Pirtobrutinib, a highly selective, non-covalent (reversible) BTK inhibitor in patients with B-cell malignancies: analysis of the Richter transformation subgroup from the multicentre, open-label, phase 1/2 BRUIN study.

Background: Richter transformation usually presents as an aggressive diffuse large B-cell lymphoma, occurs in up to 10% of patients with chronic lymphocytic leukaemia, has no approved therapies, and is associated with a poor prognosis. Pirtobrutinib has shown promising efficacy and tolerability in patients with relapsed or refractory B-cell malignancies, including those who progress on covalent Bruton tyrosine kinase (BTK) inhibitors. This study aims to report the safety and activity of pirtobrutinib monotherapy in a subgroup of patients with Richter transformation from the multicentre, open-label, phase 1/2 BRUIN study.
Methods: This analysis included adult patients (aged ≥18 years) with histologically confirmed Richter transformation, an Eastern Cooperative Oncology Group performance status score of 0-2, and no limit of previous therapies, with patients receiving first-line treatment added in a protocol amendment (version 9.0, Dec 15, 2021). Pirtobrutinib 200 mg was administered orally once a day in 28-day cycles. The primary endpoint of phase 1 of the BRUIN trial as a whole, which has been previously reported, was to establish the recommended phase 2 dose for pirtobrutinib monotherapy and the phase 2 primary endpoint was overall response rate. Safety and activity were measured in all patients who received at least one dose of pirtobrutinib monotherapy. This BRUIN phase 1/2 trial was registered with ClinicalTrials.gov and is closed to enrolment (NCT03740529).
Findings: Between Dec 26, 2019, and July 22, 2022, 82 patients were enrolled, of whom five were enrolled during phase 1 and 77 during phase 2. All but one patient received a starting dose of 200 mg pirtobrutinib once a day as the recommended phase 2 dose. The remaining patient received 150 mg pirtobrutinib once a day, which was not escalated to 200 mg. The median age of patients was 67 years (IQR 59-72). 55 (67%) of 82 patients were male and 27 (33%) were female. Most patients were White (65 [79%] of 82). 74 (90%) of 82 patients received at least one previous Richter transformation-directed therapy. Most patients (61 [74%] of 82) had received previous covalent BTK inhibitor therapy for chronic lymphocytic leukaemia or Richter transformation. The overall response rate was 50·0% (95% CI 38·7-61·3). 11 (13%) of 82 patients had a complete response and 30 (37%) of 82 patients had a partial response. Eight patients with ongoing response electively discontinued pirtobrutinib to undergo stem-cell transplantation. The most common grade 3 or worse adverse event was neutropenia (n=19). There were no treatment-related deaths.
Interpretation: Pirtobrutinib shows promising safety and activity among patients with Richter transformation, most of whom received previous Richter transformation-directed therapy, including covalent BTK inhibitors. These data suggest that further investigation is warranted of pirtobrutinib as a treatment option for patients with relapsed or refractory Richter transformation after treatment with a covalent BTK inhibitor.
Funding: Loxo Oncology.
Competing Interests: Declaration of interests WGW reports research funding from Numab Therapeutics, Loxo Oncology–Lilly, Janssens Biotech, NIH P30 CA016672/MDACC Cancer Center Support Grant, GlaxoSmithKline, AbbVie, Cyclacel, Nurix Therapeutics, Juno Therapeutics, Bristol Myers Squibb (Juno & Celgene), AstraZeneca–Acerta Pharma Miragen, Oncternal Therapeutics, Janssens Biotech, Accutar Biotechnology, Sunesis, KITE Pharma, Gilead Sciences, Genentech, Pharmacyclics, GlaxoSmithKline–Novartis; consultancy fees from AbbVie, Cyclacel Nurix Therapeutics, Bristol Myers Squibb (Juno & Celgene), AstraZeneca–Acerta Pharma; a non-relevant financial relationship with the National Comprehensive Cancer Network; support from the National Institutes of Health and National Cancer Institute under award number P30 CA016672; and use of MDACC Cancer Center Support Grant shared resources. NNS reports consultancy fees from Umoja, Janssen, Bristol Myers Squibb–Juno, LOXO