Background:Richter transformation (RT) occurs in up to 10% of patients with chronic lymphocytic leukemia (CLL), typically presents as an aggressive diffuse large B-cell lymphoma (DLBCL) and is associated with poor survival. RT has no approved standard therapy; and clinical trial enrollment is the preferred first line of therapy. Pirtobrutinib, a highly selective, non-covalent (reversible) BTKi, that inhibits both wildtype and C481-mutant BTK with equal low nM potency, has favorable oral pharmacology that enables continuous BTK inhibition throughout the dosing interval. Pirtobrutinib demonstrated durable overall response rates (ORR) and was well tolerated in patients (pts) with poor-prognosis B-cell malignancies regardless of prior therapy. Here we provide updated safety and efficacy of pirtobrutinib in RT pts from the phase 1/2 BRUIN trial (NCT03740529).
Methods: Pts with previously treated, histologically confirmed RT were eligible in the global, multicenter, phase 1/2 BRUIN study. Pts with untreated RT became eligible after Amendment 10. All but one patient received the recommended phase 2 dose of 200 mg daily. Key endpoints included investigator-assessed ORR, DoR per Lugano 2014 criteria, OS, and safety. A data cut of 05 May 2023 was utilized. To assess clonal relationship, IGH rearrangement studies were done on tissue biopsies with RT involvement, and baseline blood or bone marrow (BM) samples with CLL involvement.
Results: Among all pts with RT (N=82) the median age was 67 (range, 26-95) and the median total number of lines of prior systemic therapy was 4 (range, 0-13). Pts with prior treatment had a median of 2 CLL-directed therapies and 2 RT-directed therapies. Eight pts did not have a previous line of RT-directed therapy, and 1 patient received neither RT- nor CLL-directed therapy. Common prior RT- and CLL-directed therapies (RT, CLL) included: chemotherapy (76%, 52%), cBTKi (34%, 62%), anti-CD20 antibody (78%, 66%), BCL2i (38%, 49%), stem cell transplant (SCT; 6%, 7%), and CAR-T (11%, 4%). Of 29 pts with bone marrow screening, 41.4% had CLL alone present in BM, 13.8% had DLBCL present and 24.1% had both CLL and DLBCL present. For 39 pts with available PET data, the median SUVmax was 19.1 (range, 2.6-41.2).
For all 82 pts, the ORR was 50.0% (95% CI, 38.7-61.3) including complete (13.4%, n=11) and partial (36.6%, n=30) responses. For 61 pts who received prior cBTKi therapy, the ORR was 45.9% (95% CI 33.1-59.2). Among 28 pts with an RT-directed cBTKi and 51 pts with prior CLL-directed cBTKi, the ORR was 42.9% (95% CI, 24.5-62.8) and 43.1% (95% CI, 29.3-57.8), respectively. In 50 pts who discontinued prior cBTKi due to disease progression, the ORR was 42.0% (95% CI, 28.2-56.8). At median follow-up time of 9.7 months, the median DoR for all 82 RT pts was 7.4 months (95% CI, 3.1-19.1) and the estimated rate at 12 months was 45.9% (95% CI, 28.3-61.8). The median time on treatment for the 41pts who responded to treatment was 8.3 months. Eight pts stopped pirtobrutinib to pursue curative-intent allogeneic SCT and DoR was censored at the last preceding disease assessment. At a median survival follow-up of 18.3 months, the median OS for the entire RT cohort was 12.5 months (95% CI, 6.9-20.5). At 18 months, the OS rate was 44.3% (95% CI, 32.5-55.4).
Frequent treatment-emergent adverse events (TEAE) in the RT cohort (n=82) were neutropenia/decreased neutrophil count (29.3%, n=24), fatigue (24.4%, n=20) and diarrhea, dyspnea, thrombocytopenia, and pyrexia (18.3% each, n=15). Common grade ≥3 TEAEs were neutropenia/decreased neutrophil count (23.2%, n=19), thrombocytopenia (11.0%, n=9), plus anemia and sepsis (9.8% each, n=8). Any grade hypertension (3.7%, n=3) or atrial fibrillation (1.2%, n=1) were infrequent. Three pts (3.7%) had treatment-related AEs leading to dose reductions, but no pt had a treatment-related AE leading to pirtobrutinib discontinuation. Analyses of clonality will be presented.
Conclusions: Continued follow-up from BRUIN demonstrates encouraging response and OS in pts with RT. Pirtobrutinib remains well-tolerated with low rates of discontinuation and manageable safety profile. While RT remains a challenging diagnosis, pirtobrutinib represents a potential treatment option that warrants further investigation.
