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

Accessing BTK Inhibitors and Other Novel Therapies for Mantle Cell Lymphoma: Are We All Invited to the Party? (SOHO 2024) - "In the phase 3 RAY trial,2 ibrutinib led to better responses and significant improvements in progression-free survival (PFS) and tolerability versus temsirolimus in patients with R/R MCL...In the SHINE trial,3 the combination of ibrutinib with bendamustine and rituximab for 6 cycles, followed by rituximab maintenance and ibrutinib until progression, led to an unprecedented PFS of 80.6 months in patients not eligible for ASCT...Second-generation BTK inhibitors have also been approved for R/R MCL, including acalabrutinib and zanubrutinib with a more favorable safety profile. In first line therapy, the results of bendamustine, rituximab, and acalabrutinib are expected to be presented soon...Pirtobrutinib, a third-generation non-covalent BTK inhibitor has shown promising activity in MCL after exposure to covalent BTK inhibitors. Moreover, the BCL-2 inhibitors, venetoclax and sonrotoclax, have also shown activity in the post-BTK inhibitor scenario, and sonrotoclax is..."

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

Preclinical development of ABL206, a novel bispecific antibody-drug conjugate targeting B7-H3 and ROR1. (PubMed, MAbs) - P1 | "ABL206 consistently outperformed clinical-stage benchmark monospecific ADCs, ifinatamab deruxtecan (I-DXd) and zilovertamab vedotin, and effectively induced regression in I-DXd-pretreated regrowing tumors. Furthermore, ABL206 exhibited excellent in vitro plasma stability, a robust pharmacokinetic profile in rodents and non-human primates, and a favorable safety profile with the highest non-severely toxic dose (HNSTD) of 60 mg/kg in cynomolgus monkeys. Collectively, these data provide a comprehensive preclinical proof-of-concept for ABL206, supporting its advancement into a Phase 1 clinical trial for patients with advanced solid tumors (NCT07612176)."

Journal • Preclinical • Oncology • Solid Tumor • 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

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

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-011: Zilovertamab Vedotin Plus R-CHP vs Polatuzumab Vedotin Plus R-CHP as First-Line Therapy in Germinal Center B-Cell–Like Diffuse Large B-Cell Lymphoma (SOHO 2026) - P2 | "Context: Although first-line polatuzumab vedotin plus R-CHP prolongs PFS compared with R-CHOP in activated B-cell–like DLBCL, it provides no benefit over R-CHOP in GCB DLBCL. This abstract was accepted and previously presented at the 2026 ASCO Annual Meeting. BICR: blinded independent central review; CR: complete response; CT: computed tomography; CTCAE: Common Terminology Criteria for Adverse Events; DLBCL: diffuse large B-cell lymphoma; ECOG: Eastern Cooperative Oncology Group; EFS: event-free survival; FDG: fluorodeoxyglucose; GCB: germinal center B-cell; HGBL: high-grade B-cell lymphoma; IPI: International Prognostic Index; NCI: National Cancer Institute; OS: overall survival; PET: positron emission tomography; PFS: progression-free survival; PRO: patient-reported outcome; R-CHOP: rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone; R-CHP: rituximab, cyclophosphamide, doxorubicin, prednisone; ROR1: receptor tyrosine kinase–like orphan receptor 1."

Clinical • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • High-grade B-cell lymphoma • Indolent Lymphoma • Lymphoma • Mediastinal B Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Primary Mediastinal Large B-Cell Lymphoma • ROR1

Preclinical evaluation of the ROR1-targeting antibody-drug conjugates zilovertamab vedotin and VLS-211 against B-cell ALL patient-derived xenografts. (PubMed, Hemasphere) - "Notably, we identified pediatric patients with TCF3::HLF gene fusions, which is a highly chemoresistant ALL subtype, as having some of the highest ROR1 expression in pediatric ALL and show that this subtype is susceptible to targeting ROR1 via ADC-based therapy. Given that ZV has a favorable toxicity profile in patients with hematological malignancies, it may have some utility in the treatment of very high-risk pediatric B-ALL, particularly cases with TCF3::HLF gene fusions."

