匹妥布替尼导致的非感染性咳嗽

Abstract Introduction: Pirtobrutinib, a highly selective, noncovalent (reversible) Bruton tyrosine kinase inhibitor, has demonstrated promising efficacy in B-cell malignancies and is associated with low rates of discontinuation and dose reduction. Pirtobrutinib is administered until disease progression or toxicity, necessitating an understanding of the safety profile in patients with extended treatment. Methods: Here we report the safety of pirtobrutinib in patients with relapsed/refractory B-cell malignancies with extended (≥12 months) drug exposure from the BRUIN trial. Assessments included median time-to-first-occurrence of adverse events (AEs), dose reductions, and discontinuations due to treatment-emergent AEs (TEAEs) and select AEs of interest (AESIs). Results: Of 773 patients enrolled, 326 (42%) received treatment for ≥12 months. In the extended exposure cohort, the median time-on-treatment was 19 months. The most common all-cause TEAEs were fatigue (32%) and diarrhea (31%). TEAEs leading to dose reduction occurred in 23 (7%) and discontinuations in 11 (3%) extended exposure patients. One patient had a fatal treatment-related AE (COVID-19 pneumonia). Infections (73.0%) were the most common AESI with a median time-to-first-occurrence of 7.4 months. Majority of TEAEs and AESIs occurred during the first year of therapy. Conclusions: Pirtobrutinib therapy continues to demonstrate an excellent safety profile amenable to long-term administration without evidence of new or worsening toxicity signals. Introduction: Pirtobrutinib, a highly selective, noncovalent (reversible) Bruton tyrosine kinase inhibitor, has demonstrated promising efficacy in B-cell malignancies and is associated with low rates of discontinuation and dose reduction. Pirtobrutinib is administered until disease progression or toxicity, necessitating an understanding of the safety profile in patients with extended treatment. Methods: Here we report the safety of pirtobrutinib in patients with relapsed/refractory B-cell malignancies with extended (≥12 months) drug exposure from the BRUIN trial. Assessments included median time-to-first-occurrence of adverse events (AEs), dose reductions, and discontinuations due to treatment-emergent AEs (TEAEs) and select AEs of interest (AESIs). Results: Of 773 patients enrolled, 326 (42%) received treatment for ≥12 months. In the extended exposure cohort, the median time-on-treatment was 19 months. The most common all-cause TEAEs were fatigue (32%) and diarrhea (31%). TEAEs leading to dose reduction occurred in 23 (7%) and discontinuations in 11 (3%) extended exposure patients. One patient had a fatal treatment-related AE (COVID-19 pneumonia). Infections (73.0%) were the most common AESI with a median time-to-first-occurrence of 7.4 months. Majority of TEAEs and AESIs occurred during the first year of therapy. Conclusions: Pirtobrutinib therapy continues to demonstrate an excellent safety profile amenable to long-term administration without evidence of new or worsening toxicity signals.

Bruton tyrosine kinase inhibitors (BTKi) have transformed the treatment of B-cell malignancies, but intolerance has often led to their discontinuation. The phase I/II BRUIN study evaluated pirtobrutinib, a highly selective non-covalent (reversible) BTKi, in patients with relapsed / refractory B-cell malignancies (clinicaltrials.gov 03740529). Pirtobrutinib was investigated in 127 patients with intolerance to at least one prior BTKi therapy in the absence of progressive disease. The most common adverse event (AE) leading to BTKi discontinuation was cardiac disorders (N=40, 31.5%), specifically atrial fibrillation (N=30, 23.6%). The median follow-up was 17.4 months and the median time on pirtobrutinib was 15.3 months. The most common reasons for pirtobrutinib discontinuation were progressive disease (26.8%), AE (10.2%) or death (5.5%). The most frequent treatment-emergent AE were fatigue (39.4%) and neutropenia (37.0%). Among patients who discontinued a prior BTKi for a cardiac issue, 75% had no recurrence of their cardiac AE. No patient discontinued pirtobrutinib for the same AE that led to discontinuation of the prior BTKi. In 78 chronic lymphocytic / small lymphocytic lymphoma (CLL/SLL) and 21 mantle cell lymphoma (MCL) patients intolerant to prior BTKi, overall response rate to pirtobrutinib was 76.9% and 81.0%, respectively. Median progression-free survival for CLL/SLL was 28.4 months but was not estimable for MCL. These results suggest that pirtobrutinib was safe, well-tolerated, and an efficacious option in patients with prior BTKi-intolerance.

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]

BACKGROUND Patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) have poor outcomes after the failure of covalent Bruton's tyrosine kinase (BTK) inhibitor treatment, and new therapeutic options are needed. Pirtobrutinib, a highly selective, noncovalent (reversible) BTK inhibitor, was designed to reestablish BTK inhibition. METHODS We conducted a phase 1-2 trial in which patients with relapsed or refractory B-cell cancers received pirtobrutinib. Here, we report efficacy results among patients with CLL or SLL who had previously received a BTK inhibitor as well as safety results among all the patients with CLL or SLL. The primary end point was an overall response (partial response or better) as assessed by independent review. Secondary end points included progression-free survival and safety. RESULTS A total of 317 patients with CLL or SLL received pirtobrutinib, including 247 who had previously received a BTK inhibitor. Among these 247 patients, the median number of previous lines of therapy was 3 (range, 1 to 11), and 100 patients (40.5%) had also received a B-cell lymphoma 2 (BCL2) inhibitor such as venetoclax. The percentage of patients with an overall response to pirtobrutinib was 73.3% (95% confidence interval [CI], 67.3 to 78.7), and the percentage was 82.2% (95% CI, 76.8 to 86.7) when partial response with lymphocytosis was included. The median progression-free survival was 19.6 months (95% CI, 16.9 to 22.1). Among all 317 patients with CLL or SLL who received pirtobrutinib, the most common adverse events were infections (in 71.0%), bleeding (in 42.6%), and neutropenia (in 32.5%). At a median duration of treatment of 16.5 months (range, 0.2 to 39.9), some adverse events that are typically associated with BTK inhibitors occurred relatively infrequently, including hypertension (in 14.2% of patients), atrial fibrillation or flutter (in 3.8%), and major hemorrhage (in 2.2%). Only 9 of 317 patients (2.8%) discontinued pirtobrutinib owing to a treatment-related adverse event. CONCLUSIONS In this trial, pirtobrutinib showed efficacy in patients with heavily pretreated CLL or SLL who had received a covalent BTK inhibitor. The most common adverse events were infections, bleeding, and neutropenia. (Funded by Loxo Oncology; BRUIN ClinicalTrials.gov number, NCT03740529.).

