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Efficacy of Pirtobrutinib in Covalent BTK-Inhibitor Pre-Treated Relapsed / Refractory Mantle Cell Lymphoma: Additional Patients and Extended Follow-up from the Phase 1/2 BRUIN Study
... To date, 6 ncBTKis have been evaluated in preclinical and clinical settings, namely RN486, [6][7][8] nemtabrutinib/ARQ 531, 9,10 fenebrutinib/GDC-0853, 11 vecabrutinib/SNS-062, 12,13 luxeptinib/CG-806, 14 and pirtobrutinib/LOXO-305. [15][16][17] Pirtobrutinib is the most advanced and is approved by the US Food and Drug Administration for patients with mantle cell lymphoma or chronic lymphocytic leukemia (CLL). 18 The BRUIN (pirtobrutinib in relapsed or refractory B-cell malignancies) trial (NCT03740529) was a first-in-human phase 1/2 trial of pirtobrutinib that included 725 patients with B-cell malignancies. In this study, 16,19 all patients previously received a cBTKi and could either not tolerate it or developed resistance to it. ...
... Clinical and outcome data from the BRUIN trial clearly demonstrated that both the BTK-WT and BTK-mutated cohorts of patients with CLL had responses to treatment with pirtobrutinib. 16,18,19 Our study identified several transcriptomic and proteomic differences that may be associated with the overall positive responses to pirtobrutinib treatment in CLL that bears WT or mutated BTK. We demonstrated that although patients with WT-BTK CLL have inherent differences when compared with those with mutated-BTK CLL subtypes using omics, within the first few cycles, treatment with pirtobrutinib-suppressed, BCRmediated signal transduction in both cohorts. ...
Covalent Bruton's tyrosine kinase inhibitors (cBTKi), which bind to the BTK C481 residue, are now primary therapeutics for chronic lymphocytic leukemia (CLL). Alterations at C481, primarily C481S, prevent cBTKi binding and lead to the emergence of resistant clones. Pirtobrutinib is a noncovalent BTKi that binds to both wild-type (WT) and C481S-mutated BTK and has shown efficacy in BTK-WT and -mutated CLL patient groups. To compare baseline clinical, transcriptomic, and proteomic characteristics and their changes during treatment in these 2 groups, we used 67 longitudinal peripheral blood samples obtained during the first 3 cycles of treatment with pirtobrutinib from 18 CLL patients (11 BTK-mutated, 7 BTK-WT) enrolled in the BRUIN trial. Eastern Cooperative Oncology Group performance status, age, and Rai stage were similar in both groups. At baseline, lymph nodes were larger in the BTK-mutated cohort. All patients achieved partial remission within 4 cycles of pirtobrutinib. Lactate dehydrogenase and 2-microglobulin levels decreased in both cohorts after 1 treatment cycle. Expression analysis demonstrated upregulation of 35 genes and downregulation of 6 in the BTK-mutated group. Gene set enrichment analysis revealed that the primary pathways enriched in BTK-mutated cells were involved in cell proliferation, metabolism, and stress response. Pathways associated with metabolism and proliferation were downregulated in both groups during pirtobrutinib treatment. Proteomic data corroborated transcriptomic findings. Our data identified inherent differences between BTK-mutated and -WT CLL and demonstrated molecular normalization of plasma and omics parameters with pirtobrutinib treatment in both groups.
... Evidence for Pirtobrutinib BRUIN (NCT03740529) is an ongoing, multicenter, open-label, phase 1/2 study of pirtobrutinib in adult patients aged at least 18 years with NHL and who had received at least two previous lines of therapy, irrespective of prior cBTKi use [15,[19][20][21]. As of the data cutoff date of July 29, 2022, a total of 166 patients with MCL were enrolled. ...
Patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL) often require multiple lines of treatment and have a poor prognosis, particularly after failing covalent Bruton tyrosine kinase inhibitor (cBTKi) therapy. Newer treatments such as brexucabtagene autoleucel (brexu-cel, chimeric antigen receptor T cell therapy) and pirtobrutinib (non-covalent BTKi) show promise in improving outcomes.
