Background: The treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) has benefited from covalent (c) Bruton tyrosine kinase inhibitors (BTKi), however, therapy can fail due to progression or intolerance. Sequential treatment with B-cell lymphoma 2 protein inhibitor (BCL2i) venetoclax, either as monotherapy or combined with an anti-CD20 monoclonal antibody, has been the primary treatment option for CLL/SLL patients (pts) whose disease has progressed on cBTKi. Pirtobrutinib is a highly selective, non-covalent (reversible) BTKi that demonstrated promising efficacy in patients with relapsed or refractory CLL/SLL (Mato et al, NEJM, 2023). Here, we report on the efficacy of pirtobrutinib treatment in CLL/SLL in the post-cBTKi setting, including subgroups with or without prior BCL2i, using data from the BRUIN study (NCT03740529) with more than 2 years follow-up.

Methods: Pts with previously treated CLL/SLL were eligible for treatment with pirtobrutinib in the multicenter Phase 1/2 BRUIN study. Key endpoints included ORR (including partial response with lymphocytosis; PR-L) as assessed by an independent review committee per 2018 iwCLL response criteria, DoR, PFS, OS, and safety. A data cut of 05MAY2023 was utilized.

Results: In total, 282 pts with CLL/SLL who received prior cBTKi were included in this analysis. Median age was 69 years (range, 36-88), 68% were male, and median number of prior therapies was 4 (range, 1-11). Of 282 pts, 154 (55%) had not received prior-BCL2i therapy (Naïve; BCL2i-N) and 128 (45%) had (Exposed; BCL2i-E). BCL2i-N pts were exposed to fewer prior therapies than BCL2i-E pts (median prior therapies 3 and 5, respectively), including anti-CD20 antibody (83% and 97%), chemotherapy (74% and 89%), PI3K inhibitor (11% and 42%), CAR-T cell therapy (1% and 12%), and hematopoietic cell transplantation (1% and 6%). The ORR for all post-cBTKi pts was 72% (95% CI, 66.4-77.1), and ORR including PR-L was 82% (95% CI, 76.5-85.9). Post-cBTKi pts included a subgroup of 19 pts with one prior line of cBTKi-containing therapy and second line therapy of pirtobrutinib, who had ORR including PR-L of 89.5% (CI 95%, 66.9-98.7). The ORR including PR-L was 83.1% (95% CI, 76.2-88.7) for BCL2i-N pts, and 79.7% (95% CI, 71.7-86.3) for BCL2i-E pts. Median DoR was 18.4 months (95% CI, 15.3-20.4) for all cBTKi pre-treated pts, 24.9 months (95% CI, 18.4-32.0) for BCL2i-N, and 14.8 months (95% CI, 12.0-17.4) for BCL2i-E. With a median follow up of 27.5 months, the median PFS was 19.4 months (95% CI, 16.6-22.1) among all cBTKi pre-treated pts, 23.0 months (95% CI, 19.6-28.4) for BCL2i-N, and 15.9 months (95% CI, 13.6-17.5) for BCL2i-E (Figure). With a median follow up of 29.3 months, the median OS was not estimable for all cBTKi pre-treated pts, BCL2i-N, and BCL2i-E; the 24-month OS rates were 73.2% (95% CI, 67.4-78.2), 83.1% (95% CI,75.9-88.2), 60.6% (50.9-68.9), respectively.

In the CLL/SLL cohort (N=282), the most frequent treatment-emergent adverse events (TEAE), regardless of attribution, were fatigue (36.9%), diarrhea (28.4%), cough (27.3%) and contusion (26.2%). The most frequent Grade ≥3 TEAE was neutropenia/neutrophil count decreased (28.4%). Grade ≥3 TEAEs of hypertension (4.3%) and atrial fibrillation/flutter (1.8%) were infrequent. The AE profile of BCL2i-N and BCL2i-E pts was overall similar. Though Grade ≥3 neutropenia/neutrophil count decreased was higher in BCL2i-E pts (36.7% and 21.4%), this may have been attributed to the higher frequency of baseline neutropenia in BCL2i-E pts (27.3% and 11.0%). In total, 7 (2.5%; 4 BCL2i-N, 3 BCL2i-E) pts had treatment-related AE leading to pirtobrutinib discontinuation.