In January 2023, the U.S. Food and Drug Administration granted accelerated approval to pirtobrutinib for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL) after at least two lines of systemic therapy, including a Bruton tyrosine kinase (BTK) inhibitor. Approval was based on BRUIN, a single-arm study of pirtobrutinib monotherapy in patients with B-cell malignancies. Efficacy was based on independent review committee- assessed overall response rate (ORR) supported by durability of response in 120 patients with relapsed or refractory MCL who had received a prior BTK inhibitor and received the approved pirtobrutinib dosage of 200 mg once daily. The ORR was 50% (95% confidence interval [CI]: 41, 59) and the complete response rate was 13% (95% CI: 7, 20), with an estimated median duration of response of 8.3 months. The most common non-hematologic adverse reactions were fatigue, musculoskeletal pain, diarrhea, edema, dyspnea, pneumonia, and bruising. Warnings and Precautions in labeling include infection, hemorrhage, cytopenias, atrial arrhythmias, and second primary malignancies. Postmarketing studies were required to evaluate longer-term safety of pirtobrutinib and to verify the clinical benefit of pirtobrutinib. This article summarizes key aspects of the regulatory review, including the indication statement, efficacy and safety considerations, and postmarketing requirements.

PURPOSE Pirtobrutinib, a highly selective, noncovalent Bruton tyrosine kinase inhibitor (BTKi), has shown efficacy and safety in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) who received prior covalent BTKi. We report results, to our knowledge, from the first randomized head-to-head comparison of pirtobrutinib versus ibrutinib in BTKi-naïve CLL/SLL in both treatment-naïve (TN) patients and patients with relapsed/refractory (R/R) disease. PATIENTS AND METHODS Patients (N = 662) were randomly assigned 1:1 to receive pirtobrutinib or ibrutinib. All patients were BTKi-naïve. Primary end points were overall response rate (ORR) by independent review committee (IRC) among all randomly assigned patients (intention to treat [ITT]) and in patients with R/R disease. RESULTS The study met its primary end points, demonstrating statistically significant noninferiority (NI) of IRC-ORR for pirtobrutinib versus ibrutinib in both the ITT (87.0% [95% CI, 82.9 to 90.4] v 78.5% [95% CI, 73.7 to 82.9]; ORR ratio = 1.11 [95% CI, 1.03 to 1.19]; two-sided P < .0001) and R/R populations (n = 437; 84.0% [95% CI, 78.5 to 88.6] v 74.8% [95% CI, 68.5 to 80.4]; ORR ratio = 1.12 [95% CI, 1.02 to 1.24]; two-sided P < .0001). In TN patients (n = 225), IRC-ORR was 92.9% (95% CI, 86.4 to 96.9) with pirtobrutinib versus 85.8% (95% CI, 78.0 to 91.7) with ibrutinib. Investigator assessed ORR results were consistent. Investigator-assessed progression-free survival (PFS) favored pirtobrutinib in the ITT (hazard ratio [HR], 0.57 [95% CI, 0.39 to 0.83]), R/R (HR, 0.73 [95% CI, 0.47 to 1.13]), and TN (HR, 0.24 [95% CI, 0.10 to 0.59]) populations. Cardiac adverse event rates of atrial fibrillation/flutter and hypertension were lower with pirtobrutinib. CONCLUSION Pirtobrutinib demonstrated NI of ORR versus ibrutinib, with a favorable early PFS trend, particularly in TN patients, and a favorable safety profile including low rates of atrial fibrillation and hypertension.

PURPOSE Pirtobrutinib, a noncovalent, Bruton tyrosine kinase inhibitor (BTKi), has shown clinical efficacy and a favorable safety profile. BRUIN CLL-321 was an open-label, randomized phase III study conducted exclusively in patients with R/R chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) previously treated with cBTKi, and compared pirtobrutinib with investigator's choice (IC) of idelalisib/rituximab (IdelaR) or bendamustine/rituximab (BR). METHODS Patients were randomly assigned 1:1 to receive pirtobrutinib (200 mg once daily) or IC of IdelaR or BR, and were stratified by previous use of venetoclax and del(17p). The primary end point was independent review committee–assessed progression-free survival (PFS). Secondary end points included time to next treatment or death (TTNT), overall survival (OS), and safety. The primary PFS end point was met at the time of the primary analysis (August 29, 2023), and updated results are reported from the final OS analysis (August 29, 2024). RESULTS A total of 238 patients were randomly assigned to receive pirtobrutinib (n = 119) or IC (n = 119; IdelaR [n = 82], BR [n = 37]). The PFS hazard ratio (HR) was 0.54 ([95% CI, 0.39 to 0.75]; P = .0002), with a median PFS of 14 months (95% CI, 11.2 to 16.6) in the pirtobrutinib group and 8.7 months (95% CI, 8.1 to 10.4) with IC. The unadjusted OS HR was 1.09 ([95% CI, 0.68 to 1.75]; P = .7202), and 18-month OS rate was 73.4% (95% CI, 63.9 to 80.7) in the pirtobrutinib group and 70.8% (95% CI, 60.9 to 78.7) with IC. Median TTNT was 24 months (95% CI, 17.8 to 29.7) with pirtobrutinib versus 10.9 months (95% CI, 8.7 to 12.5) with IC (HR, 0.37 [95% CI, 0.25 to 0.52]). At a median follow-up of 17.2 months, grade ≥3 treatment-emergent adverse events (AEs) were lower with pirtobrutinib (57.7%) than IC (73.4%). Treatment discontinuation due to AE occurred in 20 (17.2%) patients receiving pirtobrutinib and 38 (34.9%) patients receiving IC. CONCLUSION Pirtobrutinib improved PFS and TTNT, and demonstrated favorable tolerability, versus IdelaR/BR in exclusively cBTKi pretreated patients with CLL/SLL.

ABSTRACT Introduction In recent years, chronic lymphocytic leukemia (CLL) treatment has changed dramatically. Chemoimmunotherapy with fludarabine/cladribine, cyclophosphamide, and rituximab have been almost completely replaced by targeted therapies with small molecules, such as Bruton’s tyrosine kinase inhibitors or B-cell lymphoma 2 (BCL-2) antagonists. However, few studies have assessed the impact of novel therapies on patient quality of life (QoL). Areas covered This article reviews the safety profile of new therapeutic options and their impact on the QoL of CLL patients. The MEDLINE database was searched for English language publications from 2010 through June 2024, including the Proceedings of the American Society of Hematology from over the past 5 years. Expert opinion CLL is a clinically heterogenous disease predominantly affecting elderly patients. The variable clinical course of disease requires personalization and individualized treatment to achieve the optimal survival outcome and acceptable safety profile, especially in the case of poor prognosis. Clinical trials performed in the past decade indicate that novel drugs, used as a single agent or as part of a conventional chemotherapy, offer promise in minimalizing relapse rates, and may allow more effective and safer treatment options by reducing the risk of adverse events, especially cytopenias and infections.

