nemtabrutinib (MK-1026) / Merck (MSD) - LARVOL DELTA

Genomic profiling in CLL patients after BTK inhibitor progression identifies enrichment of mutations in MAPK pathway and epigenetic regulators (ASH 2025) - "A total of64 blood samples were collected at different timepoints: baseline (before BTKi therapy), during treatmentand at disease progression from BTKi (Ibrutinib/Acalabrutinib/Pirtobrutinib/Nemtabrutinib). Disease progression of CLL on BTKi confirmed the existence of multiple driver genes beyondBTK, PLCG2 and TP53, including the high prevalence of mutations in MAPK pathway and epigeneticregulators, and increased genomic complexity. Ongoing efforts are focused on integrating these findingswith clinical demographics, epigenetic modifications, and preclinical drug sensitivity profiles."

Clinical • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Richter's Syndrome • BRAF • CREBBP • KMT2D • KRAS • NOTCH1 • NRAS • PLCG2 • PTPN11 • RB1 • SETD1A • SETD2 • SF3B1 • TP53

Genomic assessment of acquired mutations in participants with CLL/SLL treated with nemtabrutinib in the Phase 2 bellwave-003 study (ASH 2025) - "Analysis of nemtabrutinib-treated cell lines using next-generation sequencing showed a lack of mutation in BTK and PLCγ2, incontrast with other covalent and noncovalent BTKi such as ibrutinib and pirtobrutinib, respectively (Qi etal, Blood Adv, 2023). These data show that across all biomarker-evaluable pts with R/R CLL/SLL receivingnemtabrutinib in BELLWAVE-003, acquired resistance mutations to BTKi were rare, regardless ofresponse. While BTK mutations are the most frequent mechanism of resistance to covalent BTKi andhave also been reported after treatment with non-covalent BTKi, none were detected in pts treated withnemtabrutinib. These data support the rationale for systematically evaluating the molecular basis ofacquired resistance, which may differ from mechanisms observed with other noncovalent BTKi."

IO biomarker • P2 data • Chronic Lymphocytic Leukemia • Hematological Malignancies • Small Lymphocytic Lymphoma • BCL2 • HEY1 • MYD88 • NOTCH1 • PLCG2 • SF3B1 • TP53

Nemtabrutinib in participants with relapsed or refractory follicular lymphoma: Updated efficacy and safety from cohort g of the phase 2 bellwave-003 study (ASH 2025) - P2 | "Nemtabrutinib has additional activity versus ibrutinib against Srcfamily kinases and kinases related to ERK signaling, which may produce robust responses...Furthermore, nemtabrutinib has also showed preclinical efficacy in cell linescarrying BTK mutations derived from patients treated with pirtobrutinib... With additional follow-up, nemtabrutinib continued to show promising antitumor efficacy inparticipants with FL who had received multiple prior lines of therapy and had progressed on bothchemoimmunotherapy and immunomodulatory therapy. The safety profile remained manageable, withno unexpected AEs observed. These results support the ongoing clinical evaluation of nemtabrutinib inthe R/R setting for FL."

Clinical • IO biomarker • P2 data • Cardiovascular • Chronic Lymphocytic Leukemia • CNS Disorders • Congestive Heart Failure • Dermatology • Follicular Lymphoma • Heart Failure • Hematological Malignancies • Immunology • Infectious Disease • Lymphoma • Lymphoplasmacytic Lymphoma • Mantle Cell Lymphoma • Marginal Zone Lymphoma • Neutropenia • Pneumonia • Respiratory Diseases • Richter's Syndrome • Septic Shock • Thrombocytopenia • Urticaria • Waldenstrom Macroglobulinemia

Phase 2 bellwave-003 cohort f: Updated clinical outcomes of nemtabrutinib in participants with relapsed or refractory marginal zone lymphoma (ASH 2025) - P2 | "Analysis of nemtabrutinib-treated cell lines using next-generation sequencing showed a lackof mutation in BTK and PLCG2 domains, which contrasts with other covalent and noncovalent BTKis suchas ibrutinib and pirtobrutinib, respectively. With continued follow-up, nemtabrutinib showed sustained antitumor activity in heavilypretreated participants with MZL who had progressed after treatment with both chemoimmunotherapyand covalent BTKis. The safety profile remained consistent and manageable, with no new or unexpectedAEs observed. These outcomes reinforce the rationale for further clinical exploration in R/R MZL."