Conclusion: Pirtobrutinib continues to demonstrate promising and durable efficacy in pts with post-cBTKi heavily pretreated CLL/SLL. ORR was high regardless of prior BCL2i status. Longer PFS was observed in BCL2i-N pts than BCL2i-E pts, likely due to the more heavily pretreated status of the BCL2i-E population which can be associated with poorer prognosis. Pirtobrutinib was well-tolerated with low-rates of discontinuation due to drug-related toxicity among both BTKi-N and BTKi-E pts. These results suggest that continuation of BTK pathway inhibition following a cBTKi may be an important sequencing approach to consider in the treatment of CLL/SLL.

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:SecuraBio: Research Funding; MEI Pharma: Research Funding; Hutchmed: Consultancy; Grifols Worldwide Operations: Consultancy; Pfizer: Consultancy; Kite: Consultancy; Numab Therapeutics: Consultancy; Merck: Consultancy; Loxo@Lilly: Consultancy, Research Funding; iOnctura: Consultancy, Research Funding; TG Therapeutics: Research Funding; Alloplex Biotherapeutics: Consultancy; Beigene: Consultancy, Research Funding; Genentech/Roche: Consultancy; Pharmacyclics: Consultancy; Gilead: Research Funding; Acerta/Astra-Zeneca: Consultancy; AbbVie: Consultancy. Ghia:Roche: Consultancy, Honoraria, Research Funding; BeiGene: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Lilly/Loxo Oncology: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; MSD: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Roeker:Loxo Oncology: Consultancy, Other: travel support, Research Funding; Medscape: Other: CME speaker; Adaptive Biotechnologies: Research Funding; Curio: Other: CME speaker; DAVA: Other: CME speaker; PeerView: Other: CME speaker; Aptose Biosciences: Research Funding; Genentech: Research Funding; Janssen: Consultancy; Ascentage: Consultancy; AstraZeneca: Consultancy, Research Funding; Beigene: Consultancy; Pharmacyclics: Consultancy; Pfizer: Consultancy, Research Funding; TG Therapeutics: Consultancy; Dren Bio: Research Funding; Qilu Puget Sound Biotherapeutics: Research Funding; Abbott Laboratories: Current equity holder in publicly-traded company; AbbVie: Consultancy, Research Funding. 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Lamanna:Abbvie: Consultancy, Research Funding; Octapharma: Research Funding; Janssen: Consultancy; Oncternal: Research Funding; MingSight: Research Funding; Eli Lilly/Loxo: Research Funding; Pharmacyclics: Consultancy; Adaptive Biotechnologies: Consultancy; TG Therapeutics: Research Funding; Genentech: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding. Tam:Janssen: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Beigene: Honoraria, Research Funding; LOXO: Honoraria; Novartis: Honoraria; Roche: Honoraria. Seymour:F. Hoffmann-La Roche Ltd: Research Funding; AstraZeneca: Honoraria, 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; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; TG Therapeutics: Consultancy; 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; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genor Bio: Membership on an entity's Board of Directors or advisory committees. Tessoulin:Gilead: Honoraria; Abbvie: Honoraria; Incyte: Honoraria; Kite: Honoraria. Shah:Epizyme: Consultancy; Janssen: Consultancy; Novartis: Consultancy; TG therapeutic: Consultancy; Umoja: Consultancy; LOXO-Lilly: Consultancy, Other: Travel support; Tundra Therapeutics: Current holder of stock options in a privately-held company; 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. Ujjani:Kite, a Gilead Company: Consultancy, Other: Travel expenses , Research Funding; Lilly: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria; Beigene: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; Atara: Consultancy; Epizyme: Consultancy; Astrazeneca: Consultancy, Honoraria, Research Funding; PCYC: Research Funding. Fakhri:BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS/Juno: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genetech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genmab/Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; LOXO/Lilly: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Coombs:AbbVie, Genentech, Beigene, AstraZeneca, Lilly, Octapharma: Consultancy. Flinn:Genmab: Consultancy; BeiGene: Consultancy; Genentech: Consultancy; Secura Bio: Consultancy; Hutchinson MediPharma: Consultancy; Kite: Consultancy; Innocare Pharma: Consultancy; AbbVie: Consultancy; Novartis: Consultancy; Myeloid Therapeutics: Consultancy; Servier Pharma: Consultancy; Century Therapeutics: Consultancy; TG Therapeutics: Consultancy; Vincerx Pharma: Consultancy. Patel:ION Pharmaceuticals: Other: Leadership; Olema Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Janssen Oncology: Honoraria. Nasta:ADC Therapeutics: Honoraria; Loxo/Lilly: Research Funding; Millennium Takeda: Research Funding; Ono Pharmaceutical: Research Funding; Accrotech: Honoraria; Raphael: Research Funding; Pharmacyclics: Research Funding; Genentech/Roche: Research Funding; Merck-Data Safety Monitoring Committee: Membership on an entity's Board of Directors or advisory committees. 