Shah, Nirav N.

TPS7587 Background: Covalent (c) Bruton tyrosine kinase inhibitors (BTKi) have transformed the management of MCL, but these agents are not curative. cBTKi share pharmacologic liabilities (e.g., low oral bioavailability, short half-life), which collectively may lead to suboptimal BTK target coverage especially in rapidly proliferating tumors with high BTK protein turnover such as MCL, which can manifest as acquired resistance to BTKi. Pirtobrutinib, a highly selective, non-covalent (reversible) BTKi, has favorable oral pharmacology that enables continuous BTK inhibition throughout the dosing interval regardless of intrinsic rate of BTK turnover. In the phase 1/2 BRUIN study, pirtobrutinib demonstrated promising durable overall response rates and was well tolerated in patients (pts) with MCL regardless of prior therapy (including cBTKi), number of prior lines of therapy, or reason for prior cBTKi discontinuation. Pirtobrutinib was approved by the FDA in January 2023 for R/R MCL after 2 prior lines of therapy including a BTKi. The objective of this study is to establish whether pirtobrutinib is superior to investigator’s choice of cBTKi in pts with previously treated, BTKi naïve MCL. Methods: BRUIN MCL-321 (NCT04662255) is a randomized, open-label, global phase 3 study comparing pirtobrutinib monotherapy versus investigator’s choice of cBTKi monotherapy (ibrutinib, acalabrutinib, or zanubrutinib) in pts with previously treated, BTKi naïve MCL. Approximately 500 pts will be randomized 1:1 and stratified by sMIPI risk (low/intermediate vs high), comparator BTKi (ibrutinib vs acalabrutinib/zanubrutinib), and number of prior lines of therapy (1 vs ≥ 2). Enrollment for this study is ongoing. Adults with a diagnosis of MCL who have received ≥ 1 prior line of systemic therapy for MCL and are BTKi naïve are eligible. Pts must have measurable disease by imaging per Lugano criteria and have progressed on or relapsed following the most recent line of therapy. A history of current or prior CNS involvement, significant cardiovascular disease, stroke or intracranial hemorrhage within 6 months of randomization, and autologous stem cell transplant (SCT), allogeneic SCT or chimeric antigen receptor (CAR) T-cell therapy within 60 days of randomization are key exclusion criteria. Progression-free survival (PFS) per Lugano criteria assessed by an independent review committee is the primary endpoint. Overall response rate, duration of response, investigator-assessed PFS per Lugano criteria, overall survival, event-free survival, time to treatment failure, time to next treatment, PFS2 (time from randomization to disease progression on next line of treatment or death from any cause), safety and tolerability, and pt reported outcomes are secondary endpoints. Clinical trial information: NCT04662255 .

7513 Background: While Bruton tyrosine kinase inhibitors (BTKi) can induce sustained remissions, ongoing response requires continuous treatment and thus long-term safety/tolerability is critical for adherence, maintaining dose intensity, and delivering maximum efficacy. Pirtobrutinib is a highly selective, non-covalent (reversible) BTKi approved by the FDA in January 2023 for R/R mantle cell lymphoma after 2 prior lines of therapy including a BTKi. Pirtobrutinib has demonstrated promising efficacy with low discontinuation and dose reduction rates in patients (pts) with multiple subtypes of R/R B-cell malignancies. However, the long-term safety and tolerability of pirtobrutinib has not yet been reported. Here we report the clinical safety in pts with long-term (≥12 months) pirtobrutinib treatment from the phase 1/2 BRUIN trial. Methods: Pts with R/R B-cell malignancies who received ≥12 months of pirtobrutinib were included. Median time to onset, dose reduction, discontinuation, and cumulative incidence rates were determined for treatment emergent adverse event (TEAE) that occurred in ≥20% of pts and select AE of interest associated with BTKi. Results: As of 29 July 2022, 773 pts were enrolled, and 326 (42%) pts received treatment for ≥12 months. Among these 326 pts, median time on treatment was 19 months (IQR: 16,25), with 231 (71%) remaining on pirtobrutinib. The most common TEAE (all