Abstract 1905: The ROR1 antibody-drug conjugate, MK-2140, enhances the efficacy of established drugs in preclinical models of pediatric acute lymphoblastic leukemia
Authors: Lock Richard B. , Evans Kathryn , Watts Ben , Bowman Edward P. , Neuhauser Steven , Stearns Timothy , Chuang Jeffrey H. , Phillip Vivek M. , Jessen Katti A. , Jocoy Emily L. , Bult Carol J. , Teicher Beverly A. , Smith Malcolm A. 
Published: March 2024

Introduction: Children diagnosed with acute lymphoblastic leukemia (ALL) experience ~90% likelihood of cure. However, the outcome for high-risk ALL and children who relapse remains poor. Receptor tyrosine kinase like orphan 1 receptor (ROR1) is a cell surface antigen primarily expressed in embryonic tissue, but also overexpressed in hematological malignancies. UC961 is a humanized IgG monoclonal antibody with high affinity for ROR1. MK-2140 (Zilovertamab vedotin/VLS-101) and VLS-211 are antibody-drug conjugates (ADCs) of UC961 with monomethyl auristatin-E or PNU payloads, respectively. This study evaluated the in vivo efficacy of MK-2140 and VLS211 against pediatric ALL patient derived xenografts (PDXs).

Methods: PDXs were selected based on ROR1 mRNA (RNA-seq) and cell surface (flow cytometry) expression and grown as orthotopic disease in immune-deficient NSG mice. Engraftment and drug responses were assessed by flow cytometric enumeration of the proportion of human versus mouse CD45+ cells in peripheral blood (%huCD45+). Events were defined a priori as the %huCD45+ exceeding 25% or leukemia-related morbidity. MK-2140 (2.5 and 5.0 mg/kg) and VLS-211 (0.25 and 0.5 mg/kg) were administered intravenously, weekly x 3 weeks. 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). Drug efficacy was assessed by event-free survival of treated (T) and control (C) groups and by stringent objective response criteria. In receptor occupancy/pharmacokinetic studies, a single dose of MK-2140 was administered and samples collected for analysis at discrete timepoints thereafter.

Results: ROR1 mRNA and cell surface expression showed a significant correlation (R=0.83, P=0.021). MK-2140 significantly delayed disease progression in 4/7 PDXs compared to vehicle control (T-C, -2.6 to 20.0 days). At the highest dose, MK-2140 elicited objective responses (remissions) in two PDXs. VLS-211 significantly delayed disease progression in 5/7 PDXs (TC, -1.8 to 70.5 days), including 3 objective responses. Prior treatment with VXL followed by MK-2140 significantly delayed disease progression compared to VXL alone (T-C, 56.8 versus 35.2 days). MK-2140 bound to ROR1+ cells with near 100% occupancy within two hours of treatment, which was sustained for up to 96 h. Consistent with the receptor occupancy data, plasma levels of MK-2140 were maintained at &gt;100 nM for at least 96 h after a single dose (5 mg/kg).

Conclusions: 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.

Citation Format: Richard B. Lock, Kathryn Evans, Ben Watts, Edward P. Bowman, Steven Neuhauser, Timothy Stearns, Jeffrey H. Chuang, Vivek M. Phillip, Katti A. Jessen, Emily L. Jocoy, Carol J. Bult, Beverly A. Teicher, Malcolm A. Smith. The ROR1 antibody-drug conjugate, MK-2140, enhances the efficacy of established drugs in preclinical models of pediatric acute lymphoblastic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1905.