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    DRUG:

    zilovertamab vedotin (MK-2140)

    i
    Other names: MK-2140, VLS101, VLS 101, VLS-101
    Company:
    Merck (MSD)
    Drug class:
    Microtubule inhibitor, ROR1-targeted antibody-drug conjugate
    Related drugs:
    8d
    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
    |
    TP53 (Tumor protein P53) • ROR1 (Receptor Tyrosine Kinase Like Orphan Receptor 1)
    |
    TP53 mutation
    |
    paclitaxel • adavosertib (AZD1775) • zilovertamab vedotin (MK-2140)
    22d
    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, 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
    |
    zilovertamab vedotin (MK-2140)
    1m
    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
    |
    ROR1 (Receptor Tyrosine Kinase Like Orphan Receptor 1) • WNT5A (Wnt Family Member 5A) • WTAP (WT1 Associated Protein)
    |
    temozolomide • zilovertamab vedotin (MK-2140)
    7ms
    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, Merck Sharp & Dohme LLC | Trial primary completion date: Mar 2027 --> Mar 2029
    Trial primary completion date • Pan tumor
    |
    zilovertamab vedotin (MK-2140) • nemtabrutinib (MK-1026)
    7ms
    Phase 2 Study of Zilovertamab Vedotin in Participants With Metastatic Solid Tumors. (PubMed, Cancer Res Commun)
    Zilovertamab vedotin had minimal antitumor activity, with only a single responder, and manageable safety in participants with previously-treated metastatic solid tumors.
    P2 data • Journal
    |
    HER-2 (Human epidermal growth factor receptor 2) • ROR1 (Receptor Tyrosine Kinase Like Orphan Receptor 1)
    |
    HR positive • HER-2 negative
    |
    zilovertamab vedotin (MK-2140)
    8ms
    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, 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
    |
    zilovertamab vedotin (MK-2140)
    8ms
    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, 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
    |
    Keytruda (pembrolizumab) • zilovertamab vedotin (MK-2140) • MK-3120
    10ms
    waveLINE-010: A Study to Evaluate Zilovertamab Vedotin (MK-2140) Combination With Rituximab Plus Cyclophosphamide, Doxorubicin, and Prednisone (R-CHP) Versus Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (R-CHOP) in Participants With Previously Untreated DLBCL (MK-2140-010) (clinicaltrials.gov)
    P3, N=1046, Recruiting, Merck Sharp & Dohme LLC | Trial primary completion date: Mar 2032 --> Jul 2029
    Trial primary completion date
    |
    doxorubicin hydrochloride • cyclophosphamide • vincristine • prednisone • Truxima (rituximab-abbs) • zilovertamab vedotin (MK-2140) • prednisolone
    10ms
    A Clinical Study of Zilovertamab Vedotin (MK-2140) Plus Rituximab Plus Cyclophosphamide, Doxorubicin, and Prednisone (R-CHP) Versus Polatuzumab Vedotin Plus R-CHP in People With Diffuse Large B-cell Lymphoma (DLBL) (MK-2140-011/waveLINE-011) (clinicaltrials.gov)
    P2, N=594, Recruiting, Merck Sharp & Dohme LLC | Not yet recruiting --> Recruiting
    Enrollment open
    |
    doxorubicin hydrochloride • cyclophosphamide • prednisone • Truxima (rituximab-abbs) • zilovertamab vedotin (MK-2140) • Polivy (polatuzumab vedotin-piiq) • prednisolone
    11ms
    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, Merck Sharp & Dohme LLC | Trial completion date: Apr 2027 --> May 2029
    Trial completion date
    |
    zilovertamab vedotin (MK-2140) • nemtabrutinib (MK-1026)
    12ms
    A Clinical Study of Zilovertamab Vedotin (MK-2140) Plus Rituximab Plus Cyclophosphamide, Doxorubicin, and Prednisone (R-CHP) Versus Polatuzumab Vedotin Plus R-CHP in People With Diffuse Large B-cell Lymphoma (DLBL) (MK-2140-011/waveLINE-011) (clinicaltrials.gov)
    P2, N=594, Not yet recruiting, Merck Sharp & Dohme LLC
    New P2 trial
    |
    doxorubicin hydrochloride • cyclophosphamide • prednisone • Truxima (rituximab-abbs) • zilovertamab vedotin (MK-2140) • Polivy (polatuzumab vedotin-piiq) • prednisolone
    1year
    waveLINE-010: A Study to Evaluate Zilovertamab Vedotin (MK-2140) Combination With Rituximab Plus Cyclophosphamide, Doxorubicin, and Prednisone (R-CHP) Versus Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (R-CHOP) in Participants With Previously Untreated DLBCL (MK-2140-010) (clinicaltrials.gov)
    P3, N=1046, Recruiting, Merck Sharp & Dohme LLC | Not yet recruiting --> Recruiting
    Enrollment open
    |
    doxorubicin hydrochloride • cyclophosphamide • vincristine • prednisone • Truxima (rituximab-abbs) • zilovertamab vedotin (MK-2140) • prednisolone