PIRTOBRUTINIB IN COVALENT BTK‐INHIBITOR PRE‐TREATED MANTLE CELL LYMPHOMA: UPDATED RESULTS, SUBGROUP ANALYSIS FROM BRUIN WITH >3 YEARS FOLLOW‐UP FROM START OF ENROLLMENT (2023)

Introduction: Pirtobrutinib is a highly selective, non-covalent (reversible) BTK-inhibitor (BTKi). Here, we report updated results of pirtobrutinib in patients (pts) with cBTKi pre-treated relapsed/refractory (R/R) mantle cell lymphoma (MCL) and more than 3 years follow-up from start of enrollment. Methods: Pts with cBTKi pre-treated R/R MCL received pirtobrutinib monotherapy in a multicenter phase 1/2 BRUIN trial (NCT03740529). Efficacy was assessed in the prespecified primary efficacy cohort that comprised the first 90 enrolled pts who had measurable disease, had received a prior cBTKi, and had no known central nervous system involvement. The primary endpoint was overall response rate (ORR) as assessed by independent review committee. Secondary endpoints included duration of response (DOR) and safety. A data cut of 29 July 2022 was utilized. Results: Among MCL pts who received a prior cBTKi (n = 90), median age was 70 years (range 46–87), median prior lines of therapy were 3 (range 1–8), 82% discontinued a prior cBTKi due to disease progression, and 78% had intermediate/high risk sMIPI score. Of samples available, 17/36 (47%) had TP53 mutations and 25/34 (74%) had Ki67 ≥30%. The ORR was 57% (95% CI, 46–67), including 19% complete responses (n = 17) and 38% partial responses (n = 34). At a median follow-up time of 13 months, the median DOR among the 51 responding pts was 17.6 months (95% CI, 7.3–27.2). The 12- and 18-month estimated DOR rates were 58% (95% CI, 41–72) and 45% (95% CI, 27–61), respectively. ORR and DOR by subgroups are shown in the Table. The median progression-free survival was 7.4 months (95% CI, 5.3–13.3). The median overall survival was 23.5 months (95% CI, 15.9-NE). In the MCL safety cohort (n = 166), the most frequent treatment-emergent adverse events (TEAE) were fatigue (31%), diarrhea (22%), and anemia (17%). The most common Grade ≥3 TEAE was neutropenia (15%). Grade ≥3 TEAE of hemorrhage (3%) and atrial fibrillation/flutter (2%) were infrequent. Only 5 (3%) pts discontinued due to a treatment-related AE. Conclusion: Pirtobrutinib continues to show durable efficacy and a favorable safety profile in heavily pre-treated R/R MCL pts with prior cBTKi therapy. Responses were observed in pts with high-risk disease features including pts with blastoid/pleomorphic variants, elevated Ki67 index, and TP53 mutations. Encore Abstract—previously submitted to ASCO 2023 The research was funded by: [email protected] Keyword: molecular targeted therapies Conflicts of interests pertinent to the abstract C. Y. Cheah Consultant or advisory role: Roche, Janssen, Gilead, AstraZenecca, Lilly, TG therapeutics, Beigene, Novartis, Menarini, Daizai, Abbvie, Genmab Honoraria: Roche, Janssen, Gilead, AstraZenecca, Lilly, TG therapeutics, Beigene, Novartis, Menarini, Daizai, Abbvie, Genmab Research funding: BMS, Roche, Abbvie; MSD, Lilly N. N. Shah Consultant or advisory role: Novartis, Lilly Oncology, Milentyi Biotec, Kite Pharma, BMS, TG therapeutics, Epizyme, Incyte Honoraria: Lilly Oncology Research funding: Miltenyi Biotec Other remuneration: Incyte W. Jurczak Employment or leadership position: Maria Sklodowska-Curie National Research Institue of Oncology Consultant or advisory role: Janssen, Astra Zeneca, Mei Pharma, Lilly, Takeda, Roche, Abbvie, Beigene Research funding: Abbvie, Bayer, Beigene, Celgene, Janssen, Roche, Takeda, TgTherapeutics, Astra Zeneca, Mei Pharma, Lilly, P. L. Zinzani Consultant or advisory role: SECURA BIO, CELLTRION, GILEAD, JANSSEN-CILAG, BMS, SERVIER, SANDOZ, MSD, TG Therap., TAKEDA, ROCHE, EUSAPHARMA, KYOWA KIRIN, NOVARTIS, ADC Therap., Incyte, Beigene Other remuneration: Speakers bureau: CELLTRION, GILEAD, JANSSEN-CILAG, BMS, SERVIER, MSD, TG Therap., TAKEDA, ROCHE, EUSAPHARMA, KYOWA KIRIN, NOVARTIS, Incyte, Beigene T. A. Eyre Consultant or advisory role: Roche, AstraZeneca, KITE Gilead, Loxo Oncology, Beigene, Incyte, Abbvie, Janssen, Secura Bio Honoraria: Roche, AstraZeneca, KITE Gilead, Loxo Oncology, Beigene, Incyte, Abbvie, Janssen Research funding: Astrazeneca, Beigene Other remuneration: Roche, AstraZeneca, Janssen, Abbive C. S. Ujjani Consultant or advisory role: Epizyme, Atara, Astrazeneca, Janssen, Genentech, Abbvie, Beigene, Incyte, Pharmacyclics, Eli Lilly/Loxo Research funding: Adaptive Biotechnologies, Pharmacyclics, Abbvie, Astrazeneca, Eli Lilly/Loxo K. Izutsu Consultant or advisory role: Beigene, AstraZeneca, Ono Pharmaceutical, AbbVie, Novartis, Chugai, Eli Lilly Honoraria: Eizai, Chugai, Janssen, AstraZeneca, Novartis, Bristol Myers Squibb, Kyowa Kirin, AbbVie, Ono Pharmaceutical, Eli Lilly, MSD, Daiichi Sankyo, Symbio, Takeda Research funding: MSD, AstraZeneca, AbbVie, Eizai, Incyte, Janssen, Yakult, Kyowa Kirin, Ono Pharmaceutical, Daiichi Sankyo, Chugai, Beigene, Genmab, Loxo Oncology S. Ma Consultant or advisory role: Abbvie, Astrazeneca, BeiGene, BMS (Bristol Myers Squibb), Janssen, Pharmacyclics, TG Therapeutics Research funding: Abbvie, Astrazeneca, BeiGene, Juno, Janssen, Loxo, Pharmacyclics, TG Therapeutics Other remuneration: Speakers Bureau: Astrazeneca, BeiGene, Janssen, Pharmacyclics I. Flinn Consultant or advisory role: AbbVie, AstraZeneca, BeiGene, Century Therapeutics, Genentech, Genmab, Gilead Sciences, Great Point Partners, Hutchison MediPharma, Iksuda Therapeutics, InnoCare Pharma, Janssen, Juno Therapeutics, Kite Pharma, MorphoSys, Novartis, Nurix Therapeutics, Pharmacyclics, Roche, Seattle Genetics, Servier Pharmaceuticals, Takeda, TG Therapeutics, Unum Therapeutics, Verastem, Vincerx Pharma, Yingli Pharmaceuticals Research funding: AbbVie, Acerta Pharma, Agios, ArQule, AstraZeneca, BeiGene, Biopath, Bristol Myers Squibb, CALIBR, CALGB, Celgene, City of Hope National Medical Center, Constellation Pharmaceuticals, Curis, CTI Biopharma, Fate Therapeutics, Forma Therapeutics, Forty Seven, Genentech, Gilead Sciences, InnoCare Pharma, IGM Biosciences, Incyte, Infinity Pharmaceuticals, Janssen, Kite Pharma, Loxo, Merck, Millennium Pharmaceuticals, MorphoSys, Myeloid Therapeutics, Novartis, Nurix, Pfizer, Pharmacyclics, Portola Pharmaceuticals, Rhizen Pharmaceuticals, Roche, Seattle Genetics, Tessa Therapeutics, TCR2 Therapeutics, TG Therapeutics, Trillium Therapeutics, Triphase Research & Development Corp., Unum Therapeutics, Verastem A. J. Alencar Consultant or advisory role: Karyopharm, OncLive, Amgen, Kite, SeaGen, Epizyme, Janssen, BeiGene, Incyte, TG Therapeutics Research funding: Loxo, BeiGene, Incyte D. Lewis Consultant or advisory role: Lilly, Kite, Janssen, Roche Educational grants: Janssen, Kite Other remuneration: Janssen K. Patel Consultant or advisory role: Abbvie, ADC Therapeutics, AstraZeneca, BeiGene, Bristol Myers Squibb, Caribou Biosciences, Celgene, Epizyme, Genentech/Roche, Kite, Loxo Oncology, MEI Pharma, Morphosys, Pharmacyclics/Janssen, TG Therapeutics, Trillium Therapeutics/Pfizer, Xencor Research funding: Adaptive Biotechnologies, Aptevo Therapeutics, AstraZeneca, Bristol Myers Squibb, CRISPR Therapeutics, Celgene, Curis, Inc, Epizyme, Fate Therapeutics, Genentech/Roche, Kite, Loxo Oncology, MEI Pharma, Nurix, Pharmacyclics/Janssen, Sunesis Pharmaceuticals, Trillium Therapeutics/Pfizer, Velos Bio, Xencor K. Maddocks Consultant or advisory role: Pharmacyclics, Seattle Genetics, Morphosys, Celgene, Karyopharm, ADC Therapeutics, AstraZeneca, Bristol Myers Squibb Honoraria: Pharmacyclics, Seattle Genetics, Morphosys, Celgene Research funding: Bristol Myers Squibb Y. Wang Consultant or advisory role: Eli Lilly, TG Therapeutics, LOXO Oncology, Incyte, InnoCare, Kite, Jansen, BeiGene Honoraria: Kite Research funding: Incyte, InnoCare, LOXO Oncology, Novartis, Genentech, MorphoSys, Genmab T. Munir Employment or leadership position: St James’s Hospital Consultant or advisory role: Abbvie, AstraZeneca, Beigene, Lilly, Novartis, Alexion Honoraria: AstraZeneca, Janssen, Abbvie, Gilead, Alexion, Sobi A. D. Zelenetz Employment or leadership position: MSKCC Consultant or advisory role: BMS/Celgene/JUNO; Genentech/Roche; Gilead/Kite; BeiGene; Pharmacyclics/Abbvie; Jansen; Amgen; Astra-Zeneca; Novartis; MEI Pharma, LRF Honoraria: BMS/Celgene/JUNO; Genentech/Roche; Gilead/Kite; BeiGene; Pharmacyclics/Abbvie; Jansen; Amgen; Astra-Zeneca; Novartis; MEI Pharma Research funding: Genentech/Roche; MEI Pharma; BeiGene M. Balbas Employment or leadership position: [email protected] Stock ownership: [email protected] D. E. Tsai Employment or leadership position: [email protected] Stock ownership: [email protected] C. Wang Employment or leadership position: Eli Lilly and Company Stock ownership: Eli Lilly and Company M. L. Wang Employment or leadership position: University of Texas MD Anderson Cancer Center Consultant or advisory role: AbbVie, Acerta Pharma, AstraZeneca, BeiGene, BioInvent, Deciphera, InnoCare, Janssen, Kite Pharma, Leukemia & Lymphoma Society, Lilly, Merck, Milken Institute, Oncternal, Parexel, Pepromene Bio, Pharmacyclics, VelosBio Honoraria: AbbVie, Acerta Pharma, AstraZeneca, BeiGene, BioInvent, Dava Oncology, Eastern Virginia Medical School, IDEOlogy Health, Janssen, Kite Pharma, Leukemia & Lymphoma Society, LLC TS Oncology, Medscape, Meeting Minds Experts, , MJH Life Sciences, Merck, Moffit Cancer Center, Oncology Specialty Group, OncLive, Pharmacyclics, Physicians Education Resources (PER), Practice Point Communications (PPC), Studio ER Congressi Research funding: Acerta Pharma, AstraZeneca, BeiGene, BioInvent, Celgene, Genmab, Genentech, Innocare, Janssen, Juno Therapeutics, Kite Pharma, Lilly, Loxo Oncology, Molecular Templates, Oncternal, Pharmacyclics, VelosBio, Vincerx