Brukinsa (zanubrutinib) / BeiGene, Medison - LARVOL DELTA

Wnt5a induces ROR1 dependent NF-κB activation to enhance MMP-9 expression and invasiveness in chronic lymphocytic leukemia. (PubMed, Leukemia) - "Such effects of Wnt5a could not be inhibited by BTK inhibitors such as ibrutinib or zanubrutinib, but could be blocked by zilovertamab, a humanized mAb specific for ROR1. Moreover, siRNA directed silencing of MMP9 or treatment with an MMP-9 inhibitor (CAS 1177749-58-4) also blocked the invasive capability of CLL cells induced by Wnt5a. We conclude that Wnt5a-induced ROR1-signaling can induce expression of MMP-9 on CLL cells through activation of NF-κB, thereby enhancing the extravasation and lymphoid-tissue infiltration required for CLL cell trafficking."

Journal • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • MMP9 • ROR1

Incidence of pneumonia among bruton tyrosine kinase inhibitors in chronic lymphocytic leukemia: a systematic review and meta-analysis of clinical trials. (PubMed, Ann Hematol) - "The newer second-generation BTKi, acalabrutinib and zanubrutinib, have reduced off-target effects compared to ibrutinib. Of note, the incidence of pneumonia was higher in R/R CLL patients on BTKi therapy when compared to treatment-naïve CLL. Fungal pneumonia, including PJP, is uncommon in CLL, and the subgroup analyses were not able to distinguish any differences among different BTKi."

Journal • Retrospective data • Review • Chronic Lymphocytic Leukemia • Hematological Malignancies • Infectious Disease • Leukemia • Oncology • Pneumonia • Respiratory Diseases

PathSynergy: a deep learning model for predicting drug synergy in liver cancer. (PubMed, Brief Bioinform) - "Excitingly, six Food and Drug Administration (FDA)-approved drugs including pimecrolimus, topiramate, nandrolone_decanoate, fluticasone propionate, zanubrutinib, and levonorgestrel were predicted and validated to show synergistic effects with sorafenib or lenvatinib against liver cancer for the first time. In general, the PathSynergy model provides a new perspective to discover synergistic combinations of drugs and has broad application potential in the fields of drug discovery and personalized medicine."

Journal • Hepatology • Liver Cancer • Oncology • Solid Tumor

Response-adapted zanubrutinib and tislelizumab as a potential strategy to enhance CD19 CAR T-cell therapy in relapsed/refractory large B-cell lymphoma: A retrospective observational study. (PubMed, Clin Transl Med) - "Response-adapted zanubrutinib plus tislelizumab potentially enhances the efficacy of CAR T-cell therapy for R/R LBCL with acceptable safety profile. This regimen functions independently of genetic subtypes, rendering it more applicable for clinical practice with CAR T-cell therapy. This regimen effectively abrogates T-cell exhaustion, but fails to overcome the immunosuppressive effects of M2 macrophages, providing a rationale for remodelling TME to optimise CAR T-cell therapy."

Journal • Observational data • Retrospective data • B Cell Lymphoma • Hematological Malignancies • Large B Cell Lymphoma • Lymphoma • Metabolic Disorders • Non-Hodgkin’s Lymphoma • Oncology

Sonrotoclax, Rituximab, and Zanubrutinib in Treating Participants With Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma, and Mantle Cell Lymphoma (clinicaltrials.gov) - P2 | N=20 | Recruiting | Sponsor: Fred Hutchinson Cancer Center | Not yet recruiting ➔ Recruiting

Enrollment open • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Small Lymphocytic Lymphoma

Zanubrutinib (zanu) overcomes BTK V416L resistance in B cell lymphoma models (AACR 2025) - "Introduction: The second-generation BTK inhibitors (BTKis), e.g., zanu, acalabrutinib (acala), have further transformed the therapy landscape of chronic lymphocytic leukemia (CLL)...Non-covalent BTKi e.g., pirtobrutinib (pirto) can overcome C481 mutations, but is susceptible to other BTK mutations like the recently described kinase impaired V416L and L528W mutations, which both maintain downstream signaling... These data demonstrate that zanu retains potent antitumor activity against TMD8 cells expressing BTK V416L, whereas acala and pirto may be attenuated by steric clashes. Thus, we hypothesize that clonal expansion of V416L is less likely to occur in patients with CLL treated with zanu, whereas it may lead to resistance in patients treated with acala or pirto. This hypothesis should be validated in clinical studies."

B Cell Lymphoma • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

CDK9 pharmacological inhibition has antitumor activity in marginal zone lymphoma models and can improve the effects of BTK, PI3K, and BCL2 inhibitors (AACR 2025) - P1 | "PRT2527 has shown favorable tolerability, with manageable toxicity in a phase 1 study for solid tumor patients (Patel et al, ENA 2023), and it is now in phase 1 as a single agent and in combination with the BTK inhibitor zanubrutinib for hematological cancers patients (NCT05665530)...The combination of PRT2527 with the PI3K inhibitor idelalisib, with the BTK inhibitor ibrutinib, or triple combination with the PI3K inhibitor copanlisib and the BCL2 inhibitor venetoclax was beneficial in all parental cells, and the benefit was maintained, although reduced, in derivatives with acquired resistance to PI3K and BTK inhibitors. CDK9 inhibition with PRT2527 has in vitro antitumor activity in MZL models, which is maintained in models with acquired resistance to PI3K, BTK, or BCL2 inhibitors. CDK9 inhibition with PRT2527 can improve the sensitivity of MZL cells to BTK, PI3K, and BCL2 inhibitors."