grade, regardless of attribution) in this long-term 326 pt cohort were fatigue (32%), diarrhea (31%), Covid-19 (29%), contusion (26%), cough (25%), and back pain (21%). TEAE leading to dose reduction or discontinuation occurred in 23 (7%) and 11 (3%) pts, respectively. Four (1%) pts discontinued due to a treatment-related AE, and 1 pt had a fatal treatment-related AE (Covid-19 pneumonia). Select AE of interest for the long-term pts are shown in the Table. Comprehensive safety analyses describing the frequency of TEAE over time will be presented. Conclusions: Prolonged pirtobrutinib therapy continues to demonstrate a safety profile amenable to long-term administration at the recommended dose without evidence of new or worsening toxicity signals. The safety and tolerability observed in pts on therapy for ≥12 months was similar to previously published safety analyses on all pts enrolled regardless of follow-up. Clinical trial information: NCT03740529 . [Table: see text]

7501 Background: In patients (pts) with R/R CLL/SLL that progressed on BTKi and failed venetoclax (ven)-based regimens, achieving CR with current treatment is uncommon. New therapies that achieve deep and durable responses are needed. We report the primary analysis of the phase 1/2, single-arm, multicenter TRANSCEND CLL 004 (NCT03331198) study evaluating liso-cel in pts with R/R CLL/SLL. Methods: Pts must have received at least 2 prior lines of therapy, including a BTKi. Eligible pts received liso-cel at a target dose of either 50 (DL1) or 100 (DL2) × 106 CAR+ T cells. The primary endpoint was rate of CR and CR with incomplete marrow recovery (CRi) by IRC per 2018 iwCLL criteria in the prespecified subset of efficacy-evaluable pts with disease progression on BTKi and ven failure (primary efficacy analysis set [PEAS]) at DL2 (null hypothesis [H0]: ≤ 5%). Key secondary endpoints were ORR (H0: ≤ 40%) and rate of undetectable minimal residual disease (uMRD; 10−4) in blood (H0: ≤ 5%). Results: Of 137 leukapheresed pts, 117 received liso-cel (safety set), 96 (DL1 = 9; DL2 = 87) were efficacy evaluable, and 53 (DL1 = 4; DL2 = 49) were in the PEAS. In the safety set, median (range) age was 65 y (49–82), 83% had high-risk features, median (range) lines of prior therapy was 5 (2–12), and all pts had prior BTKi. Median (range) on-study follow-up was 21.1 mo (0.4–55.6) for the safety set. In the PEAS at DL2, the primary endpoint of CR/CRi rate was met at 18.4% (95% CI, 8.8–32.0; 1-sided P = 0.0006; Table). ORR was 42.9% and was not statistically significant (95% CI, 28.8–57.8; 1-sided P = 0.3931). The uMRD rate was 63.3% in blood and 59.2% in marrow. Median (95% CI) DOR was 35.3 mo (11.01–not reached [NR]) with a median follow-up of 19.7 mo. Median duration of CR/CRi was NR. In the safety set, rate of any-grade CRS was 84.6% (gr 3, 8.5%; no gr 4/5) and neurological events (NE) was 45.3% (gr 3, 17.9%; gr 4, 0.9%; no gr 5); 69.2% received tocilizumab and/or corticosteroids for CRS/NEs. Rate of gr ≥ 3 infections, hypogammaglobulinemia, and prolonged cytopenia was 17.1%, 15.4%, and 53.8%, respectively. One death related to liso-cel was due to hemophagocytic lymphohistiocytosis. Liso-cel exhibited rapid in vivo expansion and was detected by qPCR in blood up to 36 mo after infusion. Conclusions: Liso-cel demonstrated durable CR/CRi, high uMRD rates, and a manageable safety profile in pts with heavily pretreated, high-risk R/R CLL/SLL and high unmet need. Clinical trial information: NCT03331198 . [Table: see text]

7514 Background: Pirtobrutinib is a highly selective, non-covalent (reversible) BTKi. Here, we report updated results of pirtobrutinib in patients (pts) with cBTKi pre-treated relapsed/refractory (R/R) 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. Conclusions: 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. Clinical trial information: NCT03740529 . [Table: see text]