Oncology–Lilly, TG therapeutic, Novartis, Seattle Genetics, Gilead–Kite, Incyte, AbbVie, Lilly Oncology, and Miltenyi Biotec; research funding from Miltenyi Biotec and Lilly Oncology; having stock options in a privately-held company with Tundra Therapeutics; and travel support from Epizyme and Miltenyi Biotec. CYC reports consultancy fees, honoraria, and having an advisory role for Roche, Janssen, Gilead, AstraZenecca, Eli Lilly, BeiGene, AbbVie, Menarini, Daizai, and Genmab, and research funding from Roche, MSD, Eli Lilly, Bristol Myers Squibb, and AbbVie. DL reports consultancy fees from Kite, BeiGene, Roche, Eli Lilly, and Janssen and membership on an entity's board of directors or advisory committees with Kite, BeiGene, Roche, Eli Lilly, and Janssen. MSH reports consultancy fees and honoraria from Pharmacyclics. CCC reports consultancy fees from LOXO Oncology–Eli Lilly, BeiGene, AstraZeneca, Genentech, AbbVie, Octapharma, Allogene, Janssen, TG Therapeutics, MEI Pharma, and Mingsight; honoraria from LOXO Oncology–Eli Lilly, BeiGene, AstraZeneca, Genentech, AbbVie; research funding paid to an institution from LOXO Oncology–Eli Lilly, AbbVie, and CarnaBio; membership on an entity's board of directors or advisory committees with BeiGene, AstraZeneca, Genentech, and AbbVie; being an equity holder in a publicly-traded company with Bluebird Bio, Geron, and Pfizer; and receiving travel support from LOXO Oncology–Eli Lilly. NL reports consultancy fees from Genentech, Pharmacyclics, BeiGene, AstraZeneca, AbbVie, Adaptive Biotechnologies, Janssen, and research funding from Genentech, TG Therapeutics, BeiGene, AstraZeneca, AbbVie, MingSight, LOXO Oncology–Eli Lilly, Oncternal, and Octapharma. SM reports consultancy fees from AstraZeneca, Juno–Bristol Myers Squibb, AbbVie, Genentech, Janssen Pharmaceuticals, BeiGene; membership on a board of directors or advisory committee with AstraZeneca, Juno–Bristol Myers Squibb, Janssen Pharmaceuticals, Eli Lilly, Loxo Oncology, and BeiGene; research funding from AstraZeneca, Juno–Bristol Myers Squibb, AbbVie, Janssen Pharmaceuticals, Eli Lilly–Loxo Oncology, BeiGene; and speakers bureau with AstraZeneca, Eli Lilly–Loxo Oncology, and BeiGene. DJ reports research funding from Seagen, Trillium Pharmaceuticals, Regeneron Pharmaceuticals, MEI Pharma, Loxo Oncology, Debio Pharma, ATARA Biotherapeutics, AstraZeneca and membership on a board of directors or advisory committees with Affimed and Daiichi Sankyo. TM reports consultancy fees from BeiGene, Alexion, Sobi, Roche, AstraZeneca, Janssen, and AbbVie; honoraria from BeiGene, Alexion, Sobi, Roche, AstraZeneca, Janssen, and AbbVie; membership on a board of directors or advisory committees on BeiGene, Alexion, Sobi, Roche, AstraZeneca, Janssen, Abbvie; research Funding from Janssen, AbbVie; and speakers bureau for BeiGene, Alexion, Sobi, Roche, AstraZeneca, Janssen, and AbbVie. YW reports research funding from Incyte, InnoCare, LOXO Oncology, Eli Lilly, MorphoSys, Novartis, Genentech, Genmab, and AbbVie; membership on an advisory board with Eli Lilly, LOXO Oncology, TG Therapeutics, Incyte, InnoCare, Kite, Jansen, BeiGene, AstraZeneca, and Genmab; consultancy fees from Innocare and AbbVie; and honoraria from Kite. TAE reports membership on an entity's Board of Directors or advisory committees from Loxo Oncology, Incyte, BeiGene, AstraZeneca, KITE, AbbVie, Roche, Gilead, Secura Bio; speakers bureau from Loxo Oncology, Eli Lilly, Incyte, BeiGene, AstraZeneca, KITE, AbbVie, Loxo Oncology, Roche, Medscape, Janssen, Gilead, PeerView; research funding from BeiGene and AstraZeneca; consultancy fees from Eli Lilly, Incyte, Beigene, Autolus, AstraZeneca, KITE, AbbVie, Loxo Oncology, Roche, Janssen, and Gilead; and honoraria from Eli Lilly, BeiGene, AstraZeneca, KITE, AbbVie, Loxo Oncology, Roche, Janssen, and Gilead. JMR reports consultancy fees from Pharmacyclics, Jannsen, Genentech, GenMab, AstraZeneca, Morphosys, ADC Therapeutics, Epizyme, BeiGene, and AbbVie; research funding from Pharmacyclics, Velosbio, Loxo Oncology, Acerta, Oncternal Pharmaceuticals, Epizyme, and AbbVie; and honoraria from SeaGen. MM reports consultancy from Bayer, ADC therapeutics, Epizyme, Genentech, F Hoffmann-La