Clinical • Clinical data • IO biomarker • P2 data • Chronic Lymphocytic Leukemia • Febrile Neutropenia • Follicular Lymphoma • Hematological Malignancies • Infectious Disease • Leukemia • Lymphoma • Lymphoplasmacytic Lymphoma • Mantle Cell Lymphoma • Marginal Zone Lymphoma • Neutropenia • Non-Hodgkin’s Lymphoma • Pneumonia • Respiratory Diseases • Richter's Syndrome • Small Lymphocytic Lymphoma • Waldenstrom Macroglobulinemia • PLCG2

Nemtabrutinib plus venetoclax in relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma: Results from the dose escalation and confirmation segment of the Phase 3 bellwave-010 study (ASH 2025) - P3 | "Introduction: Venetoclax + rituximab (VR) is a standard-of-care therapy for patients with relapsed orrefractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL); however, an unmetneed remains for more effective treatments. Initial results for part 1 of the BELLWAVE-010 study showed that nemtabrutinib + venetoclaxhad very promising antitumor activity with 100% response rate for the 45 mg nemtabrutinib dose and amanageable safety profile, supporting the ongoing evaluation of this combination in pts with R/R CLL/SLL.Minimal residual disease analysis is currently ongoing."

P3 data • Chronic Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Infectious Disease • Leukemia • Lymphoma • Neutropenia • Non-Hodgkin’s Lymphoma • Pneumonia • Respiratory Diseases • Small Lymphocytic Lymphoma • Thrombocytopenia

Targeting BTKi-resistant CLL using the dual irreversible/reversible 4th generation BTK inhibitor rocbrutinib (ASH 2025) - P1 | "UsingFPCBA, rocbrutinib was the only BTKi—among ibrutinib, acalabrutinib, zanubrutinib, nemtabrutinib, andpirtobrutinib—to retain nanomolar potency against WT BTK as well as clinically relevant resistancemutations, including C481S, V416L, M437R, and L528W. Collectively, our findings demonstrate rocbrutinib is a potent and selective inhibitor of BTKwith activity even in the presence of mutations that mediate resistance to cBTKi and ncBTKi. These datasupport the continued investigation of rocbrutinib, which is currently being studied in the phase 1 settingof CLL and NHL (NCT04775745 and NCT04993690)."

Chronic Lymphocytic Leukemia • CCL3 • PLCG2

Advances in the Management of Relapsed/Refractory CLL and Richter Transformation (ICML 2025) - P=N/A, P2, P3 | "BRUIN CLL-321 is a phase 3, registrational study that evaluated pirtobrutinib compared to the investigator's choice of idelalisib plus rituximab (IdelaR) or bendamustine plus rituximab (BR) [23]...Nemtabrutinib is now being evaluated in the registrational, phase 3 BELLWAVE-010 trial (NCT05947851) for patients with R/R CLL, comparing nemtabrutinib plus venetoclax to venetoclax plus rituximab...An ongoing, open-label, first-in-human phase 1/2 study is evaluating the BTK degrader BGB-16673 as monotherapy in patients with R/R CLL [27, 28]...NX-2127 is an investigational, first-in-class BTK degrader currently being evaluated in a phase 1 trial for patients with relapsed or refractory B-cell malignancies, CLL [29, 30]...NX-5948 is another investigational and more selective BTK degrader in an ongoing Phase 1a/1b clinical trial...This trial aims to establish lisaftoclax plus acalabrutinib as a potential alternative to venetoclax-based BTKi combination..."

IO biomarker • Acute Myelogenous Leukemia • B Cell Lymphoma • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Leukemia • Non-Hodgkin’s Lymphoma • Oncology • Richter's Syndrome • Small Lymphocytic Lymphoma • BCL2L1 • TP53

The Development of Novel Therapies for Chronic Lymphocytic Leukaemia in the Era of Targeted Drugs. (PubMed, J Clin Med) - "Over the past decade, chronic lymphocytic leukaemia (CLL) treatment has shifted from chemoimmunotherapy to targeted oral agents, predominantly Bruton's tyrosine kinase inhibitors (BTKis) and the BCL-2 inhibitor venetoclax...This has driven the development of novel therapeutic strategies, including non-covalent BTKis such as pirtobrutinib and nemtabrutinib, which retain activity in BTK C481-mutated disease. Next-generation BCL-2 inhibitors (sonrotoclax, lisaftoclax) and BTK degraders are promising in early clinical trials...Minimal residual disease (MRD)-guided, fixed-duration regimens represent a significant paradigm shift toward personalised treatment and potentially deeper remissions. Ongoing clinical studies are expected to introduce new effective therapies that may further transform the management of CLL in the coming years."