Objective To provide a comprehensive review of the pharmacokinetics, pharmacodynamics, safety, and efficacy of a new Food and Drug Administration (FDA) approved Bruton's tyrosine kinase inhibitor (BTKi), pirtobrutinib for relapsed/refractory mantle cell lymphoma (r/r MCL). Data sources A literature search was conducted through PubMed MEDLINE, ClinicalTrials.gov, and the FDA website (January 2018-January 2023) using the following key terms: lymphoma, non-covalent, Bruton's tyrosine kinase (BTK), and relapse. Relevant English language monographs, studies, and abstracts conducted in humans were reviewed and considered. Data summary Pirtobrutinib, a novel non-covalent BTKi, was granted accelerated approval for treatment of r/r MCL on January 27th, 2023, based on an open-label, multi-center phase 1/2 BRUIN trial. In phase l, 61 patients with r/r MCL received seven dose levels of pirtobrutinib (25–300 mg). There was no reported maximum tolerated dose or dose-limiting toxicities during this study period. In phase 2, 56 r/r MCL evaluable efficacy patients received pirtobrutinib 200 mg daily. The overall response rate (ORR) was 52% (95% CI 38–65). Additionally, patients who received a previous covalent BTKi, ORR was 52% (95% CI 38–66). Neutropenia was the most common adverse reaction reported as a grade 3 or higher. Conclusion Pirtobrutinib has demonstrated safety and efficacy in heavily pre-treated adult patients with r/r MCL. Advantages of this drug include its usage in patients whose malignancy is resistant to current BTKi, tolerability, and response rate. Multiple clinical trials are underway to determine the efficacy of pirtobrutinib in other B-cell malignancies.

BACKGROUND Covalent Bruton tyrosine kinase (BTK) inhibitors have advanced the treatment of Waldenström macroglobulinaemia; however, the occurrence of progression, intolerance, and acquired resistance are not fully understood. We aim to report on the safety and activity of pirtobrutinib (a highly selective, non-covalent BTK inhibitor) in patients with relapsed or refractory Waldenström macroglobulinaemia, including those who received previous covalent BTK inhibitors as part of the phase 1/2 BRUIN trial. METHODS The BRUIN study was an open-label, multicentre, phase 1/2 trial that enrolled patients with relapsed or refractory B-cell malignancies from 29 sites across eight countries. Patients aged 18 years or older who previously received BTK inhibitor-containing regimens, had an Eastern Cooperative Oncology Group performance status of 0-2, and histologically confirmed Waldenström macroglobulinaemia were eligible. In phase 1, patients received 100-300 mg oral pirtobrutinib once a day in 28-day cycles and the recommended phase 2 dose (RP2D) of 200 mg pirtobrutinib once a day was determined. The phase 2 primary endpoint was antitumour activity of pirtobrutinib based on objective response rate as assessed by an investigator in patients with chronic lymphocytic leukaemia, small lymphocytic leukaemia, or mantle cell lymphoma. In patients with Waldenström macroglobulinaemia, response was evaluated using the Sixth International Workshop on Waldenström Macroglobulinemia (IWWM-6) criteria. BRUIN is registered with ClinicalTrials.gov, NCT03740529 (completed). FINDINGS BRUIN recruited patients from Aug 12, 2019, to March 14, 2022, and 778 patients received pirtobrutinib. 80 patients had relapsed or refractory Waldenström macroglobulinaemia (n=18 in phase 1 and n=62 in phase 2), with a median age of 68·5 years (IQR 61·0-75·0). 52 (65%) patients were male and 28 (35%) were female. The median number of previous lines of systemic therapy was 3·0 (2·0-5·0). 63 (79%) patients received previous covalent BTK inhibitors. 73 (91%) received 200 mg pirtobrutinib once per day (the RP2D). Using IWWM-6 criteria, the objective response rate was 82·5% (95% CI 72·4-90·1), with one (1·3%) patient reaching complete response, eight (10·0%) reaching very good partial response, 49 (61·3%) reaching partial response, and eight (10·0%) reaching minor response. The median study follow-up was 35·0 months (17·7-47·7). The objective response rate was 81·0% (69·1-89·8) for those who received previous covalent BTK inhibitors and 88·2% (63·6-98·5) for covalent BTK inhibitor-naive patients. Grade 3 or higher treatment-emergent adverse events occurred in 57 (71%) patients, with the most common being neutropenia or neutrophil count decreased (15 [19%]) and anaemia (19 [24%]). Treatment-emergent deaths were reported in five (6%) patients (bacterial sepsis, intracranial haemorrhage, COVID-19 pneumonia, hypertensive cardiomegaly and pneumonia [n=1 each unrelated to treatment], and treatment-related necrotising pneumonia [n=1]). Treatment-emergent adverse events leading to dose reductions occurred in four (5%) patients and pirtobrutinib discontinuation in 12 (15%). INTERPRETATION Pirtobrutinib was highly active and well tolerated, regardless of previous exposure to covalent BTK inhibitors, and might be a promising new therapeutic option for patients with relapsed or refractory Waldenström macroglobulinaemia, particularly in those previously exposed to covalent BTK inhibitors, for whom durable and effective treatments are needed. FUNDING Eli Lilly and Company.

… incidence rates were determined for treatment-emergent adverse events (TEAEs) that occurred in ≥20% of patients and select adverse events (AEs) of interest associated with BTKi. …

ABSTRACT Introduction Mantle cell lymphoma (MCL) is an uncommon non-Hodgkin lymphoma that is generally considered incurable. Covalent BTK inhibitors (cBTKi) are the cornerstone of treatment for relapsed or refractory (R/R) MCL, but treatment options are limited and prognosis is poor after cBTKi failure. Pirtobrutinib is a non-covalent BTK inhibitor that has demonstrated excellent efficacy and safety and represents an important new treatment in the evolving treatment landscape of R/R MCL. Areas covered This review will provide an overview of the therapeutic landscape of R/R MCL, characteristics of pirtobrutinib, and efficacy and safety data of pirtobrutinib in R/R MCL from pivotal clinical trials. PubMed and major hematology conference proceedings were searched to identify relevant studies involving pirtobrutinib. Expert opinion For patients with R/R MCL that has progressed after treatment with cBTKi, pirtobrutinib is an important and efficacious treatment that confers favorable outcomes. In the post-cBTKi setting, when chimeric antigen receptor (CAR) T-cell therapy is not available or feasible, pirtobrutinib is the preferred treatment for R/R MCL. How to sequence or combine pirtobrutinib with CAR T-cell therapy and other available or emerging therapies requires further investigation. Future studies should also explore the role of pirtobrutinib in earlier lines of therapy for MCL.

