Pirtobrutinib, A Next Generation, Highly Selective, Non-Covalent BTK Inhibitor in Previously Treated Mantle Cell Lymphoma: Updated Results from the Phase 1/2 BRUIN Study

• Published in: Blood Vol. 138; no. Supplement 1; p. 381
• Main Authors: Wang, Michael, Shah, Nirav N., Alencar, Alvaro J., Gerson, James N., Patel, Manish R., Fakhri, Bita, Jurczak, Wojciech, Tan, Xuan Ni, Lewis, Katharine, Fenske, Timothy S., Coombs, Catherine C., Flinn, Ian W., Lewis, David John, Le Gouill, Steven, Palomba, M. Lia, Woyach, Jennifer A., Pagel, John M., Lamanna, Nicole, Cohen, Jonathon B., Barve, Minal A., Ghia, Paolo, Eyre, Toby A., Zinzani, Pier Luigi Luigi, Ujjani, Chaitra S., Koh, Youngil, Izutsu, Koji, Lech-Marańda, Ewa, Tam, Constantine S., Sundaram, Suchitra, Yin, Ming, Nair, Binoj, Balbas, Minna, Tsai, Donald, Mato, Anthony R., Cheah, Chan Yoon
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 23.11.2021
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2021-149138

Background: Covalent BTK inhibitors (BTKi) have transformed the management of mantle cell lymphoma (MCL), but these treatments are not curative and the majority of patients (pts) 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, for example 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 pts, most of whom had prior treatment with a covalent BTKi (Mato et al. Lancet 2021;397, 10277:892-901). Methods: BRUIN is a multicenter phase 1/2 study (NCT03740529) of oral pirtobrutinib monotherapy in pts with advanced B-cell malignancies who have received >2 prior therapies. Pirtobrutinib was dose escalated in a standard 3+3 design in 28-day cycles. The primary objective for phase 1 was to determine the recommended phase 2 dose (RP2D) and the primary objective of phase 2 was overall response rate (ORR); secondary objectives included duration of response (DoR), progression-free survival (PFS), overall survival (OS), safety and tolerability, and pharmacokinetics. Efficacy evaluable pts included all dosed pts who underwent their first response evaluation or discontinued therapy. Response was assessed every 8 weeks from cycle 3, and every 12 weeks from cycle 13 and was measured according to Lugano Classification. Safety was assessed in all pts (CLL/SLL and NHL). Results: As of 27 September 2020, 323 pts (170 CLL/SLL, 61 MCL, 26 WM, 26 DLBCL, 13 MZL, 12 FL, 9 RT, and 6 other NHL [other transformation, B-PLL and hairy cell leukemia]) were treated on 7 dose levels (25-300mg QD). Median age was 69 (range 50-87) years for MCL pts. Among the 61 MCL pts, median number of prior lines of therapy was 3 (range, 1-8) and a majority of them had received a prior BTKi (93%), an anti-CD20 antibody (98%) or chemotherapy (92%). No DLTs were reported and MTD was not reached (n=323). 200mg QD was selected as the RP2D. Fatigue (20%), diarrhea (17%), and contusion (13%) were the most frequent treatment-emergent adverse events regardless of attribution or grade seen in >10% of pts (n=323). The most common adverse event of grade ≥3 was neutropenia (10%). Treatment-related hemorrhage and hypertension occurred in 5 (2%) and 4 (1%) pts, respectively. Five (1%) pts discontinued due to treatment-related adverse events. At the efficacy cutoff date, 52 prior BTKi treated MCL pts were efficacy evaluable with an ORR of 52% (95% CI 38-66; 13 CR [25%], 14 PR [27%], 9 SD [17%], 11 PD [21%] and 5 [10%] pts discontinued prior to first response assessment). Median follow up was 6 months (range 0.7-18.3+). Responses were observed in 9/14 pts (64%) with prior autologous or allogeneic stem cell transplant, and 2 of 2 with prior CAR-T cell therapy. Conclusion: Pirtobrutinib demonstrated promising efficacy in heavily pretreated, poor-prognosis MCL following multiple prior lines of therapy, including a covalent BTKi. Pirtobrutinib was well tolerated and exhibited a wide therapeutic index. Updated data, including approximately 60 new pts with MCL and an additional 10 months since the prior data cut will be presented. Wang: Juno: Consultancy, Research Funding; Miltenyi Biomedicine GmbH: Consultancy, Honoraria; Lilly: Research Funding; Moffit Cancer Center: Honoraria; Newbridge Pharmaceuticals: Honoraria; VelosBio: Consultancy, Research Funding; OMI: Honoraria; BGICS: Honoraria; Mumbai Hematology Group: Honoraria; BioInvent: Research Funding; CStone: Consultancy; Hebei Cancer Prevention Federation: Honoraria; Celgene: Research Funding; Oncternal: Consultancy, Research Funding; Molecular Templates: Research Funding; Epizyme: Consultancy, Honoraria; InnoCare: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Clinical Care Options: Honoraria; AstraZeneca: Consultancy, Honoraria, Research Funding; Chinese Medical Association: Honoraria; Scripps: Honoraria; Imedex: Honoraria; Physicians Education Resources (PER): Honoraria; The First Afflicted Hospital of Zhejiang University: Honoraria; DTRM Biopharma (Cayman) Limited: Consultancy; Dava Oncology: Honoraria; Genentech: Consultancy; Janssen: Consultancy, Honoraria, Research Funding; Anticancer Association: Honoraria; BeiGene: Consultancy, Honoraria, Research Funding; CAHON: Honoraria; Kite Pharma: Consultancy, Honoraria, Research Funding; Bayer Healthcare: Consultancy; Loxo Oncology: Consultancy, Research Funding; Acerta Pharma: Consultancy, Honoraria, Research Funding. Shah: Epizyme: Consultancy; Miltenyi Biotec: Consultancy, Honoraria, Research Funding; Lily: Consultancy, Honoraria, Research Funding; Incyte: Consultancy; Umoja: Consultancy; Kite: Consultancy; Legend: Consultancy. Alencar: Amgen: Consultancy; BeiGene: Consultancy; Celgene: Consultancy; Epizyme: Consultancy; Incyte: Consultancy; Janssen: Consultancy; Karyopharm: Consultancy; Kite Pharma: Consultancy; Seattle Genetics: Consultancy. Gerson: Abbvie, Genentech: Membership on an entity's Board of Directors or advisory committees; Loxo Oncology at Lilly: Research Funding. Patel: Hutchinson MediPharma: Research Funding; Florida Cancer Specialists: Research Funding; Mirati Therapeutics: Research Funding; Lycera: Research Funding; Millennium Pharmaceuticals: Research Funding; Mabspace: Research Funding; Macrogenics: Research Funding; Merck: Research Funding; Daiichi Sankyo: Research Funding; Effector Therapeutics: Research Funding; Cyteir Therapeutics: Research Funding; ADC Therapeutics: Research Funding; Vedanta: Research Funding; Loxo Oncology: Research Funding; Forma Therapeutics: Research Funding; Genentech/Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Research Funding; GlaxoSmithKline: Research Funding; LSK Biopartners: Research Funding; ModernaTX: Research Funding; ORIC Pharmaceuticals: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Phoenix Molecular Designs: Research Funding; Placon Therapeutics: Research Funding; Portola Pharmaceuticals: Research Funding; Prelude Therapeutics: Research Funding; Qilu Puget Sound Biotherapeutics: Research Funding; Revolution Medicines: Research Funding; Ribon Therapeutics: Research Funding; Exelixis: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Alexion, AstraZeneca Rare Disease: Other: Study investigator; Evelo Biosciences: Research Funding; EMD Serono: Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer Ingelheim: Research Funding; Eli Lilly: Research Funding; Curis: Research Funding; Jacobio: Research Funding; Acerta Pharma: Research Funding; AstraZeneca: Research Funding; Ciclomed: Research Funding; BioNTech: Research Funding; Clovis: Research Funding; Checkpoint Therapeutics: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Calithera: Research Funding; Bicycle Therapeutics: Research Funding; Artios Pharma: Research Funding; TopAlliance: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Stemline Therapeutics: Research Funding; Seven and Eight Biopharmaceuticals: Research Funding; Taiho: Research Funding; H3 Biomedicine: Research Funding; Vigeo: Research Funding; Tesaro: Research Funding; Aileron Therapeutics: Research Funding; Agenus: Research Funding; Ignyta: Research Funding; Xencor: Research Funding; Syndax: Research Funding; Synthorx: Research Funding; Incyte: Research Funding; Kymab: Research Funding; Hengrui: Research Funding; Verastem: Research Funding; Takeda: Research Funding; Klus Pharma: Research Funding; Jounce Therapeutics: Research Funding. Fakhri: Loxo/Lilly: Research Funding. Jurczak: European Medicines Agency, Sandoz-Novartis, Janssen China R&D, BeiGene, Epizyme, Acerta, AstraZeneca: Consultancy; Jagiellonian University: Ended employment in the past 24 months; AbbVie, AstraZeneca, Bayer, BeiGene, Celtrion, Celgene, Debbiopharm, Epizyme, Incyte, Janssen, Loxo Oncology, Merck, Mei Pharma, Morphosys, Novo Nordisk, Roche, Sandoz, Takeda, TG Therapeutics, Pharmacyclics, Affirmed, Gilead Sciences, Nordic Nanovecto: Research Funding; AstraZeneca, BeiGene, Janssen, Loxo Oncology, Sandoz, Roche: Membership on an entity's Board of Directors or advisory committees; Maria Sklodowska-Curie National Research Institute of Oncology: Current Employment. Lewis: AstraZeneca: Consultancy, Honoraria; Janssen: Honoraria, Patents & Royalties; Novartis: Patents & Royalties; Roche: Consultancy, Honoraria. Fenske: Sanofi: Speakers Bureau; Pharmacyclics: Consultancy; Servier Pharmaceuticals: Consultancy; Kite (Gilead): Speakers Bureau; MorphoSys: Consultancy; TG Therapeutics: Consultancy, Speakers Bureau; Seattle Genetics: Speakers Bureau; KaryoPharm: Consultancy; CSL Therapeutics: Consultancy; Bristol-Myers Squibb: Speakers Bureau; Biogen: Consultancy; Beigene: Consultancy; AstraZeneca: Speakers Bureau; ADC Therapeutics: Consultancy; Adaptive Biotechnologies: Consultancy; AbbVie: Consultancy. Coombs: LOXO: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; AstraZeneca: Honoraria; AbbVie: Honoraria; Genentech: Honoraria; MEI Pharma: Honoraria. Flinn: Celgene: Other