Efficacy of Pirtobrutinib, a Highly Selective, Non-Covalent (Reversible) BTK Inhibitor in Richter Transformation: Results from the Phase 1/2 BRUIN Study

Background: Richter transformation (RT) usually presents as an aggressive diffuse large B-cell lymphoma (DLBCL), has no approved therapies, and is associated with an extremely poor prognosis, with an estimated median overall survival (OS) of 3-11 months. This devastating complication is estimated to occur in up to 10% of patients (pts) with chronic lymphocytic leukemia (CLL), although the rate may rise as more pts experience progression following treatment with Bruton tyrosine kinase inhibitors (BTKi) and BCL-2 inhibitors. Pirtobrutinib, a highly selective, non-covalent (reversible) 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 is well tolerated and has demonstrated promising efficacy in pts with poor-prognosis B-cell malignancies following prior therapy, including prior covalent BTKi (Mato et al. Lancet, 2021). Here we report the first sizeable cohort of RT pts from the BRUIN study (NCT03740529).

Methods: Pts with previously treated B-cell malignancies, including those with CLL and histologically confirmed RT (all DLBCL) were eligible for treatment with pirtobrutinib monotherapy in either the dose escalation or expansion portion of the multicenter phase 1/2 BRUIN study. Initially only pts with previously treated RT were eligible. Beginning with Amendment 10, pts with untreated RT were eligible. Key endpoints included investigator-assessed overall response rate (ORR) and duration of response (DoR) per Lugano 2014 criteria, and safety. The response evaluable cohort consisted of all RT pts enrolled to either phase 1 or 2 who had undergone their first response assessment or discontinued therapy. The safety cohort consisted of all pts with B-cell malignancies who received at least one dose of pirtobrutinib monotherapy (n=725). A data cut of 31 January 2022 was utilized.

Results: Among the 57 RT pts, the median age was 67 (range, 33-86) years and 91% (n=52) received at least 1 prior RT-directed therapy. The median number of prior RT-directed therapies was 2 (range, 0-7) and the median number of CLL-directed therapies prior to developing RT was 2 (range, 0-13). Prior RT-directed therapies included anti-CD20 antibody (86%, n=49), chemotherapy (79%, n=45), BCL-2 inhibitor (35%, n=20), BTKi (28%, n=16), PI3K inhibitor (12%, n=7), CAR-T (9%, n=5), immunodulator (5%, n=3), stem cell transplant (4%, n=2), or other systemic therapy (33%, n=19). Prior CLL-directed therapies included BTKi (60%, n=34), anti-CD20 antibody (60%, n=34), chemotherapy (47%, n=27), BCL-2 inhibitor (42%, n=24), immunodulator (9%, n=5), PI3K inhibitor (7%, n=4), stem cell transplant (7%, n=4), CAR-T (2%, n=1), or other systemic therapy (11%, n=6). Overall, 98% (56/57) of pts received the recommended phase 2 dose of 200 mg once daily as starting dose. In this group of pts with predominantly heavily pre-treated RT, the ORR for the 50 response evaluable pts was 54% (95% CI, 39-68) including 5 complete responses and 22 partial responses. At a median response follow-up time of 5.5 months, the median DoR was 8.6 months (95% CI, 1.9-NE) with 63% of responses censored at the time of data cut. At a median study follow-up of 9.7 months, the median OS was 13.1 months (95% CI, 7.1-NE). Six pts electively discontinued pirtobrutinib in ongoing response to pursue curative-intent therapy (allogeneic transplant, n=6 with median time-on-therapy of 3.8 [range, 2.5-11.5] months). In the safety cohort of all pirtobrutinib treated pts with B-cell malignancies (n=725), the most frequent TEAEs, regardless of attribution, were fatigue (26%, n=191), diarrhea (22%, n=160), and contusion (19%, n=138). The most frequent Grade ≥3 TEAE was neutropenia (20%, n=143). Low rates of Grade ≥3 TEAEs of hypertension (3%, n=20), hemorrhage (2%, n=16), and atrial fibrillation/flutter (1%, n=7) were observed. Overall, 15 (2%) pts discontinued due to a treatment-related AE.

Conclusions: In this predominantly heavily pretreated RT cohort with an extremely poor prognosis, pirtobrutinib demonstrated promising preliminary efficacy, including among pts who received prior RT-directed chemoimmunotherapy and covalent BTKi. Pirtobrutinib was well-tolerated with low-rates of discontinuation due to drug-related toxicity.