Roche, and Incyte; research funding from BeiGene, Janssen, F Hoffmann-La Roche– Genentech, Celgene–Bristol Myers Squibb, and Incyte; and speakers bureau with ADC therapeutics, BeiGene, and Kite–Gilead. CT reports honoraria from Loxo Oncolgy. WJ reports consultancy fees from AbbVie, AstraZeneca, BeiGene, Eli Lilly, Pfizer, Roche, SOBI, and Takeda and research funding from AbbVie, AstraZeneca, Bayer, BeiGene, Celgene, Janssen, Eli Lilly, Roche, SOBIm, and Takeda. KI reports honoraria from Eli Lilly, SymBio Pharmaceuticals, Meiji Seika, Nihon Kayaku, Takeda, AstraZeneca, Janssen, Genmab, MSD, Pfizer, AbbVie, Ono Pharmaceuticals, Daiichi Sankyo, Novartis, Bristol Myers Squibb, Chugai Pharma, and Kyowa Kirin; consultancy fees from Takeda, AstraZeneca, Genmab, AbbVie, Otsuka, Eisai, Ono Pharmaceuticals, Nippon Shinyaku, Mitsubishi Tanabe Pharma, and Zenyaku Kogyo; and research funding from AstraZeneca, Genmab, MSD, Pfizer, AbbVie, Otsuka, Eisai, Regeneron, Loxo Oncology, BeiGene, Daiichi Sankyo, Yakult, Novartis, Bristol Myers Squibb, Incyte, Astellas Amgen, Chugai Pharma, Kyowa Kirin. AA reports membership on a board of directors or advisory committees with Genentech, Eli Lilly and Company, Amgen, TG Therapeutics, Incyte, BeiGene, Epizyme, Janssen, and SeaGen; research funding from Eli Lilly, Incyte, and BeiGene; and honoraria from Dr Reddy. MP reports consulting fees from Kura, Accutar, Mitsubishi; participating on a data safety monitoring board or advisory board with lema, Nurix, Daiichi, Kura, and Janssen; leadership with ION Pharma; honoraria from Janssen Oncology; and participating in a consulting or advisory role with Olema Pharmaceuticals, Daiichi Sankyo–UCB Japan, Kura Oncology, Accutar Biotech, and Kura. JFS reports honoraria from Hoffmann-La Roche, AbbVie, AstraZeneca, Janssen, Bristol Myers Squibb, Gilead, and BeiGene; consultancy fees from Hoffmann-La Roche, TG Therapeutics, Bristol Myers Squibb; participating on a data safety monitoring board or advisory board with Genor Bio, Hoffmann-La Roche, AbbVie, AstraZeneca, Janssen, Bristol Myers Squibb, Gilead, and BeiGene; speakers bureau with Hoffmann-La Roche, AbbVie, and BeiGene; and research funding from F Hoffmann-La Roche and AbbVie. JAW reports consultancy from Newave, Loxo Oncology, BeiGene, AstraZeneca, AbbVie, Janssen, and Pharmacyclics and research funding from Schrodinger, Morphosys, Karyopharm, Janssen, and Pharmacyclics. PAT reports consultancy and honoraria from AbbVie, Adaptive Biotechnologies, Ascentage AstraZeneca, BeiGene, Genentech, Genmab, Janssen, Lilly, Merck, Pharmacyclics; speakers bureau from AbbVie, Adaptive Biotechnologies, AstraZeneca, Janssen, and Merck; research funding from AbbVie, Pharmacyclics, Genentech, Lilly, and Adaptive Biotechnologies; and travel support from Merck. PA is a current employee of and equity holder in Eli Lilly. CH reports being an equity holder in Eli Lilly and Foundation Medicine and travel support from Eli Lilly. SCM reports current employment with, being an equity holder in, and travel support from Eli Lilly. NM reports being a current equity holder in Eli Lilly and current employment with Loxo Oncology. BN, CW, BCN, and DET reports current employment with and current equity holder in Eli Lilly. ASR reports current employment with and being equity holder in Eli Lilly and consultancy work with Telios Pharma. HL reports current employment with Loxo Oncology. LER reports serving as a consultant for AbbVie, Ascentage, AstraZeneca, BeiGene, Janssen, Loxo Oncology, Pharmacyclics, Pfizer, and TG Therapeutics; membership of a data safety monitoring committee for Ascentage; serving as a CME speaker for DAVA, Curio, Medscape, and PeerView; holding minority ownership interest in Abbott Laboratories; having received travel support from LOXO Oncology; and having received research funding (paid to the institution) from Adaptive Biotechnologies, AstraZeneca, Genentech, AbbVie, Pfizer, Loxo Oncology, Aptose Biosciences, Dren Bio, and Qilu Puget Sound Biotherapeutics. PG reports consultancy, fees, honoraria, and research funding from Janssen, Eli Lilly–Loxo Oncology, MSD, Roche, AbbVie, BMS, BeiGene, and AstraZeneca.
(Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)