… pirtobrutinib treatment from the phase 1/2 BRUIN trial. Methods: Pts with R/R B-cell malignancies who received ≥12 months of pirtobrutinib … for treatment emergent adverse event (TEAE…

Clinical bleeding events are reported here from 773 patients with B‐cell malignancies receiving pirtobrutinib monotherapy from the phase 1/2 BRUIN study (ClinicalTrials.gov identifier: NCT03740529), either in the presence or absence of antithrombotic therapy (antithrombotic exposed [AT‐E], n = 216; antithrombotic nonexposed [AT‐NE], n = 557). Among the AT‐E cohort, 51.9% received platelet aggregation inhibitors, 36.6% received direct factor Xa inhibitors, 18.5% received heparins, 5.6% received salicylic acid for indications other than platelet aggregation inhibition, and 2.3% received thrombolytics. Warfarin was not permitted. Any‐grade bleeding/bruising events occurred in 97 patients (44.9%; 95% confidence interval [CI], 38.3–51.5) in the AT‐E cohort and 181 patients (32.5%; 95% CI, 28.6–36.4) in the AT‐NE cohort. Most bleeding/bruising events in both cohorts began within the first 6 months of treatment (AT‐E: 65.4%; AT‐NE: 72.5%). Contusion was the most common bleeding/bruising event in both cohorts (AT‐E: 22.7%; AT‐NE: 18.1%). Grade ≥3 bleeding/bruising events were reported in six patients (2.8%) in the AT‐E cohort and 11 patients (2.0%) in the AT‐NE cohort. Bleeding/bruising events requiring or prolonging hospitalization were reported in 2.3% and 1.6% of patients in the AT‐E and AT‐NE cohorts, respectively. No bleeding/bruising events led to pirtobrutinib dose reduction or permanent discontinuation in the AT‐E cohort, and one patient (0.2%) in the AT‐NE cohort experienced an event requiring dose reduction. These data support the safety of pirtobrutinib in patients requiring antithrombotic therapies.

Mantle Cell Lymphoma (MCL) is an aggressive subtype of Non-hodgkin's Lymphoma (NHL). Bruton Tyrosine Kinase (BTK) is a non receptor tyrosine kinase, and is one of the therapeutic targets for B-cell-driven malignancies. Approved covalent BTK inhibitors such as ibrutinib, acalabrutinib, and zanubrutinib are associated with treatment limitations due to off-target side effects and the development of C481 substitution resistance mutations. Pirtobrutinib was approved by the US FDA on January 27, 2023, for the treatment of relapsed or refractory mantle cell lymphoma, including the resistance to covalent BTK inhibitors. In this perspective, physicochemical properties, synthesis, dosage and administration, mechanism of action, pharmacodynamics, pharmacokinetics, drug interactions, and treatment-emergent adverse events of pirtobrutinib are discussed.

… 2022 to compare the effectiveness of pirtobrutinib monotherapy and monotherapy of covalent … (17%) were the most frequent treatment-emergent adverse events, regardless of attribution …

Background: The treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) has benefited from covalent (c) Bruton tyrosine kinase inhibitors (BTKi), however, therapy can fail due to progression or intolerance. Sequential treatment with B-cell lymphoma 2 protein inhibitor (BCL2i) venetoclax, either as monotherapy or combined with an anti-CD20 monoclonal antibody, has been the primary treatment option for CLL/SLL patients (pts) whose disease has progressed on cBTKi. Pirtobrutinib is a highly selective, non-covalent (reversible) BTKi that demonstrated promising efficacy in patients with relapsed or refractory CLL/SLL (Mato et al, NEJM, 2023). Here, we report on the efficacy of pirtobrutinib treatment in CLL/SLL in the post-cBTKi setting, including subgroups with or without prior BCL2i, using data from the BRUIN study (NCT03740529) with more than 2 years follow-up. Methods: Pts with previously treated CLL/SLL were eligible for treatment with pirtobrutinib in the multicenter Phase 1/2 BRUIN study. Key endpoints included ORR (including partial response with lymphocytosis; PR-L) as assessed by an independent review committee per 2018 iwCLL response criteria, DoR, PFS, OS, and safety. A data cut of 05MAY2023 was utilized. Results: In total, 282 pts with CLL/SLL who received prior cBTKi were included in this analysis. Median age was 69 years (range, 36-88), 68% were male, and median number of prior therapies was 4 (range, 1-11). Of 282 pts, 154 (55%) had not received prior-BCL2i therapy (Naïve; BCL2i-N) and 128 (45%) had (Exposed; BCL2i-E). BCL2i-N pts were exposed to fewer prior therapies than BCL2i-E pts (median prior therapies 3 and 5, respectively), including anti-CD20 antibody (83% and 97%), chemotherapy (74% and 89%), PI3K inhibitor (11% and 42%), CAR-T cell therapy (1% and 12%), and hematopoietic cell transplantation (1% and 6%). The ORR for all post-cBTKi pts was 72% (95% CI, 66.4-77.1), and ORR including PR-L was 82% (95% CI, 76.5-85.9). Post-cBTKi pts included a subgroup of 19 pts with one prior line of cBTKi-containing therapy and second line therapy of pirtobrutinib, who had ORR including PR-L of 89.5% (CI 95%, 66.9-98.7). The ORR including PR-L was 83.1% (95% CI, 76.2-88.7) for BCL2i-N pts, and 79.7% (95% CI, 71.7-86.3) for BCL2i-E pts. Median DoR was 18.4 months (95% CI, 15.3-20.4) for all cBTKi pre-treated pts, 24.9 months (95% CI, 18.4-32.0) for BCL2i-N, and 14.8 months (95% CI, 12.0-17.4) for BCL2i-E. With a median follow up of 27.5 months, the median PFS was 19.4 months (95% CI, 16.6-22.1) among all cBTKi pre-treated pts, 23.0 months (95% CI, 19.6-28.4) for BCL2i-N, and 15.9 months (95% CI, 13.6-17.5) for BCL2i-E (Figure). With a median follow up of 29.3 months, the median OS was not estimable for all cBTKi pre-treated pts, BCL2i-N, and BCL2i-E; the 24-month OS rates were 73.2% (95% CI, 67.4-78.2), 83.1% (95% CI,75.9-88.2), 60.6% (50.9-68.9), respectively. In the CLL/SLL cohort (N=282), the most frequent treatment-emergent adverse events (TEAE), regardless of attribution, were fatigue (36.9%), diarrhea (28.4%), cough (27.3%) and contusion (26.2%). The most frequent Grade ≥3 TEAE was neutropenia/neutrophil count decreased (28.4%). Grade ≥3 TEAEs of hypertension (4.3%) and atrial fibrillation/flutter (1.8%) were infrequent. The AE profile of BCL2i-N and BCL2i-E pts was overall similar. Though Grade ≥3 neutropenia/neutrophil count decreased was higher in BCL2i-E pts (36.7% and 21.4%), this may have been attributed to the higher frequency of baseline neutropenia in BCL2i-E pts (27.3% and 11.0%). In total, 7 (2.5%; 4 BCL2i-N, 3 BCL2i-E) pts had treatment-related AE leading to pirtobrutinib discontinuation. Conclusion: Pirtobrutinib continues to demonstrate promising and durable efficacy in pts with post-cBTKi heavily pretreated CLL/SLL. ORR was high regardless of prior BCL2i status. Longer PFS was observed in BCL2i-N pts than BCL2i-E pts, likely due to the more heavily pretreated status of the BCL2i-E population which can be associated with poorer prognosis. Pirtobrutinib was well-tolerated with low-rates of discontinuation due to drug-related toxicity among both BTKi-N and BTKi-E pts. These results suggest that continuation of BTK pathway inhibition following a cBTKi may be an important sequencing approach to consider in the treatment of CLL/SLL.