Without direct comparative evidence, an unanchored matching-adjusted indirect comparison was conducted to estimate the relative treatment effects of brexu-cel and pirtobrutinib for post-cBTKi R/R MCL. Using logistic propensity score models, individual patient-level data from ZUMA-2 brexu-cel-infused population (N = 68) were weighted to match pre-specified clinically relevant prognostic factors based on study-level data from the BRUIN cBTKi pre-treated cohort (N = 90). The base-case model incorporated the five most pertinent factors reported in ≥ 50% of both trial populations: morphology, MCL International Prognostic Index, number of prior lines of therapy, disease stage, and prior autologous stem cell transplant. A sensitivity analysis additionally incorporated TP53 mutation and Ki-67 proliferation. Relative treatment effects were expressed as odds ratios (ORs) or hazard ratios (HRs) with 95% confidence intervals (CIs).
In the base-case model, brexu-cel was associated with higher rates of objective response (OR 10.39 [95% CI 2.81–38.46]) and complete response (OR 10.11 [95% CI 4.26–24.00]), and improved progression-free survival (HR 0.44 [95% CI 0.25–0.75]), compared to pirtobrutinib. Overall survival and duration of response favored brexu-cel over pirtobrutinib but the differences crossed the bounds for statistical significance. Findings were consistent across the adjusted and unadjusted analyses.
Findings suggest that brexu-cel may offer clinically and statistically significant benefits regarding objective response, complete response, and progression-free survival compared to pirtobrutinib among patients with R/R MCL after prior cBTKi therapy. Given the short follow-up and high degree of censoring in BRUIN, an analysis incorporating updated BRUIN data may provide more definitive overall survival results.
... At a median follow-up time of 12 months, the median DOR among the 52 responding patients was 22 months. Patients who discontinued their prior BTKi due to disease progression (n = 74) had an ORR of 50% and a median DOR of 14.8 months [19]. ...
Bruton’s tyrosine kinase (BTK) inhibitors have revolutionized the landscape for the treatment of hematological malignancies, solid tumors, and, recently, autoimmune disorders. The BTK receptor is expressed in several hematopoietic cells such as macrophages, neutrophils, mast cells, and osteoclasts. Similarly, the BTK receptor is involved in signaling pathways such as chemokine receptor signaling, Toll-like receptor signaling, and Fc receptor signaling. Due to their unique mechanism, these agents provide a diverse utility in a variety of disease states not limited to the field of malignant hematology and are generally well-tolerated.
... 45 In the extended follow-up of this study evaluating 90 patients with previously treated MCL (74 patients had discontinued prior BTK inhibitor therapy due to disease progression), the ORR as determined by the independent review committee (IRC) was 58% (20% CR). 46 At a median followup of 12 months, the median duration of response was 22 months for the 52 patients with responding disease. The 12-month and estimated 18-month response rates were 57% and 52%, respectively. ...
Novel targeted therapies (small molecule inhibitors, antibody–drug conjugates, and CD19-directed therapies) have changed the treatment landscape of relapsed/refractory B-cell lymphomas. Bruton’s tyrosine kinase (BTK) inhibitors continue to evolve in the management of mantle cell lymphoma (MCL), in both the relapsed/refractory and the frontline setting. Anti-CD19 CAR T-cell therapies are now effective and approved treatment options for relapsed/refractory follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and MCL. Bispecific T-cell engagers represent a novel immunotherapeutic approach for relapsed FL and DLBCL after multiple lines of therapies, including prior CAR T-cell therapy. These NCCN Guideline Insights highlight the significant updates to the NCCN Guidelines for B-Cell Lymphomas for the treatment of FL, DLBCL, and MCL.
... The trial data suggest that pirtobrutinib was well tolerated at all doses tested (the maximum tolerated dose was not reached). The updated data were presented in ASH 2022 meeting [24]. These data indicate that pirtobrutinib could be a potential treatment strategy to overcome covalent BTKi-associated resistance development in MCL. ...
Mantle cell lymphoma is a B cell non-Hodgkin lymphoma (NHL), representing 2–6% of all NHLs and characterized by overexpression of cyclin D1. The last decade has seen the development of many novel treatment approaches in MCL, most notably the class of Bruton's tyrosine kinase inhibitors (BTKi). BTKi has shown excellent outcomes for patients with relapsed or refractory MCL and is now being studied in the first-line setting. However, patients eventually progress on BTKi due to the development of resistance. Additionally, there is an alteration in the tumor microenvironment in these patients with varying biological and therapeutic implications. Hence, it is necessary to explore novel therapeutic strategies that can be effective in those who progressed on BTKi or potentially circumvent resistance. In this review, we provide a brief overview of BTKi, then discuss the various mechanisms of BTK resistance including the role of genetic alteration, cancer stem cells, tumor microenvironment, and adaptive reprogramming bypassing the effect of BTK inhibition, and then provide a comprehensive review of current and emerging therapeutic options beyond BTKi including novel agents, CAR T cells, bispecific antibodies, and antibody–drug conjugates.