Wierda:Gilead Sciences: Research Funding; Loxo Oncology, Inc./Lilly: Research Funding; Miragen: Research Funding; Bristol Meyers Squibb (Juno and Celgene): Research Funding; Kite, a Gilead Company: Research Funding; AstraZeneca/Acerta Pharma. Inc.: Research Funding; AbbVie: Research Funding; Pharmacyclics LLC: Research Funding; Sunesis: Research Funding; Xencor: Research Funding; Cyclacel: Research Funding; Genzyme: Consultancy; Genentech: Research Funding; Juno: Research Funding; Karyopharm: Research Funding; Sanofi: Consultancy; Oncternal Therapeutics, Inc.: Research Funding; Janssen: Research Funding; GSK/Novartis: Research Funding. Lewis:Roche: Consultancy; Janssen: Consultancy, Other: Speakers fees; travel grant; Kite: Consultancy, Other: Travel grant; Eli Lilly and Company: Consultancy; Beigene: Consultancy. Ghia:BeiGene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; Roche: Consultancy, Honoraria; MSD: Consultancy, Honoraria; Lilly/Loxo: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Shah:Novartis: Consultancy; Lilly Oncology: Consultancy, Honoraria; Miltenyi Biotec: Consultancy, Research Funding; Incyte Corporation: Consultancy, Honoraria, Speakers Bureau; TG therapeutics: Consultancy; Kite Pharma: Consultancy; Epizyme: Consultancy; Bristol Myers Squibb: Consultancy. Coombs:Loxo/Lilly: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria; Beigene: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; CTI Biopharma: Current equity holder in publicly-traded company; Novartis: Honoraria; MEI Pharma: Honoraria; TG Therapeutics: Honoraria. Cheah:Janssen: Consultancy, Honoraria; Merck Sharp & Dohme: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; Eli Lilly and Company: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Beigene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding. Lamanna:Mingsight: Research Funding; Loxo Oncology/Eli Lilly and Company: Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Janssen: 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; AstraZenenca: 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; Octapharma: Research Funding; Oncternal: Research Funding; TG Therapeutics: Research Funding. Rhodes:Velosbios: Research Funding; Janssen: Consultancy, Research Funding; Verastem: Consultancy; Oncternal: Research Funding; Abbive: Consultancy; TG Therapeutics: Consultancy; Genmab: Consultancy; Genentech: Consultancy; Pharmacyclics: Consultancy, Research Funding; Morphosys: Consultancy; Beigene: Consultancy; SeaGen: Consultancy; Loxo Oncology: Research Funding; Epizyme: Research Funding. Hoffmann:Kite: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; Beigene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria. Ma:TG Therapeutics: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy; BeiGene: Consultancy, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; Juno: Research Funding; Abbvie: Consultancy, Research Funding; Loxo: Research Funding. Eyre:Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: 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; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Loxo Oncology @ Lilly: Membership on an entity's Board of Directors or advisory committees, Other, Speakers Bureau; Secura Bio: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Medscape: Speakers Bureau; PeerView: Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Beigene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Munir:Janssen, AstraZeneca, Alexion, Sobi, Novartis, Roche, Abbvie, Gilead: Honoraria; Janssen, AstraZeneca, Alexion, Abbvie, Novartis, Roche: Membership on an entity's Board of Directors or advisory committees. Patel:Olema: Research Funding; Zymeworks: Research Funding; Nurix: Research Funding; Novartis: Research Funding; Black Diamond Therapeutics: Research Funding; NGM Biopharmaceuticals: Research Funding; BioTheryX: Research Funding; Pfizer: Honoraria, Research Funding; Moderna Therapeutics: Research Funding; Mirati Therapeutics: Research Funding; Millennium: Research Funding; Merck: Research Funding; Puretech: Research Funding; IgM Biosciences: Research Funding; Placon: Research Funding; Portola Pharmaceuticals: Research Funding; MabSpace: Research Funding; Treadwell: Research Funding; Prelude Therapeutics: Research Funding; Ribon Therapeutics: Research Funding; Syndax: Research Funding; Seven and Eight Biopharmaceuticals: Research Funding; ORIC: Research Funding; Artios: Research Funding; Vigeo: Research Funding; TopAlliance BioSciences Inc: Research Funding; Tesaro: Research Funding; Takeda: Research Funding; Taiho Pharmaceutical: Research Funding, Speakers Bureau; Samumed: Research Funding; Silicon Therapeutics: Research Funding; TeneoBio: Research Funding; Adagene: Research Funding; Adaptive Biotechnologies: Honoraria; Bayer: Honoraria; Pharmacyclics: Honoraria; Accutar Biotech: Research Funding; Astellas: Research Funding; Compugen: Research Funding; Immunogen: Research Funding; Blueprint Pharmaceuticals: Research Funding; Lycera: Research Funding; Macrogenics: Research Funding; LSK Biopartners: Research Funding; Loxo: Research Funding; Relay Therapeutics: Research Funding; Exelixis: Speakers Bureau; ION Pharma: Other: Leadership; Klus Pharma: Research Funding; Kymab: Research Funding; Janssen: Honoraria, Research Funding; Jacobio: Research Funding; Incyte: Research Funding; Ignyta: Research Funding; Hutchison MediPharma: Research Funding; Hengrui Therapeutics: Research Funding; H3 Biomedicine: Research Funding; GlaxoSmithKline: Research Funding; Gilead Sciences: Research Funding; Genentech/Roche: Honoraria, Research Funding, Speakers Bureau; FORMA Therapeutics: Research Funding; Evelo Therapeutics: Research Funding; EMD Serono: Research Funding; Eli Lilly and Company: Research Funding; Daiichi Sankyo: Research Funding; Cyteir Therapeutics: Research Funding; Clovis Oncology: Research Funding; CicloMed: Research Funding; Checkpoint Therapeutics: Research Funding; Celgene: Research Funding, Speakers Bureau; Boehringer Ingelheim: Research Funding; BioNTech AG: Research Funding; AstraZeneca: Research Funding; Aileron Therapeutics: Research Funding; Agenus: Research Funding; ADC Therapeutics: Research Funding; Acerta Pharma: Research Funding; Pfizer/EMD Serono: Consultancy; Pharmacyclics/Janssen: Consultancy. Alencar:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: 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; Loxo Oncology: Research Funding; Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; SeaGen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; OncLive: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Tam:AbbVie: Honoraria, Research Funding; Beigene: Honoraria, Research Funding; LOXO: Honoraria; AstraZeneca: Honoraria; Janssen: Honoraria, Research Funding. Seymour:TG Therapeutics: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: 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; BMS: 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; Genor Biopharma: Membership on an entity's Board of Directors or advisory committees. Jurczak:Bayer: Research Funding; Beigene: Consultancy, Research Funding; Celgene: Research Funding; AbbVie: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Sandoz: Consultancy, Research Funding; Loxo Oncology: Consultancy, Research Funding; TG Therapeutics: Research Funding; Takeda: Research Funding; Lilly: Consultancy, Research Funding; Mei Pharma: Research Funding; AstraZeneca: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Merck: Research Funding; Morphosys: Research Funding; Novo Nordisk: Research Funding. Roeker:Qilu Puget Sound Biotherapeutics: Research Funding; Ascentage: Consultancy; Aptose Biosciences: Research Funding; Abbott Laboratories: Current equity holder in publicly-traded company; TG Therapeutics: Consultancy; AbbVie: Consultancy, Divested equity in a private or publicly-traded company in the past 24 months; Pfizer: Consultancy, Research Funding; Pharmacyclics: Consultancy; Loxo Oncology: Consultancy, Other: Travel support, Research Funding; AstraZeneca: Consultancy; Beigene: Consultancy; Janssen: Consultancy. Thompson:AbbVie, Pharmacyclics, Adaptive Biotechnologies, Genentech: Research Funding; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; AbbVie, Gilead, Janssen, Pharmacyclics, Adaptive Biotechnologies, Genentech: Consultancy; AbbVie, Gilead, Janssen, Pharmacyclics, Adaptive Biotechnologies, Genentech, Amgen: Honoraria. Abada:Loxo Oncology/Eli Lilly and Company: Current Employment, Current equity holder in publicly-traded company. Wang:Eli Lilly and Company: Current Employment, Current equity holder in publicly-traded company. Nair:Loxo Oncology/Eli Lilly and Company: Current Employment. Liu:Loxo Oncology/Eli Lilly and Company: Current Employment. Tsai:Loxo Oncology/Eli Lilly and Company: Current Employment, Current equity holder in publicly-traded company. Mato:DTRM Biopharma: Honoraria, Research Funding; Johnson & Johnson: Honoraria, Research Funding; LOXO: Honoraria, Research Funding; Pharmacyclics, LLC: Honoraria, Research Funding; TG Therapeutics, Inc: Honoraria, Research Funding; Genmab: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Pfizer: Research Funding; Nurix: Research Funding; AstraZeneca: Honoraria, Research Funding; Octopharma: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; BeiGene: Honoraria, Research Funding; Curio: Honoraria; Dava: Honoraria; AbbVie: Honoraria, Research Funding; Adaptive Biotechnologies: Honoraria; BMS: Honoraria; Medscape: Honoraria; Acerta: Research Funding; PER: Honoraria; PerView: Honoraria.

We will be presenting data from the BRUIN trial. Pirtobrutinib is not approved yet.