Background
PROs including health-related quality of life (HRQoL) and symptom burden can provide helpful information to support benefit-risk assessment of a new treatment. Pirtobrutinib, a highly selective, non-covalent (reversible) Bruton tyrosine kinase inhibitor (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 recently received regulatory approval in the US for the treatment of patients with relapsed or refractory mantle cell lymphoma after two or more lines of systemic therapy, including a covalent BTKi (cBTKi). BRUIN (NCT03740529) is an ongoing, open-label, multi-center phase 1/2 study investigating the safety and efficacy of pirtobrutinib for the treatment of B-cell malignancies, including CLL/SLL. This current analysis reports PROs among patients enrolled in the BRUIN study with relapsed or refractory (R/R) CLL/SLL treated with prior cBTKi-containing regimens.
Methods
Pretreated patients with R/R CLL/SLL in the BRUIN study completed PRO assessments at each clinic visit. The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core-30 (QLQ-C30) was used to measure physical function (PF) and HRQoL via PF and Global Health Status/QoL subscales. Patient-reported CLL/SLL symptoms and fatigue were assessed using 13 and 6 EORTC Item Library (IL) items, respectively. All subscales are scored 0-100. Higher scores represent better PF and HRQoL; and higher scores represent worse CLL/SLL symptoms and fatigue. Pre-specified clinically meaningful within patient change (MWPC) thresholds of at least 10-point changes in each PRO score were used to categorize patients based on their individual change from Cycle 1 Day 1 (i.e., baseline). Mean changes from baseline and proportions of patients with improved, stable, and worsened PROs from baseline were summarized by treatment cycle. PRO data were presented from Cycle 1 to 24 (a 28-day cycle) since the study median progression-free survival by investigator assessment was 19.6 months. The data cutoff date was 22 July 2022.
Results
There were 263 patients with CLL/SLL at the time of analysis; median (Quartile 1 and 3) age was 69 (62, 74) years and the majority were male (68%). All patients had received prior cBTKi; 21% received 2 or more prior cBTKi lines and 20% discontinued from their most recent cBTKi treatment due to toxicity. The mean overall completion rate of PRO instruments was 83% at baseline. 76% of all patients in the analysis completed at least one subsequent PRO assessment. Baseline mean (±SD [standard deviation]) score was 80.8 (±19.5) for PF, 61.6 (±23.2) for QoL, 24.8 (±18.4) for CLL/SLL symptoms, and 33.5 (±24.7) for fatigue. The majority of patients reported stable or clinically improved outcomes from baseline at each of the post-baseline visits (through Cycle 24) for PF (proportion of stable/improved ranged from 72.5% to 95.5%), QoL (range 80.4% to 95.0%), CLL/SLL symptoms (range 77.8% to 96.3%), and fatigue (range 77.3% to 89.9%).
Conclusion
Overall, consistent with the favorable safety profile of pirtobrutinib, HRQoL and symptoms were stable or improved for over 70% of patients with pretreated R/R CLL/SLL throughout the first 24 cycles of pirtobrutinib treatment. These PRO data should be interpreted with caution due to single arm trial design and small numbers of patients available for assessment in later cycles.