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Cheah:TG therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Research Funding; Eli Lilly and Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZenecca: 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; 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; BeiGene: 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; 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; Menarini: Consultancy, Honoraria; Genmab: Consultancy, Honoraria; Daizai: Consultancy, Honoraria. Ma:Juno/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: 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; Genentech: Consultancy; Abbvie: Consultancy, Research Funding; Janssen Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Rhodes:Acerta: Research Funding; Oncternal Pharmaceuticals: Research Funding; Loxo Oncology: Research Funding; SeaGen: Consultancy; GenMab: Consultancy; Epizyme: Consultancy; ADCT: Consultancy; Morphosys: Consultancy; AstraZeneca: Consultancy; Beigene: Consultancy; Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy; Genentech: Consultancy; AbbVie: Consultancy, Research Funding; Velosbio: Research Funding; Verastem: Consultancy; PCYC: Consultancy. Jagadeesh:LOXO Pharmaceuticals: Research Funding; ATARA Biotherapeutics: Research Funding; Debio Pharma: Research Funding; Regeneron Pharmaceuticals: Research Funding; Affimed: Membership on an entity's Board of Directors or advisory committees; Trillium Pharmaceuticals: Research Funding; Seagen: Research Funding; MEI Pharma: Research Funding; AstraZeneca: Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees. 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Izutsu:Beigene: Research Funding; Takeda: Consultancy, Honoraria; Nippon Shinyaku: Consultancy; Novartis: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Mitsubishi Tanabe Pharma: Consultancy; Astellas Amgen: Research Funding; Incyte: Research Funding; Loxo Oncology: Research Funding; Eli Lilly: Honoraria; SymBio Pharmaceuticals: Honoraria; Regeneron: Research Funding; Eisai: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Genmab: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; Meiji Seika: Honoraria; Yakult: Research Funding; Janssen: Honoraria; Ono Pharmaceuticals: Consultancy, Honoraria; Nihon Kayaku: Honoraria; MSD: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Chugai Pharma: Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; Zenyaku Kogyo: Consultancy; Otsuka: Consultancy, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding. Tsai:Loxo@Lilly: Current Employment; Eli Lilly and Company: Current equity holder in publicly-traded company. Abada:Eli Lilly and Company: Current Employment, Current equity holder in publicly-traded company. Balbas:Eli Lilly and Company: Current Employment, Current equity holder in publicly-traded company. Li:Eli Lilly and Company: Current equity holder in publicly-traded company. Ruppert:Telios Pharma: Consultancy; Eli Lilly and Company: Current Employment, Current equity holder in publicly-traded company. Jurczak:SOBI: Research Funding; AbbVie: Consultancy; BeiGene: Consultancy; AstraZeneca: Research Funding; AbbVie: Research Funding; Roche: Research Funding; Eli Lilly: Consultancy; BeiGene: Research Funding; Pfizer: Consultancy; AstraZeneca: Consultancy; Bayer: Research Funding; Takeda: Research Funding; Roche: Consultancy; SOBI: Consultancy; Takeda: Consultancy; Celgene: Research Funding; Janssen: Research Funding; Eli Lilly: Research Funding; Merck: Research Funding; Pfizer: Research Funding. Wierda:Genentech: Research Funding; Juno Therapeutics: Research Funding; Sunesis: 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; Nurix THerapeutics: Research Funding; Pharmacyclics LLC: Research Funding; Gilead Sciences: Research Funding; AbbVie: Consultancy, Research Funding; Oncternal Therapeutics, Inc.: Research Funding; AstraZeneca/Acerta Pharma: Consultancy, Research Funding; Bristol Myers Squibb (Juno & Celgene): Consultancy, Research Funding; Cyclacel: Consultancy, Research Funding; Miragen: Research Funding; KITE Pharma: Research Funding; GlaxoSmithKline: Research Funding; Loxo Oncology, Inc./Lilly: Research Funding; Janssens Biotech: Research Funding; Janssens Biotech Inc: Research Funding; Numab THerapeutics: Research Funding; Accutar Biotechnology: Research Funding; NIH P30 CA016672/MDACC Cancer Center Support Grant: Research Funding; GSK/Novartis: Research Funding.

Pirtobrutinib is approved in the USA for treatment of relapsed or refractory MCL after at least 2 lines of systemic therapy, including prior BTKi.

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2023
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