- |||||||||| Review, Journal: Review of BCL2 inhibitors for the treatment of Waldenstr (Pubmed Central) - Nov 19, 2024
Five studies have published results on the use of BCL2 inhibitors in WM to date, including oblimersen sodium, venetoclax, and sonrotoclax...The combination of venetoclax with ibrutinib resulted in higher and relatively deep response rates, but unexpected deaths due to ventricular events mean this combination cannot be explored. Two pivotal trials are currently evaluating the use of fixed-duration venetoclax, either in combination with rituximab or pirtobrutinib, whereas another multi-arm study is studying the use of continuous sonrotoclax monotherapy for R/R WM or in fixed-duration combination with Zanubrutinib for treatment-na
- |||||||||| ZE66-0205 / Eilean Therap
Development of ZE66-0205, a Novel MALT1 Degrader for Treatment of B-Cell Malignancies (Halls G-H (San Diego Convention Center)) - Nov 6, 2024 - Abstract #ASH2024ASH_5202; ZE66-0205 leads to on target degradation of CBM target proteins and represents a promising new treatment strategy for DLBCL and other B-cell malignancies. Future clinical development of ZE66-0205 is warranted and ongoing.
- |||||||||| Cardiac Safety Profiles of First-Generation Vs. Second-Generation BTK Inhibitors: A Meta-Analysis (Halls G-H (San Diego Convention Center)) - Nov 6, 2024 - Abstract #ASH2024ASH_5059;
Time since market entry might partially account for the DOT and rwTTNT results. Introduction: Bruton's tyrosine kinase (BTK) inhibitors, including the first-generation ibrutinib and second-generation agents such as zanubrutinib, acalabrutinib, and pirtobrutinib, are critical in the treatment of B-cell hematologic malignancies such as chronic lymphocytic leukemia, Waldenstr
- |||||||||| Jaypirca (pirtobrutinib) / Eli Lilly
Characteristics and Outcomes of Patients with Double Refractory (DR) or Double Exposed (DE) CLL (Halls G-H (San Diego Convention Center)) - Nov 6, 2024 - Abstract #ASH2024ASH_3968; In studies including both DR and DE patients, the reported median progression-free survival has been consistently below 2 years for non-covalent BTKi (ncBTKi) pirtobrutinib (Woyach et al, 2023 ASH Meeting) and CD19 chimeric antigen receptor-modified T (CAR T) liso cel (Siddiqi et al, 2023 ASH Meeting), which are the approved third-line treatments for CLL in the United States...DE CLL represented a less aggressive disease state with preserved sensitivity to targeted and cellular therapies. Given these differences, DR and DE CLL should be clearly distinguished in clinical trials.
- |||||||||| Clinical Characteristics and Outcome in a Cohort of CLL Patients with BTK T474 Gatekeeper Mutation (Halls G-H (San Diego Convention Center)) - Nov 6, 2024 - Abstract #ASH2024ASH_3941;
The number of pts included in this series is derived predominately from the pre-pirtobrutinib era and includes only a small subset of high risk double refractory (BTKi/BCL2 inhibitor) CLL. Nonetheless, this provides justification for considering patients with T474 gatekeeper mutations as a high-risk population that will continue to expand with FDA approval of pirtobrutinib.
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie, Jaypirca (pirtobrutinib) / Eli Lilly, Imbruvica (ibrutinib) / AbbVie, J&J
Decoding the Pivotal Roles of BCL10 Activating Mutations in DLBCL Drug Resistance and Lymphomagenesis (Ballroom 20CD (San Diego Convention Center)) - Nov 6, 2024 - Abstract #ASH2024ASH_2037; The combination of venetoclax and pirtobrutinib synergistically overcomes BCL10-driven resistance and effectively kills BCL10-mutant DLBCL tumors in vitro and in vivo, suggesting BTK retains key roles protecting DLBCL tumors from apoptosis even when dispensable for CBM activation. Genetically accurate mutant-BCL10 mice revealed a novel germinal-center activation deficit and facilitated generation of valuable preclinical models to further interrogate biology of the BN2/C1 molecular subgroup through activation of the BCL6 oncogene.
