zilovertamab vedotin (MK-2140) / Merck (MSD) - LARVOL DELTA

ZILOVERTAMAB VEDOTIN PLUS STANDARD OF CARE IN RELAPSED/REFRACTORY DIFFUSE LARGE B-CELL LYMPHOMA: RESULTS FROM THE PHASE 2/3 WAVELINE-003 STUDY (EHA 2025) - P2/3 | "Zilovertamab vedotin (ZV) is a novel ROR1-targeting antibody-drug conjugate that has shown promising efficacy in patients with DLBCL.Aims: We present results of the dose confirmation phase of the waveLINE-003 (NCT05139017) study evaluating ZV plus rituximab and gemcitabine-oxaliplatin (R-GemOx) in participants with R/R DLBCL.Eligible participants were aged ≥18 years with confirmed R/R DLBCL who were ineligible for or did not respond to prior treatment with chimeric antigen receptor T-cell therapy (CAR-T) or autologous stem-cell transplant (ASCT) and have failed ≥1 line of prior therapy. In participants with R/R DLBCL, ZV in combination with R-GemOx showed promising efficacy and a manageable safety profile at the RP2D of ZV at 1.75 mg/kg. Evaluation of ZV–R-GemOx versus R-GemOx is proceeding to the randomized phase 3 portion of the study"

P2/3 data • Anemia • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Disorders • Hematological Malignancies • Infectious Disease • Lymphoma • Neutropenia • Non-Hodgkin’s Lymphoma • Oncology • Respiratory Diseases • Septic Shock • ROR1

Waveline-007: Dose Escalation and Confirmation, and Efficacy Expansion Trial of Zilovertamab Vedotin in Combination with Cyclophosphamide, Doxorubicin, and Prednisone Plus Rituximab in Patients with Diffuse Large B Cell Lymphoma (ASH 2024) - P2 | "The recommended Phase 2 dose (RP2D) of ZV was established at 1.75 mg/kg and the combination therapy at this dose level achieved objective response rate and complete response rate at end of treatment of 100%. The combination provided a robust response in patients with DLBCL and warrants further evaluation in a larger population."

Clinical • Combination therapy • B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Diffuse Large B Cell Lymphoma • Febrile Neutropenia • Hematological Disorders • Hematological Malignancies • Infectious Disease • Lymphoma • Neutropenia • Non-Hodgkin’s Lymphoma • Oncology • Pneumonia • Respiratory Diseases • ROR1

Targeting WTAP/ROR1/WNT5A-Mediated Crosstalk Between Glioma Stem Cells and Macrophages to Normalize Tumor Vasculature and Enhance Chemotherapy. (PubMed, Adv Sci (Weinh)) - "Therapeutically, targeting ROR1 via endothelial-specific Adno-Associated Virus (AAV) knockdown or the antibody-drug conjugate Zilovertamab vedotin (VLS-101) normalizes vasculature, improves temozolomide delivery, and sensitizes tumors in glioblastoma organoids and xenografts. These findings highlight the ROR1-WNT5A axis as a promising target in glioblastomas treatment."

Journal • Brain Cancer • Glioblastoma • Glioma • Oncology • Solid Tumor • ROR1 • WNT5A • WTAP

A Phase 1/2 Study of a ROR1-Targeting CAR T Cell Therapy (ONCT-808) in Adult Patients with Relapsed/Refractory (R/R) Aggressive B Cell Lymphomas (BCL) (ASH 2024) - P1/2 | "ONCT-808 utilizes a ROR1-binding moiety derived from zilovertamab, which, in a prior study of zilovertamab vedotin, demonstrated antitumor activity and no evidence of off-tumor toxicity in a population of heavily pretreated patients (pts) with aggressive lymphoma (Wang 2022, Spurgeon 2023)...ONCT-808 is administered as a single infusion following lymphodepletion with fludarabine and cyclophosphamide...Preliminary PK demonstrates successful expansion and persistence of ROR1-positive CAR T cells, including beyond 12 months post-infusion.CONCLUSIONS : ONCT-808 is a novel ROR1-targeting CAR T therapy with promising early activity and appears to be well-tolerated at 0.3 x 106 and 1 x 106 viable cells/kg dose in patients with R/R BCL. Dose escalation continues towards optimizing activity and safety (NCT 05588440)."

CAR T-Cell Therapy • Clinical • P1/2 data • B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Infectious Disease • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Pneumonia • Respiratory Diseases • Solid Tumor • ROR1

Waveline-001: Updated Results from a Phase 1 Dose Escalation and Cohort Expansion Study of Zilovertamab Vedotin (MK-2140) in Non-Hodgkin Lymphoma (ASH 2022) - P1 | "Updated results from WAVELINE-001 support prior analyses showing ZV had a tolerable safety profile and promising response rates, and favorable PFS and OS among heavily pre-treated pts with DLBCL, MCL, and RT, including pts who had received prior CAR-T/CAR-NK therapy."