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.

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.

PURPOSE BRUIN CLL-313 is a randomized, open-label, global phase III study comparing the efficacy and safety of pirtobrutinib, a highly selective, noncovalent Bruton tyrosine kinase inhibitor (BTKi), against bendamustine plus rituximab (BendaR), a common frontline chemoimmunotherapy, in treatment-naïve patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). METHODS Patients with previously untreated CLL/SLL without del(17p) were randomly assigned 1:1 to continuous pirtobrutinib monotherapy or BendaR, stratified by immunoglobulin heavy chain gene mutation status and Rai stage. The primary end point was independent review committee (IRC)–assessed progression-free survival (PFS); secondary end points included overall survival (OS), investigator (INV)–assessed PFS, safety, and tolerability. RESULTS Overall, 282 patients were randomly assigned to receive pirtobrutinib (n = 141) or BendaR (n = 141). IRC-assessed PFS was significantly improved with pirtobrutinib versus BendaR (hazard ratio [HR], 0.199 [95% CI, 0.107 to 0.367]; P < .0001), and the 24-month PFS rate was 93.4% (95% CI, 87.6 to 96.5) and 70.7% (95% CI, 61.5 to 78.1), respectively. INV-assessed PFS similarly favored pirtobrutinib (HR, 0.186 [95% CI, 0.093 to 0.371]). Interim analysis of OS favored pirtobrutinib (median follow-up 32 months; HR, 0.257 [95% CI, 0.070 to 0.934]) despite an effective crossover rate of 52.9%. In patients receiving pirtobrutinib versus BendaR: adverse event (AE)–related dose reductions occurred in 3.6% versus 31.1% of patients; grade ≥3 treatment-emergent AEs (TEAEs) occurred in 40.0% versus 67.4% of patients; and treatment discontinuations because of TEAEs occurred in 4.3% versus 15.2% of patients, respectively. CONCLUSION Pirtobrutinib demonstrated superiority over BendaR in IRC-assessed PFS in treatment-naïve CLL/SLL. OS trends favored pirtobrutinib despite the study design allowing for crossover. Pirtobrutinib was well tolerated, consistent with its known safety profile, and more favorable than BendaR.

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.

Introduction: Pirtobrutinib is a highly selective, non-covalent (nc) Bruton tyrosine kinase inhibitor (BTKi) that has demonstrated safety and efficacy in patients (pts) with relapsed/refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), including pts previously treated with a cBTKi. While cBTKi have significantly improved progression-free survival (PFS) for untreated pts with CLL/SLL, there are no Phase 3 data assessing a ncBTKi specifically in the treatment-naïve setting, and significant improvements in overall survival (OS) are uncommon with monotherapy cBTKi. A recent head-to-head phase 3 trial (BRUIN CLL-314 presented at this meeting,ASH abstract 25-2587; NCT05254743) showed a favorable overall response rate (ORR) and a positive PFS trend with pirtobrutinib compared to the cBTKi ibrutinib in a subset of pts with treatment-naïve CLL. Here we present the first results from a randomized, open-label, global phase 3 trial specifically assessing the efficacy and safety of pirtobrutinib versus bendamustine plus rituximab (BR) in treatment-naïve pts with CLL/SLL (BRUIN CLL-313; NCT05023980). Methods: Pts with previously untreated CLL/SLL, without del(17p), were randomized 1:1 to receive pirtobrutinib monotherapy (200 mg QD) or 6 cycles of BR, stratified by IGHV mutation status (mutated vs unmutated) and Rai stage (low/intermediate vs high). Pts with known CLL/SLL CNS involvement, Richter transformation, or significant cardiovascular disease were excluded. Responses were evaluated using iwCLL 2018 criteria. The primary endpoint was PFS assessed by independent review committee (IRC), and a stratified log-rank test compared IRC-assessed PFS between pirtobrutinib and BR using a 2-sided alpha level of 0.05. OS was a key secondary endpoint, gated on IRC-assessed PFS, with a small alpha of 0.000001 spent at this interim OS analysis. Other secondary endpoints included investigator (INV)-assessed PFS and safety. Efficacy analyses were based on the intent-to-treat population. Pts assigned to BR were eligible to cross over to receive pirtobrutinib if they had IRC-confirmed disease progression (PD), met study eligibility requirements, and needed therapy per iwCLL criteria. The data cutoff was 11 July 2025. Results: 282 pts were randomized to receive either pirtobrutinib (n=141) or BR (n=141). At a median follow-up of 28.1 months, the primary endpoint of IRC-assessed PFS was significantly improved with pirtobrutinib compared with BR (HR: 0.199; 95% CI: 0.107, 0.367; p<0.0001). The 24-month PFS rate was 93.4% (95% CI: 87.6, 96.5) for pirtobrutinib and 70.7% (95% CI: 61.5, 78.1) for BR. IRC-assessed PFS benefit was consistently observed with pirtobrutinib among prespecified, clinically relevant patient subgroups, including patients with mutated IGHV (HR: 0.293, 95% CI: 0.094, 0.910), and unmutated IGHV (HR: 0.172, 95% CI: 0.083, 0.357). The PFS by INV was consistent (HR: 0.186; 95% CI: 0.093, 0.371; p<0.0001). The OS HR for pirtobrutinib versus BR was 0.257 (95% CI: 0.070, 0.934; p=0.0261), despite an effective crossover rate of 52.9% (18/34 pts with INV-assessed PD). The median treatment duration was 32.3 months for 140 pts receiving pirtobrutinib and 5.6 months for 132 pts receiving BR. The incidence of grade ≥3 TEAEs was 40.0% with pirtobrutinib and 67.4% with BR. Grade 5 TEAEs occurred in 1 pt receiving pirtobrutinib and 4 pts receiving BR, with none considered pirtobrutinib related and 1 (tumor lysis syndrome) considered BR related. Discontinuation of pirtobrutinib and BR due to TEAE occurred in 6 (4.3%) and 20 (15.2%) pts, respectively. Two pts (1.4%) receiving pirtobrutinib had a TEAE of atrial fibrillation/flutter, including only 1 of 20 pts aged ≥75 years. Conclusions: In BRUIN CLL-313, pirtobrutinib significantly improved IRC-assessed PFS versus BR for pts with treatment-naïve CLL/SLL with one of the largest treatment effects ever observed for a single-agent BTKi against this comparator. Pirtobrutinib was well tolerated, consistent with its known safety profile, with low rates of discontinuation and atrial fibrillation/flutter. While OS data remained immature, a notable trend favoring pirtobrutinib was observed, despite 52.9% of BR pts crossing over to receive pirtobrutinib after PD. Taken together, these data suggest that pirtobrutinib may be considered a potential new standard-of-care treatment for pts with untreated CLL/SLL, including older pts who may receive only one line of therapy.

