Zilovertamab Vedotin Targeting of ROR1 as Therapy for Lymphoid Cancers

作者：Michael Wang, Jacqueline C. Barrientos, Richard R. Furman, Matthew Mei, Paul M. Barr, Michael Y. Choi, Sven de Vos, Avyakta Kallam, Krish Patel, Thomas J. Kipps, Simon Rule, Kate Flanders, Katti Jessen, Hong Ren, Peter Riebling, Patricia Graham, Lydia King, Archie Thurston, Michael Sun, Elizabeth Moreira dos Santos Schmidt, Brian J. Lannutti, David M. Johnson, Langdon L. Miller, Stephen E. Spurgeon · 发表于：NEJM Evidence · 年份：2021 · DOI：10.1056/evidoa2100001 · 被引用次数：78 · 研究领域：Lymphoma Diagnosis and Treatment、CAR-T cell therapy research、Chronic Lymphocytic Leukemia Research

BACKGROUND: Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is an oncofetal protein present on many cancers. Zilovertamab vedotin (ZV) is an antibody–drug conjugate comprising a monoclonal antibody recognizing extracellular ROR1, a cleavable linker, and the anti-microtubule cytotoxin monomethyl auristatin E. METHODS: In this phase 1, first-in-human, dose-escalation study, we accrued patients with previously treated lymphoid cancers to receive ZV every 3 weeks until the occurrence of cancer progression or unacceptable toxicity had occurred. RESULTS: We enrolled 32 patients with tumor histologies of mantle cell lymphoma (MCL) (n=15), chronic lymphocytic leukemia (n=7), diffuse large B-cell lymphoma (DLBCL) (n=5), follicular lymphoma (n=3), Richter transformation lymphoma (n=1), or marginal zone lymphoma (n=1). Patients had received a median of four previous drug and/or cellular therapies. 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 (mg/kg). Pharmacokinetic and pharmacodynamic data documented systemic ZV exposure and exposure-dependent ZV targeting of ROR1 on circulating tumor cells. As expected with an monomethyl auristatin E-containing antibody–drug conjugate, adverse events (AEs) included acute neutropenia and cumulative neuropathy resulting in a recommended ZV dosing regimen of 2.5 mg/kg every 3 weeks. No clinically concerning AEs occurred to suggest ROR1-mediated toxicities or nonspecific ZV binding ...