In heavily pretreated patients with lymphoid malignancies, zilovertamab vedotin demonstrated no unexpected side effects and showed evidence of antitumour activity in a phase I, first-in-human, dose-escalation study. The findings provide a clinical proof of concept for selective targeting of receptor tyrosine kinase-like orphan receptor 1 (ROR1), an oncofoetal protein, as a potential new therapeutic approach. The study findings are published by Prof. Michail L. Wang of the Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center in Houston, TX, US and colleagues on 12 October 2021 in The New England Journal of Medicine.
The authors wrote in the background that ROR1 is a cell-surface protein that mediates signaling from its ligand, Wnt5a, to drive physiologic embryonic stem cell proliferation. By birth, ROR1 expression disappears from almost all normal tissues. However, cancer cells that revert to a dedifferentiated state can express ROR1. ROR1-expressing haematologic and solid tumours have a high potential for self-renewal, exhibit increased survival and migration, and are associated with poor outcomes.
Zilovertamab vedotin is a novel antibody–drug conjugate comprising the humanised monoclonal antibody zilovertamab, which is highly specific for tumour tissue; a proteolytically cleavable maleimidocaproyl-valine-citrulline-para-aminobenzoate linker; and the antimicrotubule cytotoxin monomethyl auristatin E (linker-monomethyl auristatin E designated as vedotin). Zilovertamab vedotin binding to tumour cell ROR1 results in rapid internalisation, trafficking to lysosomes, antibody–drug conjugate cleavage, and monomethyl auristatin E release.
In mouse models of human lymphoid malignancies, zilovertamab vedotin safely induced tumour shrinkage, often causing complete regressions even with heterogenous ROR1 expression. Dose-dependent neutropenia was the only important side effect in monkeys.
In this phase I study, the authors enrolled 32 patients with previously treated (a median of 4 previous drug and/or cellular therapies) mantle cell lymphoma (n=15), chronic lymphocytic leukaemia (n=7), diffuse large B-cell lymphoma (n=5), follicular lymphoma (n=3), Richter transformation lymphoma (n=1), and marginal zone lymphoma (n=1) to receive zilovertamab vedotin every 3 weeks until the occurrence of disease progression or unacceptable toxicity had occurred.
Starting dose levels were 0.5 (n=1), 1.0 (n=3), 1.5 (n=3), 2.25 (n=11), and 2.5 (n=14) mg per kg of body weight. Pharmacokinetic and pharmacodynamic data documented systemic zilovertamab vedotin exposure and exposure-dependent zilovertamab vedotin targeting of ROR1 on circulating tumour cells.
Side effects included acute neutropenia and cumulative neuropathy resulting in a recommended zilovertamab vedotin dosing regimen of 2.5mg/kg every 3 weeks. No clinically concerning side effects occurred to suggest ROR1-mediated toxicities or non-specific zilovertamab vedotin binding to normal tissues.
Zilovertamab vedotin induced objective tumour responses (ORRs) in 7 of 15 patients with mantle cell lymphoma (47%) with 4 partial and 3 complete responses, and in 3 of 5 patients with diffuse large B-cell lymphoma (60%) with 1 partial and 2 complete responses. The ORRs were not observed among patients with other tumour types.
The study team focused on lymphoid malignancies given their near-ubiquitous ROR1 expression and known responsiveness to non–cancer-specific, lymphocyte-targeting drugs such as brentuximab vedotin and polatuzumab vedotin that deliver monomethyl auristatin E. The findings support further development of zilovertamab vedotin as monotherapy and combination therapy in patients with monomethyl auristatin E-sensitive haematological and solid tumours. The study data provide validation of ROR1 as a therapeutic target and support the concept that selective targeting of ROR1 may offer a novel and clinically beneficial approach, if these data can be extended in larger and longer clinical studies.
The study was sponsored by VelosBio Inc.
Wang ML, Barrientos JC, Furman RR, et al. Zilovertamab Vedotin Targeting of ROR1 as Therapy for Lymphoid Cancers. NEJM; Published online 12 October 2021. https://doi.org/10.1056/EVIDoa2100001