Background: Pirtobrutinib is an oral highly selective noncovalent Bruton tyrosine kinase inhibitor (BTKi) that has shown promising efficacy in heavily treated patients with relapsed/refractory (R/R) B cell lymphomas. We conducted a single-center retrospective study evaluating the safety and tolerability of pirtobrutinib in the real-world setting. Methods: The data for this study was gathered using the prescription records from the outpatient pharmacy at the H Lee Moffitt Cancer Center and Research Institute. All patients who were prescribed pirtobrutinib from June 1st, 2022 to June 1st, 2024 as part of standard-of-care regimens, off-label, or compassionate use were included in this study. All patients received at least one month of treatment with pirtobrutinib. The electronic medical records (EMR) of these patients were then accessed to review their treatment history and tolerance to pirtobrutinib. Data regarding adverse events (AEs) were collected from the medical documentation in the EMR. Descriptive analysis was performed using Statistical Package for the Social Sciences (SPSS) version 28.0. Results: A total of 29 patients received pirtobrutinib. Among these 12 (41.1%) were treated for R/R chronic lymphocytic leukemia (CLL), 11 (37.9%) for R/R mantle cell lymphoma (MCL), 4 (13.8%) for Richter's transformation, and 1 (3.4%) patient each for R/R Waldenström macroglobulinemia and R/R marginal zone lymphoma, respectively. The median age was 72 (interquartile range [IQR] 66.5-76] years. Most patients were male (n=23, 79.3%). This was a heavily treated population with a median 4 (IQR 3-5) prior lines of therapy. All patients had disease progression on a BTKi. Nine (75%) of the CLL patients had disease progression on both a BTKi and venetoclax. Six of these CLL patients had a documented BTK C481 mutation on next-generation sequencing. All patients with MCL had received at least 1 line of chemotherapy and overall, 24 (82.8%) of patients had received prior chemotherapy. A total of 6 (20.7%) patients had received prior chimeric antigen receptor (CAR) T-cell therapy, while 4 (13.8%) had undergone a hematopoietic stem cell transplant before initiating treatment with pirtobrutinib. The median follow-up time was 6 (IQR 3-10.5) months. The median duration of treatment was 4 (2-8.5) months. Ten (34.5%) patients had disease progression on pirtobrutinib. Nine (31.0%) patients received pirtobrutinib as part of the bridging therapy to CAR T- cell therapy. At the time of data cut-off, 12 (41.3%) patients were continuing treatment on pirtobrutinib. The dose of pirtobrutinib was 200 mg daily for 27 patients, while 3 patients were treated with a reduced dose of 100 mg daily due to a personal history of atrial fibrillation and/ or potential drug interactions. In terms of safety, 27 (93.1%) had at least 1 AE of any grade documented in the EMR after initiation of therapy. Most of these were grade I/II AEs (79.3%). The most common AE was fatigue (27.6%), followed by infections (17.2%) and thrombocytopenia (17.2%). Other common grade I/II AEs included hypertension (10.3%), bruising (10.3%), nausea/ vomiting (10.3%), diarrhea (10.3%), anemia (6.9%), and rash (6.9%). Six patients experienced ≥grade 3 AEs. Among them, 4 patients required temporary discontinuation of pirtobrutinib. Two of these were due to severe infection, resulting in sepsis and hospitalization, 1 for neutropenia requiring granulocyte-colony stimulating factor support, and 1 for atrial fibrillation where the drug was later resumed at a reduced dose of 100 mg. No other dose reduction due to AEs were noted. An additional 2 patients permanently discontinued pirtobrutinib due to grade IV hepatic injury and recurrent pleural effusions with negative cytology, respectively. No sudden cardiac deaths were observed. In total, 8 (27.6%) patients died during the study period, of which 6 were directly related to disease progression. Conclusion: The AE profile seen in our real-world data is comparable to that reported in the original clinical trial population suggesting pirtobrutinib is safe and well-tolerated in this high-risk population. Longer-term follow-up with larger multicenter data would be required to determine the true incidence of some rare side effects such as severe hepatic injury and pleural effusions that were recorded in our patient cohort.

