Zilovertamab Vedotin Targeting of ROR1 as Therapy for Lymphoid Cancers

Wang, Michael L.; Barrientos, Jacqueline C.; Furman, Richard R.; Mei, Matthew; Barr, Paul M.; Choi, Michael Y.; Vos, Sven de; Kallam, Avyakta; Patel, Krish; Kipps, Thomas J.; Rule, Simon; Flanders, Kate; Jessen, Katti; Ren, Hong; Riebling, P.; Graham, P.; King, Lydia; Thurston, Archie; Sun, Michael; Schmidt, Elizabeth; Lannutti, Brian J.; Johnson, David M.; Miller, Langdon L.; Spurgeon, Stephen E.

doi:10.1056/evidoa2100001

Cited by 42 publications

(27 citation statements)

References 37 publications

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“…In a phase I dose-escalation study, the novel antibody drug conjugate, zilovertamab vedotin, was studied in previously treated patients with B cell lymphomas [ 55 , 56 ]. Zilovertamab vedotin comprises zilovertamab, a monoclonal antibody that recognizes extracellular receptor tyrosine kinase-like orphan receptor 1 (ROR1), and the anti-microtubule cytotoxin, monomethyl auristatin E. Of the 51 patients enrolled, 17 had R/R MCL.…”

Section: Beyond Btk Inhibitors: Targeted Therapiesmentioning

confidence: 99%

“…The DOR was 7.8 months for all patients. There was a tolerable safety profile, with treatment-related adverse events occurring in 70.6% of patients [ 55 , 56 ]. The ongoing CIRLL study combining zilovertamab (formerly called cirmtuzumab) and ibrutinib included 26 evaluable heavily pretreated MCL patients and showed promising results.…”

Section: Beyond Btk Inhibitors: Targeted Therapiesmentioning

confidence: 99%

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Relapsed/Refractory Mantle Cell Lymphoma: Beyond BTK Inhibitors

Burkart

Karmali

2022

JPM

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Mantle cell lymphoma (MCL) is a rare mature B-cell non-Hodgkin lymphoma (B-NHL) with historically poor outcomes. Virtually all patients will eventually experience refractory or relapsed (R/R) disease, with a virulent course of resistance and serial relapses, making treatment challenging. The available therapies for R/R MCL are not curative with conventional therapy, their goal being to palliate and prolong survival. A variety of agents approved for R/R MCL, including Bruton’s tyrosine kinase inhibitors (BTKi), changed the treatment landscape of R/R MCL. In the pre-BTKi era, the median progression-free survival (PFS) in R/R disease was 4–9 months. With the introduction of ibrutinib, the median PFS improved to 13–14.6 months. Despite these impressive results, the duration of response is limited, and resistance to BTKi inevitably develops in a subset of patients. Outcomes after progression on BTKi are extremely poor, with a median overall survival (OS) of 6 to 10 months. Certain therapies, such as chimeric antigen receptor (CAR) T cells, have shown promising results after BTKi failure. The preferred combination and sequencing of therapies beyond BTKi remain unestablished and are currently being investigated. In this review, we describe the current evidence for the available treatment of R/R MCL after progression on BTKi.

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Section: Beyond Btk Inhibitors: Targeted Therapiesmentioning

confidence: 99%

Section: Beyond Btk Inhibitors: Targeted Therapiesmentioning

confidence: 99%

Relapsed/Refractory Mantle Cell Lymphoma: Beyond BTK Inhibitors

Burkart

Karmali

2022

JPM

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“…Zilovertamab vedotin is an MMAE-conjugated humanized IgG1 monoclonal antibody that targets ROR1, an oncofetal protein pathologically expressed in solid and lymphoid malignancies including DLBCL [56]. A phase I study evaluated zilovertamab in 32 patients with relapsed/refractory B-cell NHLs [57]. Three out of the five patients with relapsed/refractory DLBCL responded and two achieved a CR.…”

Section: Antibody-drug Conjugatesmentioning

confidence: 99%

“…Responses were also seen in 7 out of the 15 patients with mantle cell lymphoma (MCL). The toxicities were mainly neutropenia (grade ≥ 3, 34%) and peripheral neuropathy (44%; grade three, 13%) [57]. TRPH-222, an antibody-drug conjugate targeting CD22, resulted in limited activity in DLBCL in a phase I trial that included 10 patients with DLBCL/transformed FL with an ORR of 20% [58].…”