P1 data • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Fatigue • Hematological Disorders • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Pain • Richter's Syndrome • Transplantation • ROR1

WAVELINE-004: OPEN-LABEL, PHASE 2 STUDY OF ZILOVERTAMAB VEDOTIN (MK-2140) IN PATIENTS WITH RELAPSED OR REFRACTORY (R/R) DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL) (ICML 2023) - P2 | "This early analysis of waveLINE-004 showed ZV had clinically meaningful antitumor activity in pts with R/R DLBCL who are ineligible for or had progression after ASCT and CAR T-cell therapy. The safety profile of ZV was manageable and consistent with that of other monomethyl auristatin E–containing agents."

Clinical • P2 data • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • ROR1

Zilovertamab Vedotin (MK-2140) in Relapsed or Refractory Diffuse Large B-Cell Lymphoma (DLBCL): Updated Results from the Phase 2 Waveline-004 Study (ASH 2023) - P2 | "In this updated analysis of waveLINE-004, zilovertamab vedotin continued to demonstrate clinically meaningful antitumor activity in pts with R/R DLBCL who had progressed after or were ineligible for ASCT and/or CAR T-cell therapy. The safety profile of zilovertamab vedotin was manageable, and consistent with the known profile of MMAE-containing agents."

P2 data • Acute Kidney Injury • Anemia • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Disorders • Hematological Malignancies • Lymphoma • Metabolic Disorders • Nephrology • Non-Hodgkin’s Lymphoma • Oncology • Renal Disease • Septic Shock • ROR1

Phase 2 trial of zilovertamab vedotin in combination with cyclophosphamide, doxorubicin, and prednisone plus rituximab in diffuse large B-cell lymphoma: Updated analysis of waveline-007 (ASH 2025) - P2 | "After approximately 27 months of follow-up, ZV plus R-CHP continues to demonstraterobust efficacy and acceptable safety as front-line treatment for participants with DLBCL regardless ofcell of origin. No new safety concerns were reported."

Combination therapy • P2 data • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Febrile Neutropenia • Hematological Malignancies • Lymphoma • Neutropenia • Non-Hodgkin’s Lymphoma • ROR1

Zilovertamab vedotin plus R-CHP versus polatuzumab vedotin plus R-CHP as first-line therapy in participants with germinal center B-cell diffuse large B-cell lymphoma (DLBCL): The randomized, open-label, Phase 2 waveline-011 Study (ASH 2025) - P2 | "Polatuzumab vedotin in combination with rituximab, cyclophosphamide, doxorubicin, andprednisone (R-CHP) is a standard-of-care option for the first-line treatment of DLBCL, regardless ofsubtype. Approximately 594participants with GCB DLBCL will be enrolled. Recruitment for waveLINE-011 is currently underway."

Clinical • P2 data • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • High-grade B-cell lymphoma • Lymphoma • Mediastinal B Cell Lymphoma • Non-Hodgkin’s Lymphoma • Primary Mediastinal Large B-Cell Lymphoma • Respiratory Diseases • Solid Tumor • ROR1

Zilovertamab vedotin plus R-CHP versus R-CHOP for first-line treatment of diffuse large B-cell lymphoma: The phase 3 waveline-010 study (ASH 2025) - P3 | "The current standard of care forpreviously untreated DLBCL is rituximab plus cyclophosphamide, doxorubicin, vincristine, andprednisone (R-CHOP). Zilovertamab vedotin is an ROR1-targeting antibody-drug conjugate with amonomethyl auristatin E payload that has shown encouraging antitumor activity in patients with DLBCL.The waveLINE-010 study (NCT06717347) is a randomized, open-label, phase 3 study designed to assessthe efficacy and safety of zilovertamab vedotin in combination with rituximab plus cyclophosphamide,vincristine, and prednisone (R-CHP) versus R-CHOP in participants with previously untreated DLBCL...Reused with permission. This Abstract was acceptedand previously presented at the 2025 ASCO Annual Meeting."

Clinical • P3 data • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Epstein-Barr Virus Infections • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • ROR1

Phase 2/3 trial of zilovertamab vedotin plus standard of care in relapsed/ refractory diffuse large B-cell lymphoma: Updated analysis of waveline-003 (ASH 2025) - P2/3 | "The phase 2/3 waveLINE-003 trial (NCT05139017) evaluated the safety and efficacy of ZV plusrituximab and gemcitabine-oxaliplatin (R-GemOx) in participants with R/R DLBCL...The median number of prior therapies was 2.0 with 7 (18%) pts receiving prior CAR-T, 7 (18%)receiving prior ASCT, and 2 (5%) received prior polatuzumab vedotin... After approximately 19 months of follow-up, ZV plus R-GemOX continues to demonstratepromising efficacy and acceptable safety in R/R DLBCL at the RP2D of ZV of 1.75 mg/kg plus R-GemOx. Nonew safety concerns were reported. The efficacy expansion phase of this trial randomizing participants toZV plus R-GemOx versus R-GemOx is currently ongoing."