BACKGROUND Drug-induced cough is a prevalent adverse drug reaction; however, the risk of cough associated with various drug classes in real-world settings has not been thoroughly elucidated. OBJECTIVES This study aims to systematically identify drug risk signals that are significantly associated with cough through the FAERS database, covering data from the first quarter of 2004 to the fourth quarter of 2024. The findings will provide evidence-based support for clinical medication safety and individualized monitoring. METHODS We extracted reports in which cough was identified as the primary adverse event (AE) from the FAERS database. After data cleaning to exclude duplicate and non-drug-related records, use the Reporting Odds Ratio (ROR) and Proportional Reporting Ratio (PRR) for disproportionality analysis. Standardize the Preferred Term (PT) for cough using MedDRA 27.1. Additionally, classify each drug using the World Health Organization's Anatomical Therapeutic Chemical (ATC) classification system. RESULTS This study identified 1,951 drugs associated with the AE of "cough," affecting a total of 247,158 patients. The drug categories most commonly linked to cough included antineoplastic and immunomodulating agents, respiratory system medications, and cardiovascular system medications. The drugs (primary suspect) with the highest number of reported cough cases were adalimumab, etanercept, and sacubitril/valsartan. CONCLUSION This study is the first to systematically reveal the strength of association and baseline characteristics between multiple categories of drugs and the risk of cough, confirming the high efficiency and sensitivity of the FAERS database in pharmacovigilance. The findings of this study provide an important basis for drug risk assessment and clinical intervention.

… a drug-induced B cell deficiency is treatable by gamma globulin substitution therapy. The newly developed BTK inhibitor PCI… , with mild adverse effects like cough, fatigue, diarrhoea and …

Bruton’s tyrosine kinase (BTK), a nonreceptor tyrosine kinase, plays a remarkable role in the transmission and amplification of extracellular signals to intracellular signaling pathways. Various types of cells use the BTK pathway to communicate, including hematopoietic cells particularly B cells and T cells. The BTK pathway plays a role in controlling the proliferation, survival, and functions of B cells as well as other myeloid cells. First, second, and third-generation BTK inhibitors are currently being evaluated for the treatment of immune-mediated diseases in addition to B cell malignancies. In this article, the available evidence on the action mechanisms of BTK inhibitors is reviewed. Then, the most recent data obtained from preclinical studies and ongoing clinical trials for the treatment of autoimmune diseases, such as pemphigus vulgaris, pemphigus foliaceus, bullous pemphigoid, systemic lupus erythematosus, Sjögren’s disease, rheumatoid arthritis, systemic sclerosis, multiple sclerosis, myasthenia gravis, and inflammatory diseases such as psoriasis, chronic spontaneous urticaria, atopic dermatitis, and asthma are discussed. In addition, adverse effects and complications associated with BTK inhibitors as well as factors predisposing patients to BTK inhibitors complications are discussed.

Bruton tyrosine kinase (BTK) is an important protein of the tyrosine kinase family and plays a key role in signal transduction, proliferation, migration, and survival in B lymphocytes. The inhibition of BTK is a promising therapy for various autoimmune diseases (AD) involving abnormal B cell function, such as rheumatoid arthritis (RA), multiple sclerosis (MS), and systemic lupus erythematosus (SLE). This article briefly summarizes the role of BTK in the BCR signaling pathway, the development process of BTK inhibitors, and especially the latest progress of their clinical trials for the treatment of AD.

The clinical success of the two BTK inhibitors, ibrutinib and acalabrutinib, represents a major breakthrough in the treatment of chronic lymphocytic leukemia (CLL) and has also revolutionized the treatment options for other B cell malignancies. Increasing evidence indicates that in addition to their direct effects on B lymphocytes, both BTK inhibitors also directly impact the homeostasis, phenotype and function of many other cell subsets of the immune system, which contribute to their high efficacy as well as adverse effects observed in CLL patients. In this review, we attempt to provide an overview on the overlapping and differential effects of ibrutinib and acalabrutinib on specific receptor signaling pathways in different immune cell subsets other than B cells, including T cells, NK cells, monocytes, macrophages, granulocytes, myeloid-derived suppressor cells, dendritic cells, osteoclasts, mast cells and platelets. The shared and distinct effects of ibrutinib versus acalabrutinib are mediated through BTK-dependent and BTK-independent mechanisms, respectively. Such immunomodulatory effects of the two drugs have fueled myriad explorations of their repurposing opportunities for the treatment of a wide variety of other human diseases involving immune dysregulation.

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Chronic lymphocytic leukemia is a malignancy of mature auto-reactive B cells. Genetic and functional studies implicate B-cell receptor signaling as a pivotal pathway in its pathogenesis. Full B-cell receptor activation requires tumor-microenvironment interactions in lymphoid tissues. Spleen tyrosine kinase, Bruton’s tyrosine kinase, and the phosphatidylinositol 3-kinase (PI3K) δ isoform are essential for B-cell receptor signal transduction but also mediate the effect of other pathways engaged in chronic lymphocytic leukemia cells in the tissue-microenvironment. Orally bioavailable inhibitors of spleen tyrosine kinase, Bruton’s tyrosine kinase, or PI3Kδ, induce high rates of durable responses. Ibrutinib, a covalent inhibitor of Bruton’s tyrosine kinase, and idelalisib, a selective inhibitor of PI3Kδ, have obtained regulatory approval in chronic lymphocytic leukemia. Ibrutinib and idelalisib are active in patients with high-risk features, achieving superior disease control in difficult-to-treat patients than prior best therapy, making them the preferred agents for chronic lymphocytic leukemia with TP53 aberrations and for patients resistant to chemoimmunotherapy. In randomized trials, both ibrutinib, versus ofatumumab, and idelalisib in combination with rituximab, versus placebo with rituximab improved survival in relapsed/refractory chronic lymphocytic leukemia. Responses to B-cell receptor inhibitors are mostly partial, and within clinical trials treatment is continued until progression or occurrence of intolerable side effects. Ibrutinib and idelalisib are, overall, well tolerated; notable adverse events include increased bruising and incidence of atrial fibrillation on ibrutinib and colitis, pneumonitis and transaminase elevations on idelalisib. Randomized trials investigate the role of B-cell receptor inhibitors in first-line therapy and the benefit of combinations. This review discusses the biological basis for targeted therapy of chronic lymphocytic leukemia with B-cell receptor inhibitors, and summarizes the clinical experience with these agents.