Section: Antibody-drug Conjugatesmentioning

confidence: 99%

Relapsed/Refractory Diffuse Large B-Cell Lymphoma: A Look at the Approved and Emerging Therapies

Sawalha

2021

JPM

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Approximately 40% of patients with diffuse large B cell lymphoma (DLBCL) do not respond or develop relapsed disease after first-line chemoimmunotherapy. A minority of these patients can be cured with autologous hematopoietic stem cell transplantation (AHCT). Although chimeric antigen receptor (CAR) T cells have transformed the treatment paradigm of relapsed/refractory DLBCL, only 30–40% of patients achieve durable remissions. In addition, many patients with relapsed/refractory DLBCL are ineligible to receive treatment with CAR T cells due to comorbidities or logistical limitations. Since 2019, the following four non-CAR T-cell treatments have been approved in relapsed/refractory DLBCL: polatuzumab in combination with bendamustine and rituximab, selinexor, tafasitamab plus lenalidomide, and loncastuximab. In this article, I review the data behind these four approvals and discuss important considerations on their use in clinical practice. I also review emerging therapies that have shown promising early results in relapsed/refractory DLBCL including the bispecific antibodies, antibody–drug conjugates, Bruton tyrosine kinase inhibitors, BCL2 inhibitors, immune checkpoint inhibitors, and epigenetic modifiers.

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“…The oncofetal protein, receptor tyrosine kinase-like orphan receptor 1 (ROR1), is considered as a promising target for cancer therapy due to its overexpression on many types of tumor cells with low expression in normal adult tissues [ 20 ]. ROR1-expressing hematologic and solid tumors have a high potential for self-renewal, exhibit increased survival and migration, and are associated with poor outcomes [ 21 ]. So far, several therapeutic strategies including mAbs, bispecific mAbs, CAR-T cells and small molecule inhibitors against ROR1 have been evaluated and showed promising results in preclinical and clinical trials, but none of them have been approved for clinical use [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

Preclinical Assessment of Immunogenicity and Protectivity of Novel ROR1 Fusion Proteins in a Mouse Tumor Model

Hassannia

Amiri

Ghaedi

et al. 2022

Cancers

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The receptor tyrosine kinase-like orphan receptor 1 (ROR1) is a new tumor associated antigen (TAA) which is overexpressed in several hematopoietic and solid malignancies. The present study aimed to produce and evaluate different fusion proteins of mouse ROR1 (mROR1) to enhance immunogenicity and protective efficacy of ROR1. Four ROR1 fusion proteins composed of extracellular region of mROR1, immunogenic fragments of TT as well as Fc region of mouse IgG2a were produced and employed to immunize Balb/C mice. Humoral and cellular immune responses and anti-tumor effects of these fusion proteins were evaluated using two different syngeneic murine ROR1+ tumor models. ROR1-specific antibodies were induced in all groups of mice. The levels of IFN-γ, IL-17 and IL-22 cytokines in culture supernatants of stimulated splenocytes were increased in all groups of immunized mice, particularly mice immunized with TT-mROR1-Fc fusion proteins. The frequency of ROR1-specific CTLs was higher in mice immunized with TT-mROR1-Fc fusion proteins. Finally, results of tumor challenge in immunized mice showed that immunization with TT-mROR1-Fc fusion proteins completely inhibited ROR1+ tumor cells growth in two different syngeneic tumor models until day 120 post tumor challenge. Our preclinical findings, for the first time, showed that our fusion proteins could be considered as a potential candidate vaccine for active immunotherapy of ROR1-expressing malignancies.

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Zilovertamab Vedotin Targeting of ROR1 as Therapy for Lymphoid Cancers

Abstract: In a phase 1 trial involving patients with refractory lymphoid cancer, an antibody-drug complex directed against ROR1 had no unexpected toxicities. About half of the patients with mantle cell lymphoma and diffuse large B-cell lymphoma had clinically meaningful responses.

Cited by 42 publications

References 37 publications

Relapsed/Refractory Mantle Cell Lymphoma: Beyond BTK Inhibitors

Relapsed/Refractory Mantle Cell Lymphoma: Beyond BTK Inhibitors

Relapsed/Refractory Diffuse Large B-Cell Lymphoma: A Look at the Approved and Emerging Therapies

Preclinical Assessment of Immunogenicity and Protectivity of Novel ROR1 Fusion Proteins in a Mouse Tumor Model

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