Tsai, Donald E.

Abstract Background: Despite the efficacy of covalent Bruton tyrosine kinase inhibitors (cBTKi) in R/R MCL, patients (pts) ultimately discontinue treatment due to intolerance or development of resistance and disease relapse. Pirtobrutinib is a highly selective, non-covalent BTKi that inhibits BTK with low nM potency throughout the daily dosing interval. Pirtobrutinib was safe and effective in the phase 1/2 BRUIN study in pts with R/R B-cell malignancies, including those previously treated with a BTKi. Pirtobrutinib is approved in the EU for adults with R/R MCL after prior treatment with a BTKi (EMA Conditional Approval, Oct 2023), and in the USA for adults with R/R MCL after ≥ 2 lines of systemic therapy, including a BTKi (FDA Accelerated Approval, Jan 2023).Here, we report the final results from the phase 1/2 BRUIN study (NCT03740529), with a follow-up period of up to 5 yrs, focusing on the efficacy and safety of pirtobrutinib in all R/R MCL pts. Methods: Pts with R/R MCL who received ≥1 prior lines of therapy (including BTKi) were eligible for treatment with pirtobrutinib monotherapy. Key endpoints included overall response rate (ORR), duration of response (DOR) and progression-free survival (PFS), all assessed by independent review committee (IRC) per Lugano 2014 criteria (presented here) and investigator, overall survival (OS), and safety. Pts were included across the range of doses evaluated in dose escalation and expansion (25-300 mg/day). A data cutoff on 27 January 2025 was utilized, with a median study follow-up of 17.5 months (range, 0.5-69.6). Results: Among the 166 pts with R/R MCL, 153 (92%) received the pirtobrutinib approved dose of 200 mg/day, 152 (92%) had received prior cBTKi, of which 128 (84.2%) discontinued any prior cBTKi due to progressive disease (PD), and 15 (9.9%) due to toxicity. The cBTKi-pre-treated pts had a median age of 70 yrs (range, 46-88), 52% had intermediate-risk and 28.3% had high-risk sMIPI scores. The median number of prior lines of therapy was 3 (range 1-9), with most pts having received a prior anti-CD20 antibody (96.7%) and chemotherapy (90.1%). Additional prior therapies included hematopoietic stem cell transplantation (21.7%; 19.7% auto and 4.6% allo), BCL-2 inhibitor (15.8%), CAR-T cell therapy (8.6%). As of the data cutoff, 11 (7.2%) pts who received a prior cBTKi and 6 (42.9%) cBTKi naïve pts remained on treatment. The cBTKi pre-treated pts had an ORR of 49.3% (95% CI, 41.1-57.6), including 15.8% complete responses (CR) (n=24) and 33.6% partial responses (PR) (n=51). The 75 responding pretreated pts had a median DOR of 21.6 months (95% CI, 9.2-27.2) at a median follow-up of 24 months. The ORR among 128 pts who had discontinued any prior cBTKi due to PD and 15 pts who discontinued due to toxicity was 43.0% and 93.3%, respectively. The median PFS and OS for cBTKi pre-treated pts were 5.6 months (95% CI, 5.3-9.2) and 23.9 months (95% CI, 17.3-51.5), respectively. Fourteen pts (9.2%) were censored for PFS due to subsequent anticancer therapy without documented PD, including 8 pts who received CAR-T. The cBTKi naïve pts (n=14) had an ORR of 85.7% (95% CI, 57.2-98.2), including 50.0% CR (n=7) and 35.7% PR (n=5). The 12 responding naïve pts had a median DOR of 42.7 months (95% CI, 25.8-NE) at a median follow-up of 43 months. The median PFS and OS in the cBTKi naïve pts were 44.6 months (95% CI, 16.7-NE) and not reached (95% CI, 33.5-NE), respectively. Among all R/R MCL pts (n=166), the most frequent treatment-emergent adverse events (TEAE), regardless of attribution, were fatigue (31.9%), diarrhea (22.9%), anemia (18.1%), and dyspnea (18.1%). The most common Grade ≥3 TEAE was neutropenia/neutrophil count decreased (13.3%), and the rate of Grade ≥3 infections was 21.1%. Grade ≥3 hemorrhage/hematoma (2.4%) and all-grade atrial fibrillation/flutter (3.6%) were infrequent. In total, 13 (7.8%) pts had a fatal TEAE, with 4 (2.4%) classified as infections. Overall, 8 pts (4.8%) had treatment-related AE leading to dose reductions, and 6 (3.6%) had treatment-related AE leading to pirtobrutinib discontinuation. Conclusion: Pirtobrutinib continues to demonstrate efficacy in pts with heavily pre-treated R/R MCL including both those who previously received a cBTKi and those who were BTKi-naïve. The safety profile of pirtobrutinib remained favorable with a low-rate of dose reductions/discontinuations due to drug-related toxicity. No new safety signals were identified after up to 5 yrs of follow-up.