OffLabel Disclosure:
Coombs:Mingsight: Honoraria; MEI Pharma: Honoraria; TG Therapeutics: Honoraria; Bluebird Bio: Current equity holder in publicly-traded company; Loxo Oncology/Eli Lilly and Company: Consultancy, Honoraria, Research Funding; AstraZeneca: 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; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria; Octapharma: Consultancy. Woyach:AbbVie Inc, Karyopharm Therapeutics, Loxo Oncology Inc, a wholly owned subsidiary of Eli Lilly & Company, MingSight Pharmaceuticals, MorphoSys, Schrödinger, Verastem Inc.: Other: Contracted Research; AbbVie Inc, ArQule Inc, AstraZeneca Pharmaceuticals LP, BeiGene Ltd, Genentech, a member of the Roche Group, Janssen Biotech Inc, Loxo Oncology Inc, a wholly owned subsidiary of Eli Lilly & Company, Newave Pharmaceutical Inc, Pharmacyclics LLC, an AbbVie: Other: Advisory Committee and Consulting Agreements. Brown:Acerta/AstraZeneca: Consultancy; Pharmacyclics: Consultancy; Loxo/Lilly: Consultancy, Research Funding; TG Therapeutics: Research Funding; Numab Therapeutics: Consultancy; Kite: Consultancy; SecuraBio: Research Funding; Pfizer: Consultancy; Merck: Consultancy; MEI Pharma: Research Funding; iOnctura: Consultancy, Research Funding; Gilead: Research Funding; BeiGene: Consultancy, Research Funding; Alloplex Biotherapeutics: Consultancy; Genentech/Roche: Consultancy; Grifols Worldwide Operations: Consultancy; Hutchmed: Consultancy; Abbvie: Consultancy. Ghia:MSD: Consultancy, Honoraria, Research Funding; BeiGene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Lilly/Loxo Oncology: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding. Roeker:Aptose Biosciences: Research Funding; Adaptive Biotechnologies: Research Funding; Abbott Laboratories: Current equity holder in publicly-traded company; Dren Bio: Research Funding; Pharmacyclics: Consultancy; AbbVie: Consultancy, Research Funding; Ascentage: Consultancy; TG Therapeutics: Consultancy; Genentech: Research Funding; Beigene: Consultancy; Qilu Puget Sound Biotherapeutics: Research Funding; Loxo Oncology: Consultancy, Other: travel support, Research Funding; AstraZeneca: Consultancy, Research Funding; Janssen: Consultancy; Pfizer: Consultancy, Research Funding; PeerView: Other: CME speaker; Medscape: Other: CME speaker; Curio: Other: CME speaker; DAVA: Other: CME speaker. Patel:ADC Therapeutics: Consultancy; Abbvie: Consultancy; Nurix: Research Funding; TG Therapeutics: Consultancy, Speakers Bureau; Adaptive Biotechnologies: Research Funding; Genentech/Roche: Consultancy, Research Funding; Fate Therapeutics: Research Funding; Epizyme: Consultancy, Research Funding; Curis, Inc: Research Funding; CRISPR Therapeutics: Research Funding; Caribou Biosciences: Consultancy; Bristol Myers Squibb: Consultancy, Research Funding, Speakers Bureau; BeiGene: Consultancy; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; Morphosys: Consultancy; Pharmacyclics/Janssen: Consultancy, Research Funding; Kite: Consultancy, Research Funding, Speakers Bureau; Loxo Oncology: Consultancy, Research Funding; MEI Pharma: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Sunesis Pharmaceuticals: Research Funding; Trillium Therapeutics/Pfizer: Consultancy, Research Funding; Xencor: Consultancy, Research Funding. Eyre:Roche: Consultancy, Honoraria, Speakers Bureau; KITE Gilead: Consultancy, Honoraria, Speakers Bureau; Beigene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Incyte: Consultancy; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; Autolus: Consultancy; AbbVie: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Loxo@Lilly: Consultancy, Honoraria, Speakers Bureau. Tam:Roche: Honoraria; Novartis: Honoraria; LOXO: Honoraria; BeiGene: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Seymour:Hoffmann-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy; Genor Bio: 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; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: 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; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Research Funding. Shah:Epizyme: Consultancy; Tundra Therapeutics: Current holder of stock options in a privately-held company; LOXO-Lilly: Consultancy, Other: Travel support; Janssen: Consultancy; Novartis: Consultancy; TG therapeutic: Consultancy; Umoja: Consultancy; BMS/Juno: Consultancy; Seattle Genetics: Consultancy; Gilead/Kite: Consultancy; Incyte: Consultancy; Abbvie: Consultancy; Lilly