Efficacy of Pirtobrutinib in Covalent BTK-Inhibitor Pre-Treated Relapsed / Refractory Mantle Cell Lymphoma: Additional Patients and Extended Follow-up from the Phase 1/2 BRUIN Study

Background: Covalent Bruton tyrosine kinase inhibitors (BTKi) have transformed the treatment landscape of mantle cell lymphoma (MCL). Despite the efficacy of covalent BTKi, treatment failure often occurs through development of resistance or intolerance. Pirtobrutinib, a highly selective, non-covalent (reversible) BTKi, inhibits both wildtype and C481-mutant BTK with equal low nM potency, and has favorable oral pharmacology that enables continuous BTK inhibition throughout the dosing interval regardless of intrinsic rate of BTK turnover. Pirtobrutinib is well tolerated and has demonstrated promising efficacy in patients (pts) with poor-prognosis B-cell malignancies following prior therapy, including prior covalent BTKi (Mato et al. Lancet, 2021). Here, we report updated MCL results from the BRUIN study (NCT03740529).

Methods: Pts with previously treated B-cell malignancies, including MCL, were eligible for treatment with pirtobrutinib monotherapy in either the dose escalation or expansion portion of the multicenter BRUIN study. Key endpoints included overall response rate (ORR) based on Lugano 2014 criteria, duration of response (DOR), and safety. The response evaluable cohort consisted of the first 90 MCL pts enrolled to either phase 1 or 2 who had measurable disease, had received a prior covalent BTKi containing regimen, and had no known central nervous system involvement. A data cut of 31 January 2022 was chosen to ensure the majority of the cohort had a minimum of 9 months of follow-up from the initial response. The safety cohort consisted of all pts with B-cell malignancies who received at least one dose of pirtobrutinib monotherapy (n=725).

Results: Among the 90 pts with MCL who had received a prior BTKi, the median age was 70 (range, 46-87) years and the median number of prior lines of therapy was 3 (range, 1-8). Additional prior therapies included anti-CD20 antibody (96%), chemotherapy (88%), immunomodulator (21%), stem cell transplant (21%), BCL-2 inhibitor (16%), CAR-T-cell therapy (4%), and PI3K inhibitor (3%). The majority of pts (82%, n=74) discontinued prior BTKi therapy due to disease progression. Overall, 86% (n=77) received the recommended phase 2 dose of 200 mg once daily as starting dose. In this group of heavily pretreated relapsed/refractory (R/R) MCL pts, including all with prior BTKi use, the ORR by IRC was 58% (95% CI, 47-68), including 18 complete responses (20%) and 34 with partial responses (38%). Responses were observed in 6/8 pts (75%) with blastoid MCL and in 6/12 pts (50%) with pleomorphic MCL. At a median follow-up time of 12 months, the median DOR among the 52 responding pts was 22 months (95% CI, 7.5-not estimable [NE]). The 12-month and 18-month estimated DOR rates were 57% (95% CI, 39-72) and 52% (95% CI, 34-68), respectively. Patients who discontinued their prior BTKi due to disease progression (n=74) had an ORR of 50% (95% CI, 38-62) and a median DOR of 14.8 months (95% CI, 5.6-NE). In the safety cohort of all pirtobrutinib treated pts with B-cell malignancies (n=725), the most common TEAEs, regardless of attribution, were fatigue (26%, n=191), diarrhea (22%, n=160), and contusion (19%, n=138). The most frequent Grade ≥3 TEAE was neutropenia (20%, n=143). Low rates of Grade ≥3 TEAEs of hypertension (3%, n=20), hemorrhage (2%, n=16), and atrial fibrillation/flutter (1%, n=7) were observed. Overall, 15 (2%) pts discontinued due to a treatment-related AE.

Conclusion: In this updated analysis with additional pts and extended follow-up, pirtobrutinib continues to demonstrate promising and durable efficacy in heavily pre-treated R/R MCL pts who have been treated with a prior covalent BTKi. Pirtobrutinib was well-tolerated with low-rates of discontinuation due to drug-related toxicity.

