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

A Clinical Trial of Nemtabrutinib in Participants With Severe Kidney Disease (MK-1026-027) (clinicaltrials.gov) - P1 | N=20 | Recruiting | Sponsor: Merck Sharp & Dohme LLC | Not yet recruiting ➔ Recruiting

Enrollment open • Nephrology • Renal Disease

Phase 3 BELLWAVE-011 Study: Nemtabrutinib Versus Ibrutinib or Acalabrutinib in Previously Untreated Chronic Lymphocytic Leukemia (CLL)/ Small Lymphocytic Lymphoma (SLL) (SOHO 2024) - P3 | "Main Outcome Measures: Primary end points are objective response rate and progression-free survival per iwCLL 2018 criteria by blinded independent central review. Overall survival, duration of response, and safety are secondary."

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

Nemtabrutinib for Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Leukemia (SLL) Refractory to Covalent Bruton Tyrosine Kinase Inhibitor or Pirtobrutinib and Previously Treated With a BCL2 Inhibitor (clinicaltrials.gov) - P2 | N=32 | Not yet recruiting | Sponsor: National Heart, Lung, and Blood Institute (NHLBI)

IO biomarker • New P2 trial • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Oncology • CD20 • CD4 • CD5 • FCER2

BELLWAVE-003: A phase 2 dose escalation, confirmation, and cohort expansion study of nemtabrutinib in hematologic malignancies. (ASCO 2023) - P2 | "Enrollment for this study is ongoing. Clinical trial information: NCT04728893."

IO biomarker • P2 data • Chronic Lymphocytic Leukemia • Follicular Lymphoma • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Lymphoplasmacytic Lymphoma • Mantle Cell Lymphoma • Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Richter's Syndrome • Small Lymphocytic Lymphoma • Waldenstrom Macroglobulinemia • TP53

First in Human Study of the Reversible BTK Inhibitor Nemtabrutinib in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia and B-Cell Non-Hodgkin Lymphoma. (PubMed, Cancer Discov) - P1/2 | "The RP2D was 65 mg daily. An overall response rate of 75% was observed in patients with CLL at 65 mg daily."

Journal • P1 data • Chronic Lymphocytic Leukemia • Febrile Neutropenia • Hematological Disorders • Hematological Malignancies • Infectious Disease • Leukemia • Lymphoma • Lymphoplasmacytic Lymphoma • Neutropenia • Non-Hodgkin’s Lymphoma • Oncology • Pneumonia • Respiratory Diseases • Waldenstrom Macroglobulinemia

A Study of Nemtabrutinib in Participants With Moderate Hepatic Impairment (MK-1026-015) (clinicaltrials.gov) - P1 | N=24 | Completed | Sponsor: Merck Sharp & Dohme LLC | Active, not recruiting ➔ Completed

Trial completion • Hepatology

Nemtabrutinib With CAR T Therapy in Relapsed/Refractory Mantle Cell Lymphoma (clinicaltrials.gov) - P2 | N=25 | Recruiting | Sponsor: Vanderbilt-Ingram Cancer Center | Not yet recruiting ➔ Recruiting

Enrollment open • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Oncology

A Study of Nemtabrutinib in Participants With Moderate Hepatic Impairment (MK-1026-015) (clinicaltrials.gov) - P1 | N=32 | Active, not recruiting | Sponsor: Merck Sharp & Dohme LLC | Recruiting ➔ Active, not recruiting

Enrollment closed • Hepatology

A Clinical Trial of Nemtabrutinib in Participants With Severe Kidney Disease (MK-1026-027) (clinicaltrials.gov) - P1 | N=20 | Not yet recruiting | Sponsor: Merck Sharp & Dohme LLC

New P1 trial • Nephrology • Renal Disease

Nemtabrutinib With Venetoclax and Obinutuzumab in Patients With Chronic Lymphocytic Leukemia (clinicaltrials.gov) - P2 | N=30 | Not yet recruiting | Sponsor: Medical College of Wisconsin

New P2 trial • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Oncology

A Study of Nemtabrutinib (MK-1026) Versus Comparator (Investigator's Choice of Ibrutinib or Acalabrutinib) in First Line (1L) Chronic Lymphocytic Leukemia (CLL)/ Small Lymphocytic Lymphoma (SLL) (MK-1026-011/BELLWAVE-011) (clinicaltrials.gov) - P3 | N=1200 | Not yet recruiting | Sponsor: Merck Sharp & Dohme LLC

New P3 trial • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Small Lymphocytic Lymphoma