P2/3 data • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Infectious Disease • Lymphoma • Neutropenia • Non-Hodgkin’s Lymphoma • Septic Shock • ROR1

Trial-in-Progress: A Phase 1/2 Multi-Center Study of Onct-808, a ROR1-Specific CAR T, in Adult Patients with Relapsed/Refractory Aggressive B Cell Lymphoma (ASH 2023) - P1/2 | "Zilovertamab vedotin showed preliminary evidence of efficacy and no evidence of on-target off-tumor toxicity in patients with advanced B cell malignancies (Wang 2022)...Subjects will receive a conditioning regimen of intravenous (IV) cyclophosphamide and fludarabine, followed by ONCT-808 IV infusion...The trial is currently active and patients have been treated in the phase 1 dose escalation. Clinical Trial Identifier: NCT05588440"

Clinical • IO biomarker • P1/2 data • B Cell Lymphoma • Bone Marrow Transplantation • Hematological Malignancies • Large B Cell Lymphoma • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • ROR1

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

Updated Results from the Phase 2 Waveline-004 Study of Zilovertamab Vedotin in Relapsed or Refractory Diffuse Large B-Cell Lymphoma (ASH 2024) - P2 | "Summary/Conclusion : After additional follow-up, zilovertamab vedotin continued to demonstrate sustained antitumor activity and manageable safety in patients with R/R DLBCL whose disease progressed after or were ineligible for ASCT and/or CAR-T therapy. These results support the continued investigation of zilovertamab vedotin in patients with R/R DLBCL."

P2 data • Acute Kidney Injury • Anemia • B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Disorders • Hematological Malignancies • Lymphoma • Metabolic Disorders • Nephrology • Non-Hodgkin’s Lymphoma • Oncology • Renal Disease • Septic Shock • ROR1

Next Questions: Mantle Cell Lymphoma (SOHO 2025) - "Glofitamab is being evaluated in a phase 3 randomized clinical trial (GLOBRYTE) in patients with MCL who have relapsed following BTKi therapy, 7 which may prove to be an excellent option in this population...The combination of mosunetuzumab with the ADC polatuzumab vedotin (M-Pola) was evaluated in a phase 1b/2 study, with an ORR of 75% (15/20) and CRR of 70% (14/20)...The receptor tyrosine kinase-like orphan receptor 1 (ROR1) is an oncofetal protein that is present in MCL, and the ADC zilovertamab vedotin recognizes ROR1 and delivers the anti-microtubule cytotoxin monomethyl auristatin E. In a phase 1 study that included patients with MCL, the ORR was 47% (7/15). 12 Loncastuximab tesirine is an ADC containing a CD19 monoclonal antibody conjugated to a pyrrolobenzodiazepine dimer toxin...Novel immunomodulatory agents (ie, golcadomide) are being evaluated in both FL and DLBCL and currently demonstrate favorable outcome — especially in combination with rituximab. 16, 17..."

B Cell Lymphoma • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Lymphoplasmacytic Lymphoma • Mantle Cell Lymphoma • Marginal Zone Lymphoma • Oncology • Waldenstrom Macroglobulinemia • CD20 • CRBN • ROR1

Ongoing Phase 3 waveLINE-010 Study of Zilovertamab Vedotin (ZV) Plus R-CHP Versus R-CHOP in Participants With Untreated Diffuse Large B-Cell Lymphoma (DLBCL) (SOHO 2025) - P3 | "Design: waveLINE-010 is a randomized, open-label, phase 3 study designed to evaluate ZV in combination with rituximab plus cyclophosphamide, doxorubicin, and prednisone (R-CHP) versus rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in untreated DLBCL. Reused with permission. This abstract was accepted and previously presented at the 2025 ASCO Annual Meeting."

P3 data • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • ROR1

Phase 2 Study of Zilovertamab Vedotin in Participants With Metastatic Solid Tumors. (PubMed, Cancer Res Commun) - P2 | "Zilovertamab vedotin had minimal antitumor activity, with only a single responder, and manageable safety in participants with previously-treated metastatic solid tumors."