Background:Richter transformation (RT) occurs in up to 10% of patients with chronic lymphocytic leukemia (CLL), typically presents as an aggressive diffuse large B-cell lymphoma (DLBCL) and is associated with poor survival. RT has no approved standard therapy; and clinical trial enrollment is the preferred first line of therapy. Pirtobrutinib, a highly selective, non-covalent (reversible) BTKi, that inhibits both wildtype and C481-mutant BTK with equal low nM potency, has favorable oral pharmacology that enables continuous BTK inhibition throughout the dosing interval. Pirtobrutinib demonstrated durable overall response rates (ORR) and was well tolerated in patients (pts) with poor-prognosis B-cell malignancies regardless of prior therapy. Here we provide updated safety and efficacy of pirtobrutinib in RT pts from the phase 1/2 BRUIN trial (NCT03740529). Methods: Pts with previously treated, histologically confirmed RT were eligible in the global, multicenter, phase 1/2 BRUIN study. Pts with untreated RT became eligible after Amendment 10. All but one patient received the recommended phase 2 dose of 200 mg daily. Key endpoints included investigator-assessed ORR, DoR per Lugano 2014 criteria, OS, and safety. A data cut of 05 May 2023 was utilized. To assess clonal relationship, IGH rearrangement studies were done on tissue biopsies with RT involvement, and baseline blood or bone marrow (BM) samples with CLL involvement. Results: Among all pts with RT (N=82) the median age was 67 (range, 26-95) and the median total number of lines of prior systemic therapy was 4 (range, 0-13). Pts with prior treatment had a median of 2 CLL-directed therapies and 2 RT-directed therapies. Eight pts did not have a previous line of RT-directed therapy, and 1 patient received neither RT- nor CLL-directed therapy. Common prior RT- and CLL-directed therapies (RT, CLL) included: chemotherapy (76%, 52%), cBTKi (34%, 62%), anti-CD20 antibody (78%, 66%), BCL2i (38%, 49%), stem cell transplant (SCT; 6%, 7%), and CAR-T (11%, 4%). Of 29 pts with bone marrow screening, 41.4% had CLL alone present in BM, 13.8% had DLBCL present and 24.1% had both CLL and DLBCL present. For 39 pts with available PET data, the median SUVmax was 19.1 (range, 2.6-41.2). For all 82 pts, the ORR was 50.0% (95% CI, 38.7-61.3) including complete (13.4%, n=11) and partial (36.6%, n=30) responses. For 61 pts who received prior cBTKi therapy, the ORR was 45.9% (95% CI 33.1-59.2). Among 28 pts with an RT-directed cBTKi and 51 pts with prior CLL-directed cBTKi, the ORR was 42.9% (95% CI, 24.5-62.8) and 43.1% (95% CI, 29.3-57.8), respectively. In 50 pts who discontinued prior cBTKi due to disease progression, the ORR was 42.0% (95% CI, 28.2-56.8). At median follow-up time of 9.7 months, the median DoR for all 82 RT pts was 7.4 months (95% CI, 3.1-19.1) and the estimated rate at 12 months was 45.9% (95% CI, 28.3-61.8). The median time on treatment for the 41pts who responded to treatment was 8.3 months. Eight pts stopped pirtobrutinib to pursue curative-intent allogeneic SCT and DoR was censored at the last preceding disease assessment. At a median survival follow-up of 18.3 months, the median OS for the entire RT cohort was 12.5 months (95% CI, 6.9-20.5). At 18 months, the OS rate was 44.3% (95% CI, 32.5-55.4). Frequent treatment-emergent adverse events (TEAE) in the RT cohort (n=82) were neutropenia/decreased neutrophil count (29.3%, n=24), fatigue (24.4%, n=20) and diarrhea, dyspnea, thrombocytopenia, and pyrexia (18.3% each, n=15). Common grade ≥3 TEAEs were neutropenia/decreased neutrophil count (23.2%, n=19), thrombocytopenia (11.0%, n=9), plus anemia and sepsis (9.8% each, n=8). Any grade hypertension (3.7%, n=3) or atrial fibrillation (1.2%, n=1) were infrequent. Three pts (3.7%) had treatment-related AEs leading to dose reductions, but no pt had a treatment-related AE leading to pirtobrutinib discontinuation. Analyses of clonality will be presented. Conclusions: Continued follow-up from BRUIN demonstrates encouraging response and OS in pts with RT. Pirtobrutinib remains well-tolerated with low rates of discontinuation and manageable safety profile. While RT remains a challenging diagnosis, pirtobrutinib represents a potential treatment option that warrants further investigation.