A Study of Nemtabrutinib (MK-1026) Versus Comparator (Investigator's Choice of Ibrutinib or Acalabrutinib) in First Line (1L) Chronic Lymphocytic Leukemia (CLL)/ Small Lymphocytic Lymphoma (SLL) (MK-1026-011/BELLWAVE-011) (clinicaltrials.gov) - P3 | N=1200 | Recruiting | Sponsor: Merck Sharp & Dohme LLC | Not yet recruiting ➔ Recruiting

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

Nemtabrutinib With CAR T Therapy in Relapsed/Refractory Mantle Cell Lymphoma (clinicaltrials.gov) - P2 | N=25 | Not yet recruiting | Sponsor: Vanderbilt-Ingram Cancer Center

New P2 trial • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Oncology

Nemtabrutinib and Venetoclax for the Treatment of Patients With Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma (clinicaltrials.gov) - P2 | N=25 | Not yet recruiting | Sponsor: Jennifer Woyach | Initiation date: May 2026 ➔ Sep 2026

Trial initiation date • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Small Lymphocytic Lymphoma

NEMTABRUTINIB PLUS VENETOCLAX IN PARTICIPANTS WITH RELAPSED OR REFRACTORY CHRONIC LYMPHOCYTIC LEUKEMIA/SMALL LYMPHOCYTIC LYMPHOMA: PART 1 OF THE PHASE 3 BELLWAVE-010 STUDY (EHA 2026) - P3 | "Background Venetoclax plus rituximab (VR) is a standard-of-care regimen for patients with relapsed or refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Summary/Conclusion In part 1 of BELLWAVE-010, nemtabrutinib 45 mg plus venetoclax showed promising antitumor activity with a manageable safety profile. These findings support continued evaluation of this combination in participants with R/R CLL/SLL."

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

MECHANISMS OF RESISTANCE TO BTK INHIBITORS INDEPENDENT OF BTK AND PLCG2 MUTATIONS (EHA 2026) - "Results Seven lines of REC-1 cells that acquired resistance to pirtobrutinib or nemtabrutinib lacked BTK, PLCG2 or other known resistance- associated mutations when analyzed by tNGS (Qi J. et al...Treatment with BTKis ibrutinib or nemtabrutinib, or BTK degrader (BTKd) NX-5948 resulted in suppression of BTK phosphorylation or caused BTK degradation, respectively...Hence, BTKi resistant REC-1 did not show signiIcantly increased sensitivity to OXPHOS pathway inhibitor IACS-10759 either as single drug or in combination with BTKi/BTKd...In addition, the CDK inhibitor dinaciclib demonstrated efIcacy as monotherapy in resistant cells, and its combination with the BTKd NX-5948 showed signiIcant synergistic activity in both wild-type and resistant cells...Summary/Conclusion Dysregulation of the cell cycle contributed to acquired BTKi and BTKd resistance in REC-1 cells in the absence of BTK or PLCG2 mutation. Synergistic effects of CDK inhibitors with BTKd need to be further..."

Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • ANXA5 • CASP3 • CASP7 • CCNA2 • CDK1 • PLCG2

EFFICACY AND SAFETY OF NEMTABRUTINIB IN RELAPSED OR REFRACTORY FOLLICULAR LYMPHOMA: COHORT G OF THE PHASE 2 BELLWAVE-003 STUDY (EHA 2026) - P2 | "All-cause AEs led to discontinuation in 7 participants (12%) and 3 deaths (5%). Summary/Conclusion Nemtabrutinib showed clinically meaningful antitumor activity with a manageable safety profile in heavily pretreated participants with R/R FL, supporting ongoing clinical development of nemtabrutinib in this population."

Clinical • IO biomarker • P2 data • Constipation • Follicular Lymphoma • Gastroenterology • Gastrointestinal Disorder • Hematological Malignancies • Infectious Disease • Lymphoma • Neutropenia • Septic Shock

EFFICACY AND SAFETY OF NEMTABRUTINIB IN RELAPSED OR REFRACTORY MARGINAL ZONE LYMPHOMA: COHORT F OF THE PHASE 2 BELLWAVE-003 STUDY (EHA 2026) - P2 | "Summary/Conclusion Nemtabrutinib showed clinically meaningful antitumor activity with a manageable safety profile in heavily pretreated participants with R/R MZL who had failed prior covalent BTKi therapy and chemoimmunotherapy. These findings support ongoing clinical evaluation of nemtabrutinib in this population."