Wang:Deciphera: Consultancy; BioInvent: Consultancy, Honoraria, Research Funding; Juno Therapeutics: Consultancy, Research Funding; IDEOlogy Health: Honoraria; Celgene: Research Funding; VelosBio: Consultancy, Research Funding; Molecular Templates: Research Funding; Loxo Oncology: Research Funding; Dava Oncology: Honoraria; Oncternal: Consultancy, Research Funding; Genmab: Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Leukemia & Lymphoma Society: Consultancy, Honoraria; MJH Life Sciences: Honoraria; Medscape: Honoraria; Pepromene Bio: Consultancy; Eastern Virginia Medical School: Honoraria; LLC TS Oncology: Honoraria; Studio ER Congressi: Honoraria; Oncology Specialty Group: Honoraria; Moffit Cancer Center: Honoraria; OncLive: Honoraria; Physicians Education Resources (PER): Honoraria; Practice Point Communications (PPC): Honoraria; Meeting Minds Experts: Honoraria; Genentech: Consultancy, Research Funding; Milken Institute: Consultancy; Merck: Honoraria; Lilly: Consultancy, Research Funding; Kite Pharma: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; InnoCare: Consultancy, Research Funding; Vinverx: Research Funding; BeiGene: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; Acerta Pharma: Honoraria, Research Funding; AbbVie: Consultancy. Shah:Epizyme: Consultancy; Lilly Oncology: Consultancy, Honoraria; Incyte Corporation: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy; Bristol Myers Squibb: Consultancy; Kite Pharma: Consultancy; TG therapeutics: Consultancy; Miltenyi Biotec: Consultancy, Research Funding. Jurczak:Beigene: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Eli Lilly and Company: Consultancy, Research Funding; Mei Pharma: Consultancy; AstraZeneca: Consultancy; Janssen: Consultancy, Research Funding; Maria Sklodowska-Curie National Research Institue of Oncology: Current Employment; Celgene: Research Funding; TgTherapeutica: Research Funding. Zinzani:Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eusapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Secura Bio: Membership on an entity's Board of Directors or advisory committees; University of Bologna: Current Employment. 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Wang:Kite Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Eli Lilly and Company: Membership on an entity's Board of Directors or advisory committees; Genmab: Research Funding; MorphoSys: Research Funding; Genentech: Research Funding; Novartis: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Loxo@Lilly: Membership on an entity's Board of Directors or advisory committees, Research Funding; InnoCare: Membership on an entity's Board of Directors or advisory committees, Research Funding. Tam:Janssen: Honoraria, Research Funding; LOXO: Honoraria; Beigene: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; AstraZeneca: Honoraria. Seymour:F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau; TG Therapeutics: Consultancy; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genor Biopharma: Membership on an entity's Board of Directors or advisory committees. Munir:Janssen, AstraZeneca, Alexion, Sobi, Novartis, Roche, Abbvie, Gilead: Honoraria; Janssen, AstraZeneca, Alexion, Abbvie, Novartis, Roche: Membership on an entity's Board of Directors or advisory committees. Nagai:Nippon Shinyaku: Honoraria, Research Funding; Sumitomo Pharma: Honoraria; Celgene: Honoraria; Ono: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Eli Lilly and Company: Honoraria; Mudi Pharma: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria; Eisai: Honoraria, Research Funding; Bristol Myers Squib: Honoraria; Chugai: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; IQVIA: Research Funding; Labcorp: Research Funding; Solasia: Research Funding; lncyte: Research Funding; Daiichi-Sankyo: Research Funding; Parexel: Research Funding. Kumar:BridgeBio Pharmaceuticals: Current equity holder in publicly-traded company; Adaptive Biotechnologies: Research Funding; Abbvie: Research Funding; Celgene: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Research Funding; AstraZeneca: Honoraria, Research Funding; Kite Pharma: Honoraria; Janssen: Honoraria. Zelenetz:Janssen: Consultancy, Honoraria; Pharmacyclics/Abbvie: Consultancy, Honoraria; Beigene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; MBS: Consultancy, Honoraria; Gilead/Kite Pharma: Consultancy, Honoraria; Genentech/Roche: Consultancy, Honoraria, Research Funding; Juno Pharmaceuticals: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria. Jain:Eli Lilly and Company: Consultancy, Honoraria; Kite Pharma: Consultancy, Research Funding; Beigene: Research Funding; AstraZeneca: Research Funding; Aptitude Health: Membership on an entity's Board of Directors or advisory committees; Pharmacy Times: Membership on an entity's Board of Directors or advisory committees. Nair:Loxo Oncology/Eli Lilly and Company: Current Employment. Tsai:Loxo Oncology/Eli Lilly and Company: Current Employment, Current equity holder in publicly-traded company. Balbas:Loxo Oncology/Eli Lilly and Company: Current Employment, Current equity holder in publicly-traded company. Walgren:Eli Lilly and Company: Current Employment, Current equity holder in publicly-traded company. Abada:Loxo Oncology/Eli Lilly and Company: Current Employment, Current equity holder in publicly-traded company. Wang:Eli Lilly and Company: Current Employment, Current equity holder in publicly-traded company. Zhao:Loxo Oncology at Lilly: Current Employment, Current equity holder in publicly-traded company. Mato:Adaptive Biotechnologies: Honoraria; AstraZeneca: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; DTRM Biopharma: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; BeiGene: Honoraria, Research Funding; Octopharma: Honoraria, Research Funding; TG Therapeutics, Inc: Honoraria, Research Funding; Nurix: Research Funding; Pharmacyclics, LLC: Honoraria, Research Funding; LOXO: Honoraria, Research Funding; Genmab: Honoraria, Research Funding; Johnson & Johnson: Honoraria, Research Funding; Pfizer: Research Funding; Curio: Honoraria; Dava: Honoraria; BMS: Honoraria; Medscape: Honoraria; Acerta: Research Funding; PER: Honoraria; PerView: Honoraria.

We will be presenting data from the BRUIN trial. Pirtobrutinib is not approved yet.