... Pirtobrutinib is now being further explored in four global, randomized phase III trials in patients with CLL/SLL, which has been outlined in Table 1. Of note, based on the results of patients with MCL treated with pirtobrutinib on the phase I/II BRUIN study, pirtobrutinib was granted accelerated approval by the Food and Drug Administration for the treatment of relapsed and/or refractory mantle cell lymphoma (at least two prior lines of therapy, including a prior cBTKi) in January 2023 [45]. ...
Simple Summary
Non-covalent Bruton’s tyrosine kinase inhibitors (ncBTKi) are being investigated for the treatment of B-cell malignancies, including chronic lymphocytic leukemia (CLL). These agents hold promise for the treatment of CLL, especially CLL requiring treatment after prior discontinuation of covalent Bruton’s tyrosine kinase inhibitors such as ibrutinib, acalabrutinib and zanubrutinib for either intolerance or progression of disease. This review outlines current preclinical and clinical data for the use of ncBTKi in CLL. Recently reported data has shown durable responses for the ncBTKi pirtobrutinib in CLL patients previously treated with a covalent BTKi with a median PFS of 19.6 months. We also discuss recently discovered mechanisms of resistance to ncBTKis, including acquired mutations in the BTK protein not in the C481 position. In addition, we highlight ongoing clinical trials that are incorporating ncBTKis in CLL as monotherapy or in combination therapies with other agents. The results of these trials as well as ongoing research regarding mechanisms of resistance to ncBTKi and covalent Bruton’s Tyrosine Kinase inhibitors will be important to determine where ncBTKi may fit into the treatment of CLL.
Abstract
Covalent Bruton’s tyrosine kinase inhibitors (cBTKi) have led to a paradigm shift in the treatment of chronic lymphocytic leukemia (CLL). These targeted oral therapies are administered as standard treatments in both the front-line and relapsed and/or refractory settings. Given their administration as a continuous therapy with a “treat-to-progression” strategy, limitations of their use include discontinuation due to toxicity or from progression of the disease. Non-covalent Bruton’s tyrosine kinase inhibitors (ncBTKi) distinguish themselves by binding reversibly to the BTK target, which may address the limitations of toxicity and acquired resistance seen with cBTKi. Several ncBTKis have been studied preclinically and in clinical trials, including pirtobrutinib and nemtabrutinib. Pirtobrutinib, which is now FDA approved for relapsed and/or refractory mantle cell lymphoma (MCL), has shown outstanding safety and preliminary efficacy in CLL in phase 1 and 2 clinical trials, with phase 3 trials underway. This agent may fill an unmet medical need for CLL patients requiring treatment after a cBTKi. Pirtobrutinib is particularly promising for the treatment of “double exposed” CLL, defined as CLL requiring treatment after both a cBTKi and venetoclax. Some patients have now developedacquired resistance to pirtobrutinib, and resistance mechanisms (including novel acquired mutations in BTK outside of the C481 position) have been recently described. Further study regarding the mechanisms of resistance to pirtobrutinib in patients without prior cBTKi exposure, as well as the potential for cross-resistance between cBTKi and ncBTKis, may be important to help inform where ncBTKis will ultimately fit in the treatment sequencing paradigm for CLL. An emerging clinical challenge is the treatment of CLL after ncBTKi discontinuation. Novel therapeutic strategies are being investigated to address the treatment of patients following disease progression on ncBTKis. Such strategies include novel agents (BTK degraders, bispecific antibody therapy, CAR T-cell therapy, PKC-beta inhibitors) as well as combination approaches incorporating a ncBTKi (e.g., pirtobrutinib and venetoclax) that may help overcome this acquired resistance.
... Despite allowing patients with a history of prior atrial fibrillation on cBTKi to enroll, atrial fibrillation rates observed here were consistent with that expected in agematched population controls. 17,26 Rates of grade ≥3 infection and bleeding were also low, despite enrolling patients with a history of these events on prior cBTKi. Finally, the frequency of any grade hypertension was low, and no high-grade hypertension was observed, which has been usually reported with cBTKi therapy with longer follow-up. ...