Oncology: Consultancy, Research Funding; Miltenyi Biotec: Consultancy, Other: Travel support, Research Funding. Flinn:Genmab: Consultancy; Innocare Pharma: Consultancy; Secura Bio: Consultancy; Century Therapeutics: Consultancy; Genentech: Consultancy; Hutchinson MediPharma: Consultancy; BeiGene: Consultancy; Myeloid Therapeutics: Consultancy; Novartis: Consultancy; Servier Pharma: Consultancy; Kite: Consultancy; AbbVie: Consultancy; TG Therapeutics: Consultancy; Vincerx Pharma: Consultancy. Cheah: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; Dizal: Consultancy, Honoraria; Gilead: 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; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding. Ma:AstraZeneca: Consultancy, 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; Eli Lilly and Company/Loxo Oncology: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Research Funding; Genentech: Consultancy. Rhodes:Pharmacyclics: Consultancy, Research Funding; Beigene: Consultancy; AstraZeneca: Consultancy; Morphosys: Consultancy; ADC Therapeutics: Consultancy; Epizyme: Consultancy, Research Funding; GenMab: Consultancy; SeaGen: Honoraria; Oncternal Pharmaceuticals: Research Funding; Acerta: Research Funding; Loxo Oncology: Research Funding; Velosbio: Research Funding; Abbvie: Consultancy, Research Funding; Genetech: Consultancy; Jannsen: Consultancy. Izutsu:Astellas Amgen: Research Funding; Takeda: Consultancy, Honoraria; Eisai: Consultancy, Honoraria, Research Funding; Ono Pharmaceuticals: Consultancy, Honoraria; Nippon Shinyaku: Consultancy; Nihon Kayaku: Honoraria; Pfizer: Honoraria, Research Funding; Zenyaku Kogyo: Consultancy; Kyowa Kirin: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Yakult: Research Funding; Incyte: Research Funding; Chugai Pharma: Honoraria, Research Funding; Mitsubishi Tanabe Pharma: Consultancy; MSD: Honoraria, Research Funding; Genmab: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; Otsuka: Consultancy, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Beigene: Research Funding; Loxo Oncology: Research Funding; Regeneron: Research Funding; Janssen: Honoraria; SymBio Pharmaceuticals: Honoraria; Eli Lilly: Honoraria; Meiji Seika: Honoraria. Jurczak:Eli Lilly: Research Funding; AstraZeneca: Consultancy; Celgene: Research Funding; Takeda: Research Funding; BeiGene: Consultancy; AbbVie: Consultancy; Janssen: Research Funding; Eli Lilly: Consultancy; Pfizer: Consultancy; Roche: Consultancy; SOBI: Consultancy; Takeda: Consultancy; AbbVie: Research Funding; AstraZeneca: Research Funding; Bayer: Research Funding; BeiGene: Research Funding; Merck: Research Funding; Pfizer: Research Funding; Roche: Research Funding; SOBI: Research Funding. Wierda:Sunesis: Research Funding; AstraZeneca/Acerta Pharma: Consultancy, Research Funding; Miragen: Research Funding; KITE Pharma: Research Funding; Genentech: Research Funding; Pharmacyclics LLC: Research Funding; Bristol Myers Squibb (Juno & Celgene): Consultancy, Research Funding; Gilead Sciences: Research Funding; Oncternal Therapeutics, Inc.: Research Funding; Cyclacel: Consultancy, Research Funding; Loxo Oncology, Inc./Lilly: Research Funding; GlaxoSmithKline: Research Funding; Janssens Biotech Inc: Research Funding; Janssens Biotech: Research Funding; Juno Therapeutics: Research Funding; Nurix THerapeutics: Research Funding; Numab THerapeutics: Research Funding; Accutar Biotechnology: Research Funding; NIH P30 CA016672/MDACC Cancer Center Support Grant: 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; AbbVie: Consultancy, Research Funding; GSK/Novartis: Research Funding. Loubert:Modus Outcomes: Current Employment. Payakachat:Eli Lilly and Company: Current Employment, Current equity holder in publicly-traded company. Hess:Eli Lilly and Company: Current Employment, Current equity holder in private company. Abada:Eli Lilly and Company: Current Employment, Current equity holder in publicly-traded company. Lamanna:Octapharma: Research Funding; Abbvie: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Janssen: Consultancy; Pharmacyclics: Consultancy; MingSight: Research Funding; Eli Lilly/Loxo: Research Funding; Adaptive Biotechnologies: Consultancy; Oncternal: Research Funding; TG Therapeutics: Research Funding.
Pirtobrutinib is approved in the USA for the treatment of relapsed or refractory MCL after at least 2 lines of systemic therapy, including prior BTKi.
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