IO biomarker • Journal • Review • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology

MODULE 5: Promising Investigational Agents and Strategies (ASH 2023) - "Supported by educational grants from AstraZeneca Pharmaceuticals LP, BeiGene Ltd, Bristol Myers Squibb, and Lilly. Biological rationale for the investigation of CD19-directed chimeric antigen receptor T-cell therapy for patients with CLL Published and emerging findings with lisocabtagene maraleucel (liso-cel) monotherapy in the Phase I/II TRANSCEND CLL 004 trial; rates of complete response compared to historical controls Early findings with liso-cel in combination with ibrutinib for heavily pretreated CLL Mechanism of action of nemtabrutinib; early efficacy and safety data with nemtabrutinib for R/R CLL and ongoing Phase III evaluation for treatment-naïve disease Antitumor activity observed with bispecific antibody therapy, such as epcoritamab or NVG-111, among patients with CLL, including those with Richter's transformation Other promising agents and strategies under investigation for CLL"

Oncology • Richter's Syndrome

BELLWAVE-003: Efficacy and Safety of Nemtabrutinib (MK-1026) in Participants With Hematologic Malignancies (MK-1026-003) (clinicaltrials.gov) - P2 | N=490 | Recruiting | Sponsor: Merck Sharp & Dohme LLC | Trial completion date: Mar 2027 ➔ Jan 2029 | Trial primary completion date: Mar 2027 ➔ Jan 2029

Trial completion date • Trial primary completion date • B Cell Lymphoma • Chronic Lymphocytic Leukemia • Follicular Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Lymphoplasmacytic Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Waldenstrom Macroglobulinemia • CCND1 • CD4 • TP53

A Study of Nemtabrutinib in Participants With Moderate Hepatic Impairment (MK-1026-015) (clinicaltrials.gov) - P1 | N=16 | Recruiting | Sponsor: Merck Sharp & Dohme LLC | Trial completion date: Dec 2025 ➔ Sep 2026 | Trial primary completion date: Dec 2025 ➔ Sep 2026

Trial completion date • Trial primary completion date • Hepatology

Merck…announced that new data across multiple hematologic malignancies will be presented at the American Society of Hematology (ASH) Annual Meeting and Exposition in Orlando, Fla. from Dec. 6-9. (Merck (MSD) Press Release) - "Data presentations will feature Merck’s pipeline candidates, including: MK-1045, an investigational CD19xCD3 T-cell engager; bomedemstat (MK-3543), an investigational, orally available lysine-specific demethylase 1 (LSD1) inhibitor; and nemtabrutinib (MK-1026), an investigational, non-covalent Bruton’s tyrosine kinase (BTK) inhibitor. Additionally, Merck will present new and updated results highlighting zilovertamab vedotin (MK-2140), an investigational antibody-drug conjugate (ADC) that targets receptor tyrosine kinase-like orphan receptor 1 (ROR1)."

Clinical data • B Acute Lymphoblastic Leukemia • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Essential Thrombocythemia • Follicular Lymphoma • Marginal Zone Lymphoma • Polycythemia Vera

Narazaciclib, a Differentiated CDK4/6 Antagonist, Prolongs Cell Cycle Arrest and Metabolomic Reprogramming, Enabling Restoration of Ibrutinib Sensitivity in Btki-Resistant Mantle Cell Lymphoma (ASH 2023) - "We compared the efficacy and safety profiles of narazaciclib with three health authority-approved CDKi (palbociclib, abemaciclib or ribociclib) in association with covalent (ibrutinib, acalabrutinib) and non-covalent (pirtobrutinib, ARQ-531) BTKi, across a panel of 10 MCL cell lines with distinct sensitivity to the first-in-class BTKi, ibrutinib. In conclusion, our findings demonstrate that narazaciclib is safe and effective as a single agent in preclinical models of MCL, including BTKi-resistant cases. Its combination with ibrutinib achieved a synergistic tumoricidal effect in vitro and in vivo, accelerating cell cycle blockade and reverting the metabolic reprogramming characterizing MCL refractoriness to BTKi therapy."

Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Oncology • CDK4 • CDKN1A

Targeting Covalent and Non-Covalent Btki-Resistant CLL Using the Dual Irreversible/Reversible 4th Generation BTK Inhibitor LP-168 (ASH 2023) - P1 | "Pirtobrutinib and nemtabrutinib are non-covalent BTK inhibitors (ncBTKi) developed to target and inhibit C481S mutant BTK...We treated mice daily via oral gavage and found that 50 mg/kg of LP-168 significantly improved survival in the Eµ-TCL1 model when compared to vehicle (median 51 vs 44 days; p=0.0018) or ibrutinib at 50 mg/kg (median 51 vs 45 days; p=0.0098) and the Eµ-MTCP1 model when compared with vehicle (median 122 vs 62 days; p<0.0001) or ibrutinib at 50 mg/kg (median 122 vs 96 days; p=0.0162) (Figure 1B). Collectively, our data demonstrate that LP-168 is a potent and selective inhibitor of BTK with activity against CLL, even in the presence of mutations that mediate resistance to cBTKi and ncBTKi. These data support the continued preclinical and clinical investigation of LP-168, which is currently being studied in the phase 1 setting of CLL (NCT04775745) and NHL (NCT04993690)."

Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • ANXA5 • CCL3 • CXCL12 • CXCL13 • CXCL14 • PLCG2

The Reversible BTK Inhibitor Nemtabrutinib Demonstrates Favorable Antitumor Efficacy and Enhances the Function of CAR T Cells in Mantle Cell Lymphoma (ASH 2023) - "In January 2023, the reversible BTK inhibitor pirtobrutinib was approved by the FDA for the treatment of relapsed or refractory MCL...ResultsNemtabrutinib demonstrated comparable growth inhibitory activity to ibrutinib in MCL cell lines with IC 50 values at micromolar concentrations (IC 50 = 0...The result demonstrated that nemtabrutinib enhanced the effector function and anti-MCL activity of anti-CD19 CAR T cells. ConclusionNemtabrutinib demonstrated favorable anti-MCL efficacy in both in vitro and in vivo studies, the promising synergistic effects observed in combination with CAR T cells warrants further investigation in both preclinical and clinical settings."

CAR T-Cell Therapy • Clinical • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Oncology • ANXA5 • IFNG • SYK • TNFA

A Study of the Effect of Diltiazem on the Plasma Levels of Nemtabrutinib (MK-1026-022) (clinicaltrials.gov) - P1 | N=24 | Not yet recruiting | Sponsor: Merck Sharp & Dohme LLC

New P1 trial

A Study of Nemtabrutinib Plus Venetoclax vs Venetoclax + Rituximab (VR) in Second-line (2L) + Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) (MK-1026-010/BELLWAVE-010). (clinicaltrials.gov) - P3 | N=735 | Recruiting | Sponsor: Merck Sharp & Dohme LLC | Trial completion date: Mar 2035 ➔ Jul 2035 | Trial primary completion date: Mar 2035 ➔ Jun 2032

Trial completion date • Trial primary completion date • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Small Lymphocytic Lymphoma • BTK • IGH • TP53

Bellwave-010: Phase 3, Open-Label, Randomized Study of Nemtabrutinib Plus Venetoclax Versus Venetoclax Plus Rituximab in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Following at Least One Prior Therapy (ASH 2023) - P3 | "Secondary end points for part 2 include undetectable minimal residual disease in bone marrow at month 14 as assessed by central laboratory, ORR, and DOR per iwCLL 2018 criteria by BICR, OS, and safety. Exploratory end points include ORR including partial response with lymphocytosis, pharmacokinetics, and health-related quality of life."

Clinical • P3 data • Chronic Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Richter's Syndrome • Small Lymphocytic Lymphoma • BTK • TP53

Outcomes of Therapies Following Discontinuation of Non-Covalent Bruton's Tyrosine Kinase Inhibitors for Patients with Chronic Lymphocytic Leukemia and Richter Transformation: Results from an International, Multicenter Study (ASH 2024) - "Pirtobrutinib is a standard treatment (tx) for CLL pts after covalent BTKi (cBTKi) and venetoclax (ven), and additional ncBTKi including nemtabrutinib are in development. The median PFS for ven as first tx following ncBTKi dc was 23 months in this largely ven-naïve, but heavily pre-treated pt population, supporting that ven may be sequenced after ncBTKi dc. There is an unmet need for novel tx approaches for CLL and RT pts following ncBTKi dc."

Clinical • IO biomarker • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • Richter's Syndrome • IGH • PD-1 • TP53

LP-168 (Rocbrutinib), a Novel Covalent and Non-Covalent Next-Generation Inhibitor of Bruton's Tyrosine Kinase: Updates on the Phase 1 Trial and Initial Results of the CLL Gatekeeper Mutation Cohort (ASH 2024) - P1 | "Preliminary encouraging efficacy is observed in this GM cohort, including those treated with one or more BTKi such as pirtobrutinib and nemtabrutinib. Rocbrutinib could potentially fill an unmet need in CLL for pts with resistant CLL. Ongoing and future clinical trials will focus on dose optimization and combination studies."