B Cell Lymphoma • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor • CDK9 • MCL1

An oral BTK degrader TGRX-3911 overcomes resistance conferred by kinase-proficient and kinase-impaired mutations (AACR 2025) - "TGRX-3911 potently inhibited proliferation of TMD8 parental cells and those harboring knock-in BTK mutations that are resistant to currently approved ibrutinib, zanubrutinib and/or pirtobrutinib, including C481S, T474I, L528W, V416L, A428D, T474I/C481S, T474I/L528W and C481S/L528W (IC50 from 0.4 to 9.9 nM). Remarkably, TGRX-3911 potently inhibited the A428D mutant which is still resistant to current BTK degraders, NX-5948, BGB-16673 and ABBV-101...By eliminating both the catalytic and scaffold functions of BTK, TGRX-3911 has the potential to overcome clinical resistance which can hardly be achieved by conventional BTKi. The potential clinical application of TGRX-3911 for patients with B-cell malignancies is worth exploring."

B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CD86 • PLCG2

Investigating druggability of myeloid and lymphoid lineage gene mutations in advanced phase CML by employing drug discovery tools: Implications in fatal blast crisis CML precision oncology (AACR 2025) - "We also found that some FDA-approved drugs for different hematological malignancies (e.g. VENETOCLAX, DECITABINE, AZACITIDINE, BORTEZOMIB, ZANUBRUTINIB, IVOSIDENIB, TAZEMETOSTAT, RUXOLITINIB, PACRITINIB, ARSENIC TRIOXIDE etc.) can effectively target multiple gene groups mutated in our advanced phase CML patients (Table 1-4, Figures 1-4). NGS analysis of AP- & BC-CML found mutations in many AML-/ALL-lineage genes, which is much higher than previously reported. NGS analysis of AP- & BC-CML found mutations in many AML-/ALL-lineage genes, which is much higher than previously reported. This shows a huge genetic similarity between BC-CML and AML/ALL. FDA-approved and various novel experimental drugs under clinical trials are available against some of the genes we reported."

IO biomarker • Metastases • Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Oncology • AKT1 • BCL2 • DNMT3A • IDH1 • JAK2 • NPM1 • TET2

The BTK degrader BGB-16673 shows anti-tumor activity in marginal zone lymphoma models (AACR 2025) - "Effect on cell viability was assessed by MTT assay after 5 days of exposure to increasing concentrations of compounds or DMSO (control) in MZL cell lines and in cell lines with secondary resistance to idelalisib (n.=2), copanlisib (n.=1), ibrutinib (n.=2), and copanlisib/venetoclax. Oxidative phosphorylation, commonly associated with resistance to multiple therapies, was repressed by BGB-16673 but upregulated by zanubrutinib.Conclusions. Its ability to degrade BTK protein and its antitumor activity position the BTK degrader BGB-16673 as a promising candidate for further development in MZL patients."

B Cell Lymphoma • Hematological Malignancies • Lymphoma • Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CRBN

CFON-026 is a macrocycle that disrupts the BTK protein scaffold thereby inhibiting all clinically relevant BTK resistance mutations (AACR 2025) - "The first generation BTK inhibitors bind covalently to Cys481 and include ibrutinib, acalabrutinib and zanubrutinib...Pirtobrutinib was developed as a second generation non-covalent BTK inhibitor, though resistance has emerged via the acquisition of BTK mutant variants BTKT474I and BTKL528W...CFON-026 disrupts the BTK kinase structure, abrogating both kinase activity and scaffold functions. CFON-026 can overcome resistance mutations emerging from all existing covalent and non-covalent BTK inhibitor therapies."

Clinical • Oncology

BRZ-WM: Zanubrutinib Combined With BR in the First-line Treatment of Waldenström's Macroglobulinemia (clinicaltrials.gov) - P=N/A | N=104 | Not yet recruiting | Sponsor: Peking Union Medical College Hospital

New trial • Hematological Disorders • Hematological Malignancies • Lymphoma • Lymphoplasmacytic Lymphoma • Non-Hodgkin’s Lymphoma • Waldenstrom Macroglobulinemia

ZeTA: A Study to Evaluate Zanubrutinib and Tislelizumab in Progressive Lymphoma Post CAR-T (clinicaltrials.gov) - P2 | N=76 | Not yet recruiting | Sponsor: University Health Network, Toronto | Trial primary completion date: Dec 2025 ➔ Apr 2026

Trial primary completion date • B Cell Lymphoma • Hematological Malignancies • Large B Cell Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

Zanubrutinib Combined With Standard Chemotherapy in the Treatment for Patients With Diffuse Large B Cell Lymphoma (clinicaltrials.gov) - P2 | N=59 | Suspended | Sponsor: Henan Cancer Hospital | Recruiting ➔ Suspended | Trial primary completion date: Dec 2023 ➔ Nov 2024