PURPOSE Pirtobrutinib is a highly selective, noncovalent (reversible) Bruton tyrosine kinase inhibitor (BTKi). We report the safety and efficacy of pirtobrutinib in patients with covalent Bruton tyrosine kinase inhibitor (cBTKi) pretreated mantle-cell lymphoma (MCL), a population with poor prognosis. METHODS Patients with cBTKi pretreated relapsed/refractory (R/R) MCL received pirtobrutinib monotherapy in a multicenter phase I/II trial (BRUIN; ClinicalTrials.gov identifier: NCT03740529 ). Efficacy was assessed in the first 90 consecutively enrolled patients who met criteria for inclusion in the primary efficacy cohort. The primary end point was overall response rate (ORR). Secondary end points included duration of response (DOR) and safety. RESULTS The median patient age was 70 years (range, 46-87), the median prior lines of therapy was 3 (range, 1-8), 82.2% had discontinued a prior cBTKi because of disease progression, and 77.8% had intermediate- or high-risk simplified MCL International Prognostic Index score. The ORR was 57.8% (95% CI, 46.9 to 68.1), including 20.0% complete responses (n = 18). At a median follow-up of 12 months, the median DOR was 21.6 months (95% CI, 7.5 to not reached). The 6- and 12-month estimated DOR rates were 73.6% and 57.1%, respectively. In the MCL safety cohort (n = 164), the most common treatment-emergent adverse events (TEAEs) were fatigue (29.9%), diarrhea (21.3%), and dyspnea (16.5%). Grade ≥3 TEAEs of hemorrhage (3.7%) and atrial fibrillation/flutter (1.2%) were less common. Only 3% of patients discontinued pirtobrutinib because of a treatment-related adverse event. CONCLUSION Pirtobrutinib is a first-in-class novel noncovalent (reversible) BTKi and the first BTKi of any kind to demonstrate durable efficacy after prior cBTKi therapy in heavily pretreated R/R MCL. Pirtobrutinib was well tolerated with low rates of treatment discontinuation because of toxicity.

Abstract Background: Covalent Bruton's Tyrosine Kinase (BTK) inhibitors (BTKi) have transformed the management of relapsed mantle cell lymphoma (MCL), but these treatments are not curative and the majority of patients will require additional treatment. Covalent BTKi share pharmacologic liabilities (e.g. low oral bioavailability, short half-life) that collectively may lead to suboptimal BTK target coverage especially in rapidly proliferating tumors with high BTK protein turnover such as MCL. To address these limitations, pirtobrutinib, a highly selective, non-covalent BTKi that inhibits both wild type (WT) and C481-mutated BTK with equal low nM potency was developed. In the phase 1/2 BRUIN study, pirtobrutinib achieved pharmacokinetic exposures that exceeded its BTK IC96 at trough, was well tolerated, and demonstrated promising efficacy in heavily pretreated, poor-prognosis MCL patients, most of whom had prior treatment with a covalent BTKi (Mato et al. Lancet 2021;397,10277:892-901). The purpose of this randomized study is to demonstrate the superiority of pirtobrutinib compared to investigator's choice of covalent BTKi in patients with previously treated MCL. Study Design and Methods: BRUIN MCL-321 is a randomized, open-label, global phase 3 study comparing pirtobrutinib monotherapy versus investigator's choice of covalent BTKi monotherapy (ibrutinib, acalabrutinib, or zanubrutinib) in patients with previously treated, BTKi naïve MCL. Approximately 500 patients will be randomized 1:1. Randomization will be stratified by sMIPI risk (low/intermediate vs high), comparator BTKi (ibrutinib vs acalabrutinib/ zanubrutinib), and number of prior lines of therapy (1 vs ≥ 2). Eligible patients are adults aged ≥18 years with a confirmed diagnosis of MCL (cyclin D1 overexpression, and ≥ 1 B-cell marker) who have received ≥ 1 prior line of systemic therapy for MCL that did not include a prior BTKi. Patients must have measurable disease per Lugano criteria and must have progressed on or relapsed following the most recent line of therapy prior to study enrollment. Key exclusion criteria include a history of current or prior CNS involvement, significant cardiovascular disease, stroke, or intracranial hemorrhage within 6 months of randomization, and allogeneic stem cell transplant (SCT), autologous SCT or chimeric antigen receptor (CAR) T-cell therapy within 60 days of randomization. The primary endpoint is progression-free survival (PFS) per Lugano criteria assessed by an independent review committee (IRC), with the goal of demonstrating superiority of pirtobrutinib over investigator's choice of covalent BTKi. Secondary endpoints