Disclosures
Wierda:Numab THerapeutics: Research Funding; Loxo Oncology, Inc./Lilly: Research Funding; Janssens Biotech Inc: Research Funding; NIH P30 CA016672/MDACC Cancer Center Support Grant: Research Funding; GlaxoSmithKline: Research Funding; AbbVie: Consultancy, Research Funding; Cyclacel: Consultancy, Research Funding; Nurix THerapeutics: Research Funding; Juno Therapeutics: Research Funding; National Comprehensive Cancer Network: Other: Nonrelevant Financial Relationship/Chair, CLL). Supported by the NIH/NCI under award number P30 CA016672 and used MDACC Cancer Center Support Grant (CCSG) shared resources; Miragen: Research Funding; Oncternal Therapeutics, Inc.: Research Funding; Janssens Biotech: Research Funding; Accutar Biotechnology: Research Funding; Sunesis: Research Funding; KITE Pharma: Research Funding; Bristol Myers Squibb (Juno & Celgene): Consultancy, Research Funding; Gilead Sciences: Research Funding; AstraZeneca/Acerta Pharma: Consultancy, Research Funding; Genentech: Research Funding; Pharmacyclics LLC: Research Funding; GSK/Novartis: Research Funding. Shah:Umoja: Consultancy; Janssen: Consultancy; BMS/Juno: Consultancy; Tundra Therapeutics: Current holder of stock options in a privately-held company; LOXO-Lilly: Consultancy, Other: Travel support; Epizyme: Consultancy; TG therapeutic: Consultancy; Novartis: Consultancy; Seattle Genetics: Consultancy; Gilead/Kite: Consultancy; Incyte: Consultancy; Abbvie: Consultancy; Lilly Oncology: Consultancy, Research Funding; Miltenyi Biotec: Consultancy, Other: Travel support, Research Funding. Cheah:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Ascentage Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZenecca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Lilly: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Research Funding; Menarini: Consultancy, Honoraria; Genmab: Consultancy, Honoraria; Daizai: Consultancy, Honoraria. Lewis:Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Lilly: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees. Hoffmann:ADC Therapeutics: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy, Honoraria; Kite: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Coombs:Loxo Oncology/Eli Lilly and Company: Consultancy, Honoraria, Research Funding; BeiGene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Honoraria; MEI Pharma: Honoraria; Mingsight: Honoraria; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Bluebird Bio: Current equity holder in publicly-traded company; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Consultancy. Lamanna:Genentech: Consultancy, Research Funding; Pharmacyclics: Consultancy; TG Therapeutics: Research Funding; BeiGene: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; MingSight: Research Funding; Eli Lilly/Loxo: Research Funding; Adaptive Biotechnologies: Consultancy; Janssen: Consultancy; Oncternal: Research Funding; Octapharma: Research Funding. Ma:AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Juno/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Research Funding; Genentech: Consultancy; Janssen Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Eli Lilly and Company/Loxo Oncology: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Jagadeesh:Seagen: Research Funding; Trillium Pharmaceuticals: Research Funding; Regeneron Pharmaceuticals: Research Funding; MEI Pharma: Research Funding; LOXO Pharmaceuticals: Research Funding; Debio Pharma: Research Funding; ATARA Biotherapeutics: Research Funding; AstraZeneca: Research Funding; Affimed: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees. Munir:BeiGene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sobi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Wang:Novartis: Research Funding; Genentech: Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Genmab: Research Funding; Kite: Honoraria, 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; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Innocare: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Eli Lilly: Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: 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: Consultancy. Eyre:Janssen: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau; Beigene: Consultancy, Honoraria, Research Funding, Speakers Bureau; KITE Gilead: Consultancy, Honoraria, Speakers Bureau; AbbVie: Consultancy, Honoraria, Speakers Bureau; Loxo@Lilly: Consultancy, Honoraria, Speakers Bureau; Autolus: Consultancy; Incyte: Consultancy; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau. Rhodes:Pharmacyclics: Consultancy, Research Funding; Jannsen: Consultancy; Genetech: Consultancy; Velosbio: Research Funding; Loxo Oncology: Research Funding; Acerta: Research Funding; Oncternal Pharmaceuticals: Research Funding; SeaGen: Honoraria; GenMab: Consultancy; AstraZeneca: Consultancy; Morphosys: Consultancy; ADC Therapeutics: Consultancy; Epizyme: Consultancy, Research Funding; Beigene: Consultancy; Abbvie: Consultancy, Research Funding. McKinney:Bayer, ADC