P1 data • Atrial Fibrillation • Cardiovascular • Chronic Lymphocytic Leukemia • Constipation • Cough • Fatigue • Gastroenterology • Gastrointestinal Disorder • Hematological Disorders • Hematological Malignancies • Hypertension • Infectious Disease • Leukemia • Neutropenia • Oncology • Pneumonia • Respiratory Diseases • PLCG2 • TP53

Nemtabrutinib Versus Ibrutinib or Acalabrutinib for Untreated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: The Phase 3, Open-Label, Randomized Bellwave-011 Study (ASH 2024) - P3 | "Reused with permission. This abstract was accepted and previously presented at the 2024 ASCO Annual Meeting."

Clinical • P3 data • Anemia • Chronic Lymphocytic Leukemia • Fatigue • Hematological Disorders • Hematological Malignancies • Immunology • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Richter's Syndrome • Small Lymphocytic Lymphoma • Thrombocytopenia

Zilovertamab Vedotin Monotherapy for Patients with Relapsed or Refractory Mantle Cell Lymphoma: Cohort a of the Multicenter, Open-Label, Phase 2 Waveline-006 Study (ASH 2024) - P2 | "The phase 2, multicohort, waveLINE-006 study (NCT05458297) was designed to assess the efficacy and safety of zilovertamab vedotin as monotherapy and in combination with the BTKi nemtabrutinib in R/R aggressive and indolent B-cell malignancies. Conclusions : Zilovertamab vedotin monotherapy demonstrated antitumor activity and manageable safety in heavily pretreated pts with R/R MCL in cohort A of waveLINE-006. Further investigation is warranted to better understand the efficacy of zilovertamab vedotin for R/R MCL."

Clinical • Monotherapy • P2 data • Hematological Disorders • Hematological Malignancies • Indolent Lymphoma • Lymphoma • Mantle Cell Lymphoma • Neutropenia • Non-Hodgkin’s Lymphoma • Oncology • ROR1 • TP53

Zilovertamab Vedotin in Combination with Nemtabrutinib for Patients with Relapsed or Refractory Mantle Cell Lymphoma: Cohort C of the Open-Label, Phase 2 Waveline-006 Study (ASH 2024) - P2 | "Further investigation into efficacy of this combination is warranted for pts with R/R MCL. The study is ongoing and the RP2D is yet to be determined."

Clinical • Combination therapy • P2 data • Fatigue • Hematological Disorders • Hematological Malignancies • Indolent Lymphoma • Lymphoma • Mantle Cell Lymphoma • Neutropenia • Oncology • ROR1 • TP53

Nemtabrutinib, a Noncovalent Reversible BTK Inhibitor in Relapsed or Refractory Marginal Zone Lymphoma: Results from the Phase 2 Bellwave-003 Study (ASH 2024) - P2 | "Safety was manageable, and no new safety signals were identified. Enrollment and follow-up are ongoing."

P2 data • Anemia • Atrial Fibrillation • Cardiovascular • Chronic Lymphocytic Leukemia • Fatigue • Follicular Lymphoma • Hematological Disorders • Hematological Malignancies • Infectious Disease • Lymphoma • Lymphoplasmacytic Lymphoma • Mantle Cell Lymphoma • Marginal Zone Lymphoma • Neutropenia • Oncology • Pneumonia • Respiratory Diseases • Richter's Syndrome • Waldenstrom Macroglobulinemia

Nemtabrutinib, a Noncovalent Reversible BTK Inhibitor in Relapsed or Refractory Follicular Lymphoma: Results from the Phase 2 Bellwave-003 Study (ASH 2024) - P2 | "All pts had prior chemoimmunotherapy, 32 (89%) had prior lenalidomide, and 11 (31%) had prior PI3K inhibitor. Nemtabrutinib was well tolerated, and no new safety signals were identified. Enrollment and follow-up are ongoing."

P2 data • Anemia • Atrial Fibrillation • Cardiovascular • Chronic Lymphocytic Leukemia • Dermatology • Follicular Lymphoma • Hematological Disorders • Hematological Malignancies • Immunology • Infectious Disease • Lymphoma • Lymphoplasmacytic Lymphoma • Mantle Cell Lymphoma • Marginal Zone Lymphoma • Neutropenia • Oncology • Richter's Syndrome • Septic Shock • Thrombocytopenia • Urticaria • Waldenstrom Macroglobulinemia