Journal • P2 data • Platinum resistant • Breast Cancer • Fatigue • Hematological Malignancies • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Lymphoma • Non Small Cell Lung Cancer • Non-Hodgkin’s Lymphoma • Oncology • Ovarian Cancer • Pain • Pancreatic Cancer • Small Cell Lung Cancer • Solid Tumor • Triple Negative Breast Cancer • HER-2 • ROR1

waveLINE-006: A Study of Zilovertamab Vedotin (MK-2140) as Monotherapy and in Combination in Participants With Aggressive and Indolent B-cell Malignancies (MK-2140-006) (clinicaltrials.gov) - P2 | N=223 | Recruiting | Sponsor: Merck Sharp & Dohme LLC | Trial primary completion date: Mar 2027 ➔ Mar 2029

Monotherapy • Pan tumor • Trial primary completion date • Chronic Lymphocytic Leukemia • Follicular Lymphoma • Hematological Malignancies • Indolent Lymphoma • Leukemia • Lymphoma • Mantle Cell Lymphoma • Oncology • Richter's Syndrome

waveLINE-004: A Study to Evaluate Zilovertamab Vedotin (MK-2140) for Relapsed or Refractory Diffuse Large B-Cell Lymphoma (DLBCL) (MK-2140-004) (clinicaltrials.gov) - P2 | N=140 | Active, not recruiting | Sponsor: Merck Sharp & Dohme LLC | Trial completion date: Jun 2025 ➔ Jan 2026 | Trial primary completion date: Jun 2025 ➔ Jan 2026

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

PHASE 2/3 waveLINE-003 STUDY: ZILOVERTAMAB VEDOTIN PLUS STANDARD OF CARE IN RELAPSED OR REFRACTORY DIFFUSE LARGE B-CELL LYMPHOMA (ICML 2025) - P2/3 | "The phase 2/3 waveLINE-003 (NCT05139017) study was designed to evaluate ZV plus rituximab and gemcitabine-oxaliplatin (R-GemOx) in participants (pts) with R/R DLBCL. ZV plus R-GemOx had a manageable safety profile and promising efficacy in pts with R/R DLBCL at the RP2D of ZV 1.75 mg/kg. The randomized phase 3 portion of the study will proceed to evaluate ZV plus R-GemOx versus R-GemOx alone."

P2/3 data • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • ROR1

KEYMAKER-U04 substudy 04A: A Substudy of Investigational Agents in Programmed Cell Death-1/Ligand 1 (PD-1/L1) Refractory Locally Advanced or Metastatic Urothelial Carcinoma (mUC) (MK-3475-04A) (clinicaltrials.gov) - P1/2 | N=48 | Active, not recruiting | Sponsor: Merck Sharp & Dohme LLC | Trial completion date: Oct 2027 ➔ May 2028 | Trial primary completion date: Oct 2027 ➔ May 2028

Trial completion date • Trial primary completion date • Oncology • Solid Tumor • Urothelial Cancer

WaveLINE-003: Phase 2/3 trial of zilovertamab vedotin plus standard of care in relapsed/refractory diffuse large B-cell lymphoma. (ASCO 2025) - P2/3 | "Here we present results of the dose confirmation part of the waveLINE-003 (NCT05139017) trial evaluating ZV plus rituximab and gemcitabine-oxaliplatin (R-GemOx) in pts with R/R DLBCL. Zilovertamab vedotin in combination with R-GemOx demonstrated promising efficacy and acceptable safety in R/R DLBCL at the RP2D of ZV of 1.75 mg/kg plus R-GemOx. The study is proceeding to the phase 3 portion randomizing patients to ZV-RGemOx versus RGemOx."

P2/3 data • Anemia • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Disorders • Hematological Malignancies • Infectious Disease • Lymphoma • Neutropenia • Non-Hodgkin’s Lymphoma • Oncology • Respiratory Diseases • Septic Shock • ROR1

waveLINE-010: Zilovertamab vedotin plus R-CHP versus R-CHOP in untreated diffuse large B-cell lymphoma. (ASCO 2025) - P3 | "Modest improvements have been made over standard-of-care with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) immunochemotherapy being used in the first-line setting. Adverse events will be graded per NCI CTCAE v5.0. Recruitment is ongoing."

B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Epstein-Barr Virus Infections • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • ROR1

Phase 1/2 study of zilovertamab vedotin in pediatric and young adult hematologic malignancies or solid tumors (LIGHTBEAM-U01A). (ASCO 2025) - P1/2 | "Approximately 50-90 pts will be enrolled. Recruitment is underway."

Clinical • P1/2 data • Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • B Cell Lymphoma • Burkitt Lymphoma • Diffuse Large B Cell Lymphoma • Ewing Sarcoma • Hematological Malignancies • Leukemia • Lymphoma • Neuroblastoma • Non-Hodgkin’s Lymphoma • Oncology • Pediatrics • Sarcoma • Solid Tumor • ROR1