Purpose:
Pirtobrutinib is a highly selective, non-covalent (reversible) Bruton tyrosine kinase inhibitor (BTKi). We report the safety and efficacy of pirtobrutinib in patients with covalent (c) BTKi pre-treated mantle cell lymphoma (MCL), a population with poor prognosis.
Patients and methods:
Patients with cBTKi pre-treated relapsed/refractory MCL received pirtobrutinib monotherapy in a multicenter phase 1/2 trial (BRUIN, NCT03740529). Efficacy was assessed in the first 90 consecutively enrolled patients who met criteria for inclusion in the primary efficacy cohort. The primary endpoint was overall response rate (ORR). Secondary endpoints included duration of response (DOR) and safety.
Results:
Median patient age was 70 years (range, 46-87), median prior lines of therapy 3 (range, 1-8), 82.2% had discontinued a prior cBTKi due to disease progression, and 77.8% had intermediate or high risk sMIPI score. The ORR was 57.8% (95% CI, 46.9-68.1), 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-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 (TEAE) were fatigue (29.9%), diarrhea (21.3%), and dyspnea (16.5%). Grade ≥3 TEAE of hemorrhage (3.7%) and atrial fibrillation/flutter (1.2%) were less common. Only 3% of patients discontinued pirtobrutinib due to a treatment-related AE.
Conclusion:
Pirtobrutinib is a first-in-class novel non-covalent (reversible) BTKi, and the first BTKi of any kind to demonstrate durable efficacy following prior cBTKi therapy in heavily pre-treated relapsed/refractory MCL. Pirtobrutinib was well tolerated with low rates of treatment discontinuation due to toxicity.
... The ORR was 58%, including CR in 20%, and notably responses were seen in six of eight patients with blastoid MCL and in six of 12 with pleomorphic histology. 70 CAR T-cell therapy in aggressive MCL Whilst the availability of BTK inhibitors has significantly improved outcomes for patients requiring second-line therapy for MCL, they are not curative. Early observational series of patients who experienced disease progression following ibrutinib reported a median OS of only 3-8 months after ibrutinib treatment failure. ...
Mantle cell lymphoma (MCL) is a mature B‐cell lymphoma with a variable clinical course and historically poor prognosis. Management is challenging in part due to the heterogeneity of the disease course, with indolent and aggressive subtypes now well recognised. Indolent MCL is often characterised by a leukaemic presentation, SOX11 negativity and low proliferation index (Ki‐67). Aggressive MCL is characterised by rapid onset widespread lymphadenopathy, extra‐nodal involvement, blastoid or pleomorphic histology and high Ki‐67. Tumour protein p53 (TP53) aberrations in aggressive MCL are recognised with clear negative impact on survival. Until recently, trials have not addressed these specific subtypes separately. With the increasing availability of targeted novel agents and cellular therapies, the treatment landscape is constantly evolving. In this review, we describe the clinical presentation, biological factors, and specific management considerations of both indolent and aggressive MCL and discuss current and potential future evidence which may help move to a more personalised approach.
... In a phase 1/2, multicenter, open-label clinical trial 14 with 725 patients treated across 7 dose levels, pirtobrutinib monotherapy was shown to be safe and have activity in patients with multiple cBTKi-treated Bcell malignancies, including those with resistance in the absence of BTK C481 mutations. [15][16][17][18] The objective of this study was to provide a detailed preclinical characterization of pirtobrutinib. ...