Background: Despite the efficacy of covalent (c) Bruton tyrosine kinase inhibitors (BTKi) in R/R MCL, disease relapse arises through evolution of resistance mechanisms or development of cBTKi intolerance. Pirtobrutinib, a highly selective, non-covalent (reversible) BTKi has favorable oral pharmacology that enables continuous BTK inhibition throughout the daily dosing interval regardless of the intrinsic rate of BTK turnover. Pirtobrutinib is the first BTKi to demonstrate durable efficacy following prior cBTKi therapy in heavily pre-treated R/R MCL and was well-tolerated with a low frequency of treatment discontinuation due to toxicity (Wang et al., JCO, 2023). Pirtobrutinib is approved in the USA to treat relapsed or refractory MCL after at least two lines of systemic therapy including a prior cBTKi. Here, we report updated results of pirtobrutinib therapy in all patients (pts), including those with biologically high-risk R/R MCL with a median survival follow-up of 24.2 months (range, 18.2-29.8). Methods: Pts with R/R MCL received pirtobrutinib monotherapy in the multicenter Phase 1/2 BRUIN trial (NCT03740529). Efficacy was assessed in all cBTKi pre-treated pts, as well as in cBTKi treatment-naïve pts. Key endpoints included overall response rate (ORR) as assessed by independent review committee per Lugano 2014 criteria, duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Pts were included across the dose escalation range and expansion (25-300 mg/day) with 93% (n=141) receiving at least one dose of 200 mg/day, the FDA-approved dose. A data cut of 05 May 2023 was utilized. Results: Among all 152 pts with R/R MCL who received a prior cBTKi, the median age was 70 years (range, 46-88), and 52% had intermediate-risk and 28.3% had high-risk sMIPI scores. Median prior lines of therapy were 3 (range, 1-9), including an anti-CD20 antibody (96.7%), chemotherapy (90.1%), immunomodulator (17.1%), stem cell transplant (21.7%), BCL-2 inhibitor (15.8%), CAR-T cell therapy (8.6%), and PI3K inhibitor (3.9%). Among pts with high-risk biomarker data available, 30/60 (50%) had TP53 mutations and 45/63 (71%) had a Ki-67 index of ≥30%. The ORR for cBTKi pre-treated pts was 49.3% (95% CI, 41.1-57.6), including 15.8% complete responses (n=24) and 33.6% partial responses (n=51), whilst cBTKi naïve pts (n=14) had an ORR of 85.7% (95% CI, 57.2-98.2). The ORR among 128 pts who had discontinued a prior cBTKi due to PD and 21 pts who had discontinued for toxicity/other reasons was 43.0% and 90.5%, respectively. Among the 75 responding cBTKi pre-treated pts, the median DOR was 21.6 months (95% CI, 9.2-27.2) at a median follow-up of 24 months. The 18- and 24-month DOR rates were 51.9% (95% CI, 37-64.8) and 38.9% (95% CI, 22.7-54.8), respectively. ORR and DOR by high-risk subgroups (including blastoid/pleomorphic variants, Ki-67 index ≥30%, and TP53 mutations) are shown in Table 1. The 18- and 24-month DOR rates among 12 responding cBTKi naïve pts were both 90.0% (95% CI, 47.3-98.5). The median PFS and OS for cBTKi pre-treated pts was 5.6 months (95% CI, 5.3-9.2), and 23.5 months (95% CI, 17.1-NE), respectively. In the MCL cohort (n=166), the most frequent treatment-emergent adverse events (TEAEs) were fatigue (31.9%), diarrhea (22.3%), and dyspnea (17.5%). The most common Grade ≥3 TEAE was neutropenia/neutrophil count decreased (13.3%) and the rate of Grade ≥3 infections was (19.9%). Grade ≥3 hemorrhage/hematoma (2.4%) and all-grade atrial fibrillation/flutter (3.6%) were infrequent. Overall, 8 pts (5%) had treatment-related AEs leading to dose reductions and 5 (3%) had treatment-related AEs leading to pirtobrutinib discontinuation. Conclusion: Pirtobrutinib continues to demonstrate durable efficacy and a favorable safety profile in heavily pre-treated R/R MCL pts with prior cBTKi therapy. High ORRs were observed in pts who had PD on a prior cBTKi, and in pts with high-risk disease features including blastoid/pleomorphic variants, elevated Ki-67 index, and TP53 mutations.

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]

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.