therapeutics, Epizyme, Genentech, Inc. / F. Hoffmann-La Roche Ltd, Incyte: Consultancy; BeiGene, Janssen, F. Hoffmann-La Roche Ltd / Genentech, Inc., Celgene/BMS, Incyte: Research Funding; ADC therapeutics, BeiGene, Kite/Gilead: Speakers Bureau. Tam:AbbVie: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; BeiGene: Honoraria, Research Funding; LOXO: Honoraria; Novartis: Honoraria; Roche: Honoraria. Jurczak:AbbVie: Consultancy; AstraZeneca: Consultancy; BeiGene: Consultancy; Eli Lilly: Consultancy; Pfizer: Consultancy; Roche: Consultancy; SOBI: Consultancy; Takeda: Consultancy; AbbVie: Research Funding; AstraZeneca: Research Funding; Bayer: Research Funding; BeiGene: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Eli Lilly: Research Funding; Merck: Research Funding; Pfizer: Research Funding; Roche: Research Funding; SOBI: Research Funding; Takeda: Research Funding. Izutsu:Eli Lilly: Honoraria; SymBio Pharmaceuticals: Honoraria; Meiji Seika: Honoraria; Nihon Kayaku: Honoraria; Takeda: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria, Research Funding; Janssen: Honoraria; Genmab: Consultancy, Honoraria, Research Funding; MSD: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Chugai Pharma: Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; Zenyaku Kogyo: Consultancy; Mitsubishi Tanabe Pharma: Consultancy; Nippon Shinyaku: Consultancy; Astellas Amgen: Research Funding; Incyte: Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Yakult: Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Beigene: Research Funding; Loxo Oncology: Research Funding; Regeneron: Research Funding; Ono Pharmaceuticals: Consultancy, Honoraria; Eisai: Consultancy, Honoraria, Research Funding; Otsuka: Consultancy, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding. Alencar:Genentech: Membership on an entity's Board of Directors or advisory committees; Lilly: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Epizyme: Membership on an entity's Board of Directors or advisory committees; SeaGen: Membership on an entity's Board of Directors or advisory committees; Dr Reddy: Honoraria. Patel:Janssen Oncology: Honoraria; Olema Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; ION Pharmaceuticals: Other: Leadership. Seymour:Genor Bio: Membership on an entity's Board of Directors or advisory committees; Hoffmann-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; F. Hoffmann-La Roche Ltd: Research Funding; TG Therapeutics: Consultancy; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, 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; Beigene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Woyach:Newave: Consultancy; Loxo: Consultancy; Beigene: Consultancy; AstraZeneca: Consultancy; Abbvie: Consultancy; Schrodinger: Research Funding; Morphosys: Research Funding; Karyopharm: Research Funding; Janssen: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding. Roeker:Beigene: Consultancy; Ascentage: Consultancy; Qilu Puget Sound Biotherapeutics: Research Funding; AbbVie: Consultancy, Research Funding; Curio: Other: CME speaker; Abbott Laboratories: Current equity holder in publicly-traded company; Medscape: Other: CME speaker; Janssen: Consultancy; AstraZeneca: Consultancy, Research Funding; TG Therapeutics: Consultancy; Loxo Oncology: Consultancy, Other: travel support, Research Funding; Dren Bio: Research Funding; Adaptive Biotechnologies: Research Funding; Genentech: Research Funding; Aptose Biosciences: Research Funding; Pharmacyclics: Consultancy; Pfizer: Consultancy, Research Funding; DAVA: Other: CME speaker; PeerView: Other: CME speaker. Thompson:beigene: Consultancy; astrazeneca: Consultancy, Speakers Bureau; genentech: Consultancy; janssen: Consultancy, Speakers Bureau; Lilly: Consultancy; merck: Consultancy, Speakers Bureau; pharmacyclics: Consultancy; adaptive biotechnologies: Consultancy, Research Funding, Speakers Bureau; abbvie: Consultancy. Abada:Eli Lilly and Company: Current Employment, Current equity holder in publicly-traded company. Ho:Eli Lilly and Company: Current equity holder in publicly-traded company; Loxo@Lilly: Current Employment. Marella:Eli Lilly and Company: Current equity holder in publicly-traded company; Loxo@Lilly: Current Employment. Wang:Eli Lilly and Company: Current Employment, Current equity holder in publicly-traded company. Ruppert:Eli Lilly and Company: Current Employment, Current equity holder in publicly-traded company; Telios Pharma: Consultancy. Chandrasekharan Nair:Loxo@Lilly: Current Employment; Eli Lilly and Company: Current equity holder in publicly-traded company. Liu:Loxo@Lilly: Current Employment. Tsai:Eli Lilly and Company: Current equity holder in publicly-traded company; Loxo@Lilly: Current Employment. Ghia:Janssen: Consultancy, Honoraria, Research Funding; Lilly/Loxo Oncology: Consultancy, Honoraria, Research Funding; MSD: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; BeiGene: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding.
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