Bruton tyrosine kinase (BTK), a nonreceptor tyrosine kinase, is a major therapeutic target for B-cell driven malignancies. However, approved covalent BTK inhibitors (cBTKi) are associated with treatment limitations due to off-target side effects, suboptimal oral pharmacology, and development of resistance mutations (eg, C481) that prevent inhibitor binding. Here we describe the preclinical profile of pirtobrutinib, a potent, highly selective, non-covalent (reversible) BTK inhibitor. Pirtobrutinib binds BTK with an extensive network of interactions to BTK and water molecules in the adenosine triphosphate (ATP)-binding region and shows no direct interaction with C481. As a result, pirtobrutinib inhibits both BTK and BTK C481 substitution mutants in enzymatic and cell-based assays with similar potencies. In differential scanning fluorimetry studies, BTK bound to pirtobrutinib exhibited a higher melting temperature than cBTKi-bound BTK. Pirtobrutinib, but not cBTKi, prevented Y551 phosphorylation in the activation loop. These data suggest pirtobrutinib uniquely stabilizes BTK in a closed, inactive conformation. Pirtobrutinib inhibits BTK signaling and cell proliferation in multiple B-cell lymphoma cell lines and significantly inhibits tumor growth in human lymphoma xenografts in vivo. Enzymatic profiling showed pirtobrutinib was highly selective for BTK in >98% of the human kinome, and in follow-up cellular studies pirtobrutinib retained >100-fold selectivity over other tested kinases. Collectively, these findings suggest pirtobrutinib represents a novel BTK inhibitor with improved selectivity and unique pharmacologic, biophysical and structural attributes with the potential to treat B-cell driven cancers with improved precision and tolerability. Pirtobrutinib is being tested in phase 3 clinical studies for a variety of B-cell malignancies.
PURPOSE
Report primary analysis results from the mantle cell lymphoma (MCL) cohort of the phase I seamless design TRANSCEND NHL 001 (NCT02631044) study.
PATIENTS AND METHODS
Patients with relapsed/refractory MCL after ≥2 lines of prior therapy, including Bruton tyrosine kinase inhibitor (BTKi), alkylating agent, and CD20-targeted agent, received lisocabtagene maraleucel (liso-cel) at a target dose level of 50×10 ⁶ (DL1) or 100×10 ⁶ (DL2) CAR ⁺ T cells. Primary endpoints were adverse events, dose-limiting toxicities, and objective response rate (ORR) by independent review committee per Lugano criteria.
RESULTS
Of 104 leukapheresed patients, liso-cel was infused into 88. Median (range) number of prior lines of therapy was 3 (1‒11) with 30% receiving ≥5 prior lines of therapy, 73% of patients were aged ≥65 years, 69% had refractory disease, 53% had BTKi refractory disease, 23% had TP53 mutation, and 8% had secondary central nervous system lymphoma. Median (range) on-study follow-up was 16.1 months (0.4‒60.5). In the efficacy set (n=83; DL1+DL2), ORR was 83.1% (95% CI, 73.3%‒90.5%) and complete response (CR) rate was 72.3% (95% CI, 61.4%‒81.6%). Median duration of response was 15.7 months (95% CI, 6.2‒24.0) and progression-free survival was 15.3 months (95% CI, 6.6‒24.9). Most common grade ≥3 treatment-emergent adverse events were neutropenia (56%), anemia (37.5%) and thrombocytopenia (25%). Cytokine release syndrome (CRS) was reported in 61% of patients (grade 3/4, 1%; grade 5, 0), neurological events (NE) in 31% (grade 3/4, 9%; grade 5, 0), grade ≥3 infections in 15%, and prolonged cytopenia in 40%.
CONCLUSION
Liso-cel demonstrated high CR rate and deep, durable responses with low incidence of grade ≥3 CRS, NE, and infections in patients with heavily pretreated relapsed/refractory MCL, including those with high-risk, aggressive disease.
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.
Patients with lymphoproliferative disorders such as CLL and Mantle Cell Lymphoma (MCL) who are resistant to covalent BTK inhibitors (cBTKi), especially if also venetoclax-refractory, have an unmet therapeutic need. Pirtobrutinib, a non-covalent BTK inhibitor, achieves high response rates in cBTKi refractory patients regardless of mechanism of cBTKi resistance. This led to recent accelerated FDA approval in MCL. The toxicity profile in early studies suggests suitability for use in combination approaches. We summarize existing pre-clinical and clinical data with pirtobrutinib.
Pirtobrutinib (JaypircaTM), a highly selective, non-covalent, reversible Bruton's tyrosine kinase (BTK) inhibitor, is being developed by Eli Lilly and Company (Lilly) for the treatment of B-cell leukemias and lymphomas. In January 2023, pirtobrutinib was approved in the USA under the Accelerated Approval pathway for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL) after at least two lines of systemic therapy, including a BTK inhibitor. This indication is approved under accelerated approval based on response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. This article summarizes the milestones in the development of pirtobrutinib leading to this first approval for the treatment of adult patients with relapsed or refractory MCL.
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