Journal • Preclinical • Acute Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • Pediatrics • PBX1 • ROR1 • TCF3

ZILOVERTAMAB VEDOTIN IN PEDIATRIC AND YOUNG ADULT HEMATOLOGIC MALIGNANCIES OR SOLID TUMORS: PHASE 1/2 LIGHTBEAM-U01A STUDY (EHA 2026) - P1/2 | "Secondary end points include pharmacokinetics, immunogenicity, duration of response, and eligibility for transplant/CAR-T therapy in patients with B-ALL or DLBCL/Burkitt lymphoma. Recruitment is ongoing."

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

waveLINE-011: Zilovertamab vedotin plus R-CHP versus polatuzumab vedotin plus R-CHP as first-line therapy in germinal center B-cell–like (GCB) diffuse large B-cell lymphoma (DLBCL). (ASCO 2026) - P2 | "The standard-of-care first-line treatment option for DLBCL regardless of subtype is polatuzumab vedotin plus rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP). Approximately 594 participants will be enrolled. Recruitment is ongoing."

Clinical • 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 • ROR1

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 | Completed | Sponsor: Merck Sharp & Dohme LLC | Active, not recruiting ➔ Completed

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

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 | Recruiting | Sponsor: Merck Sharp & Dohme LLC | Trial completion date: Jun 2030 ➔ Feb 2029 | Trial primary completion date: Jun 2030 ➔ Feb 2029

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

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 | Recruiting | Sponsor: Merck Sharp & Dohme LLC | Active, not recruiting ➔ Recruiting | Trial completion date: Jun 2028 ➔ Jun 2030 | Trial primary completion date: Jun 2028 ➔ Jun 2030

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

NW006-296, a novel ROR1 targeting ADC, demonstrates compelling anti-tumor efficacy in preclinical studies (AACR 2026) - "When compared to the benchmark ADC (MK-2140), NW006-296 demonstrated superior anti-tumor activity in all CDX models investigated. NW006-296 has compelling anti-tumor efficacy and supports clinical development for ROR1-targeting ADCs across a broad spectrum of cancers. Further preclinical safety assessment, pharmacokinetics and IND-enabling studies are on-going with the goal to develop NW006-296 as a transformative therapeutic candidate for the treatment of colorectal cancer, breast cancer and hematological malignancies."

ADC • IO biomarker • Preclinical • Breast Cancer • Colorectal Cancer • Hematological Malignancies • Oncology • Solid Tumor • ROR1

NEOK001 (ABL206): A first in class B7-H3xROR1 bispecific ADC demonstrated enhanced efficacy and promising tolerability (AACR 2026) - "NEOK001 demonstrates greater efficacy compared to monospecific ADCs such as zilovertamab vedotin (ROR1 ADC) and I-Dxd (B7-H3 ADC) in SCLC, ovarian and NSCLC xenograft models (P<0.01-0.001). NEOK001 is a first in class B7-H3xROR1 bispecific ADC, combining the broad expression of B7-H3 with the selective expression of ROR1 to enhance tumor-specific binding while reducing toxicity to normal tissue. Therefore, NEOK001 will be a promising therapeutic drug and will enter the clinic in early 2026."

ADC • Bispecific • Clinical • Head and Neck Cancer • Hematological Malignancies • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Sarcoma • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • Triple Negative Breast Cancer • CD276 • ROR1

ALM-401: A first-in-class next generation bispecific ADC configured to deliver superior efficacy in selected solid tumor indications (AACR 2025) - "This bsADC significantly outperforms a zilovertamab vedotin biosimilar, which exhibits an ORR of 22% (2/9) in these models at the same payload equivalent dose. ALM-401 has excellent plasma stability, a PK profile in line with approved ADCs, and good overall manufacturing and developability characteristics, with the potential to deliver significantly improved patient outcomes across a range of solid tumor indications with high unmet need."