Chronic lymphocytic leukemia (CLL) and lymphoplasmacytic lymphoma (LPL) are malignancies of mature B cells. In LPL, mutations of the adaptor protein MYD88 (L265P) in the Toll-like receptor pathway have been recognized recently as being a hallmark of the disease and indicate a dependence of the tumor on this pathway. In CLL, functional studies have implicated BCR activation in the tissue microenvironment as a pivotal pathway in the pathogenesis. Bruton's tyrosine kinase (BTK) and the PI3Kδ isoform are essential for BCR signaling and also seem to be required for signal transduction in LPL cells, even if the role of BCR signaling in this disease remains less well defined. Ibrutinib, a covalent inhibitor of BTK approved by the Food and Drug Administration as a second-line treatment for CLL, and idelalisib, a selective inhibitor of PI3Kδ, achieve excellent clinical responses in both diseases irrespective of classic markers indicating high-risk disease. Several additional inhibitors targeting BTK and PI3Kδ, as well as the spleen tyrosine kinase, have entered clinical trials. This review discusses the biologic basis for kinase inhibitors as targeted therapy for CLL and LPL and summarizes the clinical experience with these agents.

The anticancer drugs have evolved significantly, spanning molecular targeted therapeutics (MTTs), immune checkpoint inhibitors (ICIs), chimeric antigen receptor T-cell (CAR-T) therapy, and antibody-drug conjugates (ADCs). Complications associated with these drugs vary widely based on their mechanisms of action. MTTs that target angiogenesis can often lead to complications related to ischemia or endothelial damage across various organs, whereas non-anti-angiogenic MTTs present unique complications derived from their specific pharmacological actions. ICIs are predominantly associated with immune-related adverse events, such as pneumonitis, colitis, hepatitis, thyroid disorders, hypophysitis, and sarcoid-like reactions. CAR-T therapy causes unique and severe complications including cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome. ADCs tend to cause complications associated with cytotoxic payloads. A comprehensive understanding of these drug-specific toxicities, particularly using medical imaging, is essential for providing optimal patient care. Based on this knowledge, radiologists can play a pivotal role in multidisciplinary teams. Therefore, radiologists must stay up-to-date on the imaging characteristics of these complications and the mechanisms underlying novel anticancer drugs.

… To our knowledge, BRUIN CLL-313 1 is the first phase III trial of pirtobrutinib in previously untreated patients with CLL/SLL. Oral pirtobrutinib 200 mg once daily was administered …

TPS7100 Background: Bruton tyrosine kinase covalent inhibitors (cBTKi) have been transformative in CLL treatment. Despite achieving extended remissions, in most patients disease still relapses despite cBTKi therapy, often associated with BTK C481 mutations. Non-covalent BTKi (ncBTKi), including pirtobrutinib, can overcome this resistance (Sharman et al. ASCO . 2025). Pirtobrutinib received FDA approval in Dec 2025, for R/R CLL/CLL patients pretreated with cBTKi. Rocbrutinib (LP-168) is a highly selective next-generation BTKi that can covalently bind wild-type and gatekeeper mutations (T474X, commonly seen in patients relapsed after pirtobrutinib) and non-covalently target C481-mutated BTK , with preclinical efficacy in treatment-naïve and BTKi-resistant CLL (Gordon et al. IWCLL . 2025). In the rocbrutinib phase 1 trial (NCT04775745), encouraging safety and efficacy have been observed in CLL patients with prior exposure to BTKi and/or BCL2 inhibitor (BCL2i) (Woyach et al. Blood. 2025). Presented here is the design of a phase 3 trial aiming to compare the efficacy of rocbrutinib versus pirtobrutinib in cBTKi-pretreated R/R CLL/SLL patients. Methods: ROCKET-CLL (NCT07342478) is a randomized, open-label, multicenter, phase 3 study comparing rocbrutinib (Arm 1) to pirtobrutinib (Arm 2) in R/R CLL/SLL subjects who previously received treatments including covalent BTKi. Eligible subjects must require treatment per 2018 iwCLL criteria, have measurable lesions by CT, an ECOG performance score of 0-2, and adequate hematologic and other organ functions. About 306 subjects will be randomized 1:1 based on stratification factors such as 17p deletion/ TP53 mutation presence, reasons for discontinuing prior cBTKi, prior BCL2i treatment, and geographic region. Participants assigned to each arm will receive rocbrutinib (200 mg QD) or pirtobrutinib (200 mg QD) tablets continuously until disease progression, unacceptable toxicity, withdrawal, or other study discontinuation criteria are met. The primary endpoint is progression-free survival (PFS), assessed by an independent review committee (IRC) per iwCLL 2018 criteria with CLL (Hallek et al. 2018) and Lugano 2014 criteria with SLL (Cheson et al. 2014). Important secondary endpoints include overall survival (OS), time to next treatment (TTNT), event-free survival (EFS), overall response rate (ORR), duration of response (DOR), PFS assessed by investigator (INV), concordance between IRC and INV PFS, safety and tolerability, and population PK. Exploratory endpoints include health-related quality of life and biomarker assessment. Recruitment is ongoing. Clinical trial information: NCT07342478 .

Objective: The objective was to evaluate the efficacy/safety of pirtobrutinib in the treatment of B-cell malignancies and distinguish it from other available Bruton’s tyrosine kinase (BTK) inhibitors. Data sources: A literature search of PubMed (January 2021 through November 2023) and Clinicaltrials.gov was conducted using terms pirtobrutinib, Jaypirca, and LOXO 305. Licensing trials of available BTK inhibitors were also reviewed. Study selection and data extraction: Relevant English-language clinical trials were evaluated. Data synthesis: Pirtobrutinib was approved by the US Food and Drug Administration for the treatment of relapsed/refractory mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) based largely on a phase 1/2 study in B-cell malignancies. Pirtobrutinib demonstrated a 73% overall response rate (ORR) in the CLL population and 58% in MCL. Pirtobrutinib has activity in patients resistant to earlier-generation, covalent BTK inhibitors. In fact, the ORRs were similar in BTK-pretreated and naïve patients. Adverse effects include fatigue, diarrhea, bleeding, and infection. Atrial fibrillation, a class effect of BTK inhibitors, may be less common with pirtobrutinib. Relevance to patient care and clinical practice in comparison with existing drugs: Compared with earlier-generation BTK inhibitors, pirtobrutinib is more selective for BTK and binds noncovalently to the receptor. Ongoing studies are evaluating pirtobrutinib’s use in multiple B-cell malignancies and comparing it with other BTK inhibitors. Conclusion: The characteristics of pirtobrutinib render it useful in the treatment of B-cell malignancies no longer responding to a previous BTK inhibitor, and results from ongoing clinical trials may support future expanded use.