*signifies non-member of ASH