Clinical • IO biomarker • P2 data • Febrile Neutropenia • Hematological Malignancies • Infectious Disease • Lymphoma • Marginal Zone Lymphoma • Neutropenia • Oncology • Pneumonia • Respiratory Diseases • BTK

BELLWAVE-001: A Study of Nemtabrutinib (MK-1026) in Participants With Relapsed or Refractory Hematologic Malignancies (ARQ 531-101/MK-1026-001) (clinicaltrials.gov) - P1/2 | N=190 | Active, not recruiting | Sponsor: ArQule, Inc., a subsidiary of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. (Rahway, NJ USA) | Trial completion date: Sep 2026 ➔ Sep 2027 | Trial primary completion date: Sep 2026 ➔ Sep 2027

Trial completion date • Trial primary completion date • B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Indolent Lymphoma • Leukemia • Lymphoma • Lymphoplasmacytic Lymphoma • Mantle Cell Lymphoma • Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Richter's Syndrome • Small Lymphocytic Lymphoma • Waldenstrom Macroglobulinemia • BCL2 • BCL6

MODULE 4: Selection and Sequencing of Therapy for R/R CLL (ASCO 2026) - "Supported by This activity is supported by educational grants from AstraZeneca Pharmaceuticals LP and Eli Lilly. Clinical and biological factors guiding decision-making for patients with R/R CLL; impact of the evolving up-front CLL treatment paradigm on the management of R/R disease Long-term follow-up from Phase III trials evaluating covalent BTK inhibitors and Bcl-2 inhibitors for patients with R/R CLL; current role of rechallenge with an agent or class of agents received in a prior line of therapy Published findings from key trials, such as BRUIN and BRUIN CLL-321, supporting the use of pirtobrutinib for patients with R/R CLL Emerging positive findings from the Phase III BRUIN CLL-322 trial of pirtobrutinib in combination with venetoclax and rituximab versus venetoclax and rituximab for patients with R/R CLL Available and emerging efficacy and safety data with and ongoing evaluation of other noncovalent BTK inhibitors, such as nemtabrutinib and rocbrutinib, for R/R..."

Chronic Lymphocytic Leukemia

Efficacy and safety of non-covalent BTK inhibitors: A systematic review focused on indolent lymphomas. (ASCO 2026) - "Non-covalent (reversible) BTK inhibitors, including pirtobrutinib (LOXO-305), nemtabrutinib (ARQ-531) which bind BTK independently of C481. Non-covalent BTK inhibitors are effective, well tolerated, and capable of overcoming cBTKi resistance in relapsed or refractory indolent B-cell lymphomas (excluding CLL/SLL), supporting further prospective studies and real-world use."

Clinical • Review • B Cell Lymphoma • Chronic Lymphocytic Leukemia • Follicular Lymphoma • Hematological Malignancies • Indolent Lymphoma • Lymphoma • Lymphoplasmacytic Lymphoma • Marginal Zone Lymphoma • Neutropenia • Thrombocytopenia • Waldenstrom Macroglobulinemia

From covalent to reversible: the expanding role of BTK inhibitors in chronic lymphocytic leukemia. (PubMed, Expert Opin Pharmacother) - "Covalent BTKis and ncBTKis revolutionized CLL treatment in the last decade Three cBTKis, ibrutinib, acalabrutinib and zanubrutinib, are approved by FDA for the treatment of CLL. The most advanced ncBTKis are pirtobrutinib and nemtabrutinib. Of these, only pirtobrutinib is recommended for patients refractory to cBTKis. However, further clinical trials focusing on dose optimization are needed, as well as combination studies with existing drugs and novel agents."

Journal • Chronic Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology

A Study of the Effect of Diltiazem on the Plasma Levels of Nemtabrutinib (MK-1026-022) (clinicaltrials.gov) - P1 | N=26 | Completed | Sponsor: Merck Sharp & Dohme LLC | Active, not recruiting ➔ Completed

Trial completion

Non-covalent BTK Inhibitor Nemtabrutinib in Combination With the CD20 Monoclonal Antibody Rituximab for the Treatment of Marginal Zone Lymphoma (clinicaltrials.gov) - P2 | N=35 | Not yet recruiting | Sponsor: City of Hope Medical Center

New P2 trial • Extranodal Marginal Zone Lymphoma • Hematological Malignancies • Lymphoma • Marginal Zone Lymphoma • Nodal Marginal Zone Lymphoma • Oncology • Splenic Marginal Zone Lymphoma • CD4

Nemtabrutinib and Lisocabtagene Maraleucel for the Treatment of Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic 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 • Non-Hodgkin’s Lymphoma • Oncology • Small Lymphocytic Lymphoma