ADC • Bispecific • Clinical • Late-breaking abstract • Gastric Cancer • Gastroesophageal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR • ROR1

Receptor tyrosine kinase-like orphan receptor 1 (ROR1) in BTKi-treated mantle cell lymphoma (AACR 2025) - P2 | "Here, we explored which biomarkers might be associated with resistance to acalabrutinib, a second generation BTKi, by analyzing samples from MCL patients who were on treatment or progressed on acalabrutinib from the ACE-LY-004 study (NCT02213926), as well as using a pre-clinical MCL cell line model...It was previously attributed to a bypass resistance mechanism to first generation BTKi ibrutinib (Zhang et al., 2019)...To assess potential therapeutic implications of decreased surface expression of ROR1 in MCL post BTKi treatment, we assessed activity of a ROR1-targeted ADC (Zilovertamab vedotin; Wang et al., 2021) in BTKi-R cells...These preliminary results highlight the possible association between ROR1 expression on MCL tumor cells and BTKi response. To further dissect the interplay between ROR1 and second generation/reversible BTKi treatment in MCL, studies utilizing a multi-omics integration approach, BTKi-R MCL cell lines, and ex vivo propagated MCL patient cell..."

B Cell Non-Hodgkin Lymphoma • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CD5 • ROR1

The ROR1 antibody-drug conjugate, MK-2140, enhances the efficacy of established drugs in preclinical models of pediatric acute lymphoblastic leukemia (AACR 2024) - "Vincristine (0.15 mg/kg once weekly), dexamethasone (5 mg/kg daily x 5) and Lasparaginase (1,250 U/kg daily x 5) (VXL) were administered intraperitoneally for 3 weeks, followed by MK-2140 (5 mg/kg weekly x 3 weeks). MK-2140 and VLS-211 exerted significant single-agent in vivo activity against a panel of pediatric ALL PDXs. MK-2140 significantly enhanced the efficacy of an induction-type regimen and should be considered for further evaluation in a minimal residual disease setting."

ADC • Preclinical • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • PTPRC • ROR1

Zilovertamab vedotin in pediatric and young adult hematologic malignancies or solid tumors: Phase 1/2 LIGHTBEAM-U01A study (AACR 2025) - P1/2 | "Secondary end points include pharmacokinetics, immunogenicity, duration of response, and eligibility for transplant/CAR-T therapy in pts with B-ALL or DLBCL/Burkitt lymphoma. Recruitment is ongoing."

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 • Sarcoma • Solid Tumor

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 | Active, not recruiting | Sponsor: Merck Sharp & Dohme LLC | Recruiting ➔ Active, not recruiting

Enrollment closed • Monotherapy • Pan tumor • Chronic Lymphocytic Leukemia • Follicular Lymphoma • Hematological Malignancies • Indolent Lymphoma • Leukemia • Lymphoma • Mantle Cell Lymphoma • Oncology • Richter's Syndrome

ROR1-PI3K/AKT signaling drives adaptive resistance to cell cycle blockade in TP53 mutated ovarian cancer. (PubMed, Cell Death Dis) - "In this study, we developed long-term resistant (lt-res, several months) pre-clinical models of two drugs inducing mitotic arrest in TP53-mutated cells: adavosertib (ADA), an investigational WEE1 inhibitor targeting the DNA damage response and currently evaluated in clinical trials, and paclitaxel (PTX), a widely used chemotherapeutic agent in cancer care targeting microtubules. Notably, upregulation of receptor tyrosine kinases, such as ROR1, was observed in both ADA and PTX lt-res models with activated PI3K/AKT signaling. Targeting ROR1 with zilovertamab-vedotin, a monoclonal antibody-drug conjugate, resulted in enhanced cytotoxicity, demonstrating a new approach against recurrent drug-resistant ovarian cancer."

Journal • Oncology • Ovarian Cancer • Solid Tumor • ROR1 • TP53

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: Jan 2026 ➔ Apr 2026 | Trial primary completion date: Jan 2026 ➔ Apr 2026

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

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