- |||||||||| Review, Journal: Advances in Targeted Therapy: Addressing Resistance to BTK Inhibition in B-Cell Lymphoid Malignancies. (Pubmed Central) - Oct 26, 2024
The first-in-class covalent BTK inhibitor, Ibrutinib, binds to the C481 amino acid residue to block the BTK enzyme and prevent the downstream signaling...To bypass the C481S mutation, non-covalent BTKi, such as Pirtobrutinib, were developed and are active against both wild-type and the C481S mutation...In addition, we discuss the new emerging class of BTK degraders, which utilize the evolution of proteolysis-targeting chimeras (PROTACs) to degrade the BTK protein and constitute an important avenue of overcoming resistance. The moving landscape of resistance to BTKi and the development of new therapeutic strategies highlight the ongoing advances being made towards the pursuit of a cure for B-cell lymphoid malignancies.
- |||||||||| Jaypirca (pirtobrutinib) / Eli Lilly, Rituxan (rituximab) / Roche
Trial completion date, Trial initiation date, Trial primary completion date, Combination therapy: OSU-23307: Pirtobrutinib in Combination With Rituximab in Newly Diagnosed Marginal Zone Lymphoma (R+Pirto in Newly Diagnosed MZL) (clinicaltrials.gov) - Oct 18, 2024 P2, N=23, Not yet recruiting, Furthermore, WS-11 would have a good druglikeness properties predicted by pkCSM and SwissADME, which provided a promising lead for further optimization and development. Trial completion date: Dec 2025 --> Dec 2032 | Initiation date: May 2024 --> Dec 2024 | Trial primary completion date: Dec 2025 --> Dec 2031
- |||||||||| Jaypirca (pirtobrutinib) / Eli Lilly
Journal: Pirtobrutinib: the 'brute' with a softer side. (Pubmed Central) - Oct 17, 2024 These data support the safety of pirtobrutinib in patients requiring antithrombotic therapies. Not available.
- |||||||||| Review, Journal: Current Approaches and Novel New Agents in the Treatment of Chronic Lymphocytic Leukemia. (Pubmed Central) - Oct 14, 2024
Promising novel approaches include BTK degraders, bispecific antibodies, and chimeric antigen receptor T-cell (CAR-T)-cell therapy. What is clear is that CIT is archaic, and current and future targeted approaches will continue to improve the outcome for patients with chronic lymphocytic leukemia.
- |||||||||| Jaypirca (pirtobrutinib) / Eli Lilly, nemtabrutinib (MK-1026) / Merck (MSD)
MODULE 4: Integration of Noncovalent BTK Inhibitors into the Management of R/R CLL (Manchester Grand Hyatt San Diego, Seaport Ballroom EFGH; In-Person; Virtual) - Oct 5, 2024 - Abstract #ASH2024ASH_78; What is clear is that CIT is archaic, and current and future targeted approaches will continue to improve the outcome for patients with chronic lymphocytic leukemia. This program is supported by educational grants from AstraZeneca Pharmaceuticals LP, BeiGene Ltd and Lilly.Clinical and biological factors guiding decision-making for patients with R/R CLL; current role of rechallenge with an agent or class of agents received in a prior line of therapy Mechanistic similarities and differences between noncovalent and covalent BTK inhibitors; implications for efficacy and tolerability Antitumor activity documented with pirtobrutinib from the Phase I/II BRUIN study in patients with R/R CLL, including those who experience disease progression on covalent BTK inhibitors Spectrum, frequency and severity of toxicities with pirtobrutinib relative to covalent BTK inhibitors Recent FDA approval and current clinical role of pirtobrutinib for R/R CLL Ongoing Phase III trials (eg, BRUIN CLL-313, BRUIN CLL-314, BRUIN CLL-321, BRUIN CLL-322) evaluating pirtobrutinib for CLL Similarities and differences between pirtobrutinib and nemtabrutinib; early efficacy and safety data with nemtabrutinib for R/R CLL and ongoing Phase III evaluation for treatment-na
- |||||||||| Jaypirca (pirtobrutinib) / Eli Lilly
Journal: Pirtobrutinib combinations in CLL. (Pubmed Central) - Sep 26, 2024 This program is supported by educational grants from AstraZeneca Pharmaceuticals LP, BeiGene Ltd and Lilly.Clinical and biological factors guiding decision-making for patients with R/R CLL; current role of rechallenge with an agent or class of agents received in a prior line of therapy Mechanistic similarities and differences between noncovalent and covalent BTK inhibitors; implications for efficacy and tolerability Antitumor activity documented with pirtobrutinib from the Phase I/II BRUIN study in patients with R/R CLL, including those who experience disease progression on covalent BTK inhibitors Spectrum, frequency and severity of toxicities with pirtobrutinib relative to covalent BTK inhibitors Recent FDA approval and current clinical role of pirtobrutinib for R/R CLL Ongoing Phase III trials (eg, BRUIN CLL-313, BRUIN CLL-314, BRUIN CLL-321, BRUIN CLL-322) evaluating pirtobrutinib for CLL Similarities and differences between pirtobrutinib and nemtabrutinib; early efficacy and safety data with nemtabrutinib for R/R CLL and ongoing Phase III evaluation for treatment-na No abstract available
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie, Jaypirca (pirtobrutinib) / Eli Lilly, Breyanzi (lisocabtagene maraleucel) / BMS
Biomarker, Review, Journal, IO biomarker: Utilizing risk factors to guide treatment decisions in chronic lymphocytic leukemia. (Pubmed Central) - Sep 20, 2024 Testing for prognostic biomarkers will remain relevant to identify patients who may have increased benefit from novel therapeutic strategies, such as combination therapies and novel agents. Patients with high-risk disease should be encouraged to participate in clinical trials.