Trial primary completion date • Trial suspension • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • BCL2 • CD79A • CD79B • MYC

Meta Analysis Shows Efficacy Trend Favoring Zanubrutinib in High-Risk R/R CLL (OncLive) - "The NMA, which was published in Blood, included patients with high-risk, relapsed/refractory CLL who were treated in the phase 3 ALPINE (NCT03734016), ELEVATE-RR (NCT02477696), and ASCEND (NCT02970318) studies....In the COVID-19–adjusted analysis, zanubrutinib reduced the risk of disease progression or death compared with ibrutinib (HR, 0.49; 95% credible interval [CrI], 0.31-0.78), acalabrutinib (HR, 0.55; 95% CrI, 0.32-0.94), and BR/IR (HR, 0.12; 95% CrI, 0.05-0.26)....Overall survival (OS) outcomes showed a numerical benefit with zanubrutinib compared with ibrutinib (HR, 0.59; 95% CrI, 0.31-1.11; probability better, 94.8%), acalabrutinib (HR, 0.72; 95% CrI, 0.35-1.50; probability better, 81.5%), and BR/IR (HR, 0.65; 95% CrI, 0.23-1.75; probability better, 80.0%), although these findings did not reach statistical significance."

Retrospective data • Chronic Lymphocytic Leukemia

Real-world zanubrutinib treatment patterns in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) among US community oncology patients with prior acalabrutinib therapy. (ASCO 2025) - "The abstract will be released to the public on May 22, 2025 at 5:00 PM EDT"

Clinical • Real-world • Real-world evidence • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Small Lymphocytic Lymphoma

Real-world zanubrutinib treatment patterns in mantle cell lymphoma (MCL) among US community oncology patients with prior Bruton tyrosine kinase inhibitor (BTKi) therapy. (ASCO 2025) - "The abstract will be released to the public on May 22, 2025 at 5:00 PM EDT"

Clinical • Real-world • Real-world evidence • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Oncology

Comparing real-world treatment patterns and outcomes of zanubrutinib and acalabrutinib in CLL/SLL at University of California academic health centers. (ASCO 2025) - "The abstract will be released to the public on May 22, 2025 at 5:00 PM EDT"

Clinical • HEOR • Real-world • Real-world evidence • Chronic Lymphocytic Leukemia • Small Lymphocytic Lymphoma

Comparative efficacy of zanubrutinib (ZANU) versus fixed-duration acalabrutinib plus venetoclax (AV) for first-line treatment of chronic lymphocytic leukemia (CLL): A matching-adjusted indirect comparison (MAIC). (ASCO 2025) - "The abstract will be released to the public on May 22, 2025 at 5:00 PM EDT"

Clinical • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology

A network meta-analysis (NMA) of efficacy of zanubrutinib versus fixed-duration acalabrutinib plus venetoclax in treatment-naïve (TN) chronic lymphocytic leukemia (CLL). (ASCO 2025) - "The abstract will be released to the public on May 22, 2025 at 5:00 PM EDT"

Retrospective data • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology

Serious infections in patients with CLL/SLL treated with combination venetoclax and obinutuzumab compared with those treated with zanubrutinib: A real-world study. (ASCO 2025) - "The abstract will be released to the public on May 22, 2025 at 5:00 PM EDT"

Clinical • Real-world • Real-world evidence • Chronic Lymphocytic Leukemia • Infectious Disease • Small Lymphocytic Lymphoma

Adverse events of interest (AEIs) with zanubrutinib vs fixed-duration combination of venetoclax + obinutuzumab in treatment-naive (TN) chronic lymphocytic leukemia (CLL). (ASCO 2025) - P3 | "Clinical Trial Registration Number: NCT03336333, NCT02242942 The abstract will be released to the public on May 22, 2025 at 5:00 PM EDT"

Adverse events • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology

Efficacy of continuous zanubrutinib vs fixed-duration venetoclax in combination with obinutuzumab in treatment-naive (TN) chronic lymphocytic leukemia (CLL): A matching-adjusted indirect comparison (MAIC). (ASCO 2025) - "The abstract will be released to the public on May 22, 2025 at 5:00 PM EDT"

Clinical • Combination therapy • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology

SEQUOIA 5-year follow-up in arm C: Frontline zanubrutinib monotherapy in patients with del(17p) and treatment-naive chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). (ASCO 2025) - P3 | "Clinical Trial Registration Number: NCT03336333 The abstract will be released to the public on May 22, 2025 at 5:00 PM EDT"

Clinical • Monotherapy • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Small Lymphocytic Lymphoma

Combination of zanubrutinib (zanu) + venetoclax (ven) for treatment-naive (TN) CLL/SLL: Results in SEQUOIA arm D. (ASCO 2025) - P3 | "Clinical Trial Registration Number: NCT03336333 The abstract will be released to the public on May 22, 2025 at 5:00 PM EDT"

Chronic Lymphocytic Leukemia • Small Lymphocytic Lymphoma