include overall response rate (ORR), duration of response (DoR), investigator-assessed PFS per Lugano criteria, overall survival (OS), event-free survival (EFS), time to treatment failure (TTF), time to next treatment (TTNT), time from randomization to disease progression on next line of treatment or death from any cause (PFS2), safety and tolerability, and patient reported outcomes. This global study is currently enrolling patients (NCT04662255). Disclosures Eyre: Gilead/KITE: Honoraria, Other: Travel support for conferences, Research Funding, Speakers Bureau; Janssen: Honoraria; Loxo Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Abbvie: Consultancy, Honoraria, Other: Travel to conferences; Roche: Consultancy, Honoraria; AstraZeneca: Honoraria, Research Funding; Beigene: Honoraria, Research Funding; Secura Bio: Consultancy, Honoraria. Shah: Miltenyi Biotec: Consultancy, Honoraria, Research Funding; Kite: Consultancy; Epizyme: Consultancy; Umoja: Consultancy; Legend: Consultancy; Incyte: Consultancy; Lily: Consultancy, Honoraria, Research Funding. Dreyling: Novartis: Consultancy, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy, Research Funding, Speakers Bureau; Astra Zeneca: Consultancy, Speakers Bureau; BeiGene: Consultancy; Celgene: Consultancy, Research Funding, Speakers Bureau; Amgen: Speakers Bureau; Genmab: Consultancy; Bayer HealthCare Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau; Gilead/Kite: Consultancy, Research Funding, Speakers Bureau; Abbvie: Research Funding; Incyte: Consultancy, Speakers Bureau. Vandenberghe: Jansnens: Honoraria; Abbvie: Honoraria. Jurczak: Abbvie, AstraZeneca, BeiGene, Celtrion, Celgene, Debbiopharm, Epizyme, Incyte, Janssen, Loxo Oncology, Merck, Mei Pharma, Morphosys, Novo Nordisk, Roche, Sandoz, Takeda, TG Therapeutics: Research Funding; Astra Zeneca, BeiGene, Janssen, Loxo Oncology, Sandoz, Roche,: Membership on an entity's Board of Directors or advisory committees. Wang: Genentech: Research Funding; Eli Lilly: 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; Novartis: Research Funding; InnoCare: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees. Cheah: Loxo/Lilly: Consultancy, Honoraria, Other: advisory; Janssen: Consultancy, Honoraria, Other: advisory; Roche: Consultancy, Honoraria, Other: advisory and travel expenses, Research Funding; TG Therapeutics: Consultancy, Honoraria, Other: advisory; AstraZeneca: Consultancy, Honoraria, Other: advisory; Celgene: Research Funding; AbbVie: Research Funding; Beigene: Consultancy, Honoraria, Other: advisory; Ascentage pharma: Consultancy, Honoraria, Other: advisory; Gilead: Consultancy, Honoraria, Other: advisory; MSD: Consultancy, Honoraria, Other: advisory, Research Funding. Gandhi: Karyopharm Therapeutics: Honoraria; TG Therapeutics: Honoraria; GlaxoSmithKline: Honoraria. Sharman: AstraZeneca: Consultancy; Lilly: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy; Centessa: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy; BMS: Consultancy; TG Therapeutics: Consultancy; AbbVie: Consultancy. Andorsky: Abbvie: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; Epizyme: Research Funding. Yin: Loxo Oncology at Lilly: Current Employment; AstraZeneca: Ended employment in the past 24 months. Balbas: Nektar Therapeutics: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Loxo Oncology at Lilly: Current Employment, Current equity holder in publicly-traded company. Kherani: Loxo Oncology at Lilly: Current Employment, Current equity holder in publicly-traded company. Wang: AstraZeneca, Bayer Healthcare, BeiGene, CSTone, DTRM Biopharma (Cayman) Limited, Epizyme, Genentech, InnoCare, Janssen, Juno, Kite Pharma, Loxo Oncology, Miltenyi Biomedicine GmbH, Oncternal, Pharmacyclics, VelosBio: Consultancy; Acerta Pharma, AstraZeneca, BeiGene, BioInvent, Celgene, Innocare, Janssen, Juno, Kite, Pharma, Lilly, Loxo Oncology, Molecular Templates, Oncternal, Pharmacyclics, VelosBio: Research Funding; Acerta Pharma, Anticancer Association, AstraZeneca, BeiGene, CAHON, Chinese Medical Association, Clinical Care Options, Dava Oncology, Epizyme, Hebei Cancer Prevention Federation, Imbruvica, Imedex, Janssen, Kite Pharma, Miltenyi Biomedicine GmbH, Moffit : Honoraria.