- |||||||||| Jaypirca (pirtobrutinib) / Eli Lilly
Review, Journal: Pirtobrutinib: A New and Distinctive Treatment Option for B-Cell Malignancies. (Pubmed Central) - Sep 15, 2024 Ongoing studies are evaluating pirtobrutinib's use in multiple B-cell malignancies and comparing it with other BTK inhibitors. 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.
- |||||||||| Jaypirca (pirtobrutinib) / Eli Lilly, Tecartus (brexucabtagene autoleucel) / Gilead
Enrollment open: Phase 2 Open Label Randomized Study of Pirtobrutinib and Brexucabtagene Autoleucel in R/R MCL (clinicaltrials.gov) - Sep 4, 2024 P2, N=60, Recruiting, 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. Not yet recruiting --> Recruiting
- |||||||||| Mantle Cell Lymphoma: Next Steps () - Aug 30, 2024 - Abstract #SOHO2024SOHO_1055;
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. The most commonly used agents are the Bruton tyrosine kinase (BTK) inhibitors, with ibrutinib becoming Food and Drug Administration (FDA)-approved in 2013, acalabrutinib in 2017, and zanubrutinib in 2019...Excitingly, pirtobrutinib, a BTK inhibitor that binds noncovalently and reversibly to BTK, is also now FDA-approved and is providing acceptable results even in many patients with prior relapse to covalent BTK inhibitors...Brexucabtagene autoleucel (brexu-cel) is an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy that was approved by the FDA in 2020...Most excitingly, a second anti-CD19 CAR T-cell therapy, lisocabtagene maraleucel (lisocel), was approved a week ago...The most advanced ones include glofitamab (CD20/CD3) and epcoritamab (CD20/CD3), both of which are approved for diffuse large B-cell lymphoma and are currently being tested for mantle cell lymphoma as well...In this phase 3 trial, ibrutinib plus venetoclax produced a high complete response (CR) rate, longer progression-free survival (PFS), and a trend of improved overall survival (OS)...In the near future, I
- |||||||||| Accessing BTK Inhibitors and Other Novel Therapies for Mantle Cell Lymphoma: Are We All Invited to the Party? () - Aug 30, 2024 - Abstract #SOHO2024SOHO_1051;
Finally, chimeric antigen receptor T cells (CARTs) have also shown great efficacy in heavily treated MCL patients, leading to the approval of both brexucabtagene autoleucel and lisocabtagene maraleucel for these patients...Enrollment of patients in clinical trials may not help the accessibility of study drugs in the future, but it will guarantee that some patients receive proper therapy. There is a clear need to discuss ethical aspects of these studies, including post-protocol therapy, but we strongly believe that clinical trials are an important tool for optimizing therapy for MCL patients in LICs and LMICs.
- |||||||||| BTK Inhibitor Therapy Can be Stopped in CLL () - Aug 30, 2024 - Abstract #SOHO2024SOHO_1048;
P2, P3 There is a clear need to discuss ethical aspects of these studies, including post-protocol therapy, but we strongly believe that clinical trials are an important tool for optimizing therapy for MCL patients in LICs and LMICs. Results and Discussion Because deep responses are rare with BTKi monotherapy and BTKis have relatively short half-lives (ibrutinib: 4
|