Citations

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.