Abstract CT181: First-in-human phase I of anti-VISTA monoclonal antibody W0180 with and without anti-PD-1 pembrolizumab in patients with locally advanced or metastatic solid tumors
Authors: Gomez-Roca Carlos , Champiat Stéphane , Cassier Philippe , Jegou David , Primard Marie , Pétain Aurélie , Gueguen-Dorbes Geneviève , Fabre Claire , Melero Ignacio , Marabelle Aurélien 
Published: April 2024

Abstract
Background: V-domain Immunoglobulin Suppressor of T cell Activation (VISTA) is an immune checkpoint regulator highly expressed on myeloid cells. VISTA has been shown to maintain tumor microenvironment (TME) in an immunosuppressive state. Its expression is reported as a resistance mechanism to immune checkpoint blockers, making it an attractive target for cancer treatment. Preclinical data showed that VISTA blockade mediates antitumor activity by activating the antitumor immune response and is enhanced in combination with anti-PD-1. W0180 is a humanized, Fc competent, IgG1 antibody targeting VISTA with high affinity. This study investigates W0180 with/without pembrolizumab (pembro) in patients (pts) with solid tumors.
Methods: Pts initially received W0180 monotherapy in dose escalation (3.5-600 mg weekly (QW)). Following evaluation of the first 3 dose levels in monotherapy, dose escalation of W0180 (60 to 300 mg QW) in combination with pembro (200 mg Q3W) started in pts treated with prior anti-PD-(L)1. Objectives were to characterize safety and tolerability of W0180, determine RDE and PK/PD on blood and paired tumor biopsies.
Results: By October 2023, 33 pts were treated in dose escalation, 24 pts with W0180 monotherapy and 9 pts with W0180 + pembro. Two dose-limiting toxicities were observed, Grade 2 subacute cerebral infarction and Grade 3 infusion related reaction (IRR). Overall, 33 pts experienced ≥1 treatment-emergent AE (TEAE). Most common TEAEs were IRR (32/33), fatigue (14/33), and anemia (11/33). Grade 3/4 TEAEs occurred in 23 pts, neutropenia (6/23) and anemia (6/23) were the most common. There was no treatment-related death. 6 (18%) pts discontinued due to AEs. Following the observation of Grade 3 arterial thromboembolism (n=1) and Grade 2 subacute cerebral infarction (n=1), eligibility criteria were amended to require adequate lipid profile, troponin and exclude pts with history of arterial thrombotic events and current smoking. W0180 PK was nonlinear with a rapid clearance at 3.5-600 mg doses. No objective response was observed but 5 pts had stable disease (SD) lasting for &gt;16 weeks. One pt with appendix cancer treated at 600mg monotherapy had SD for &gt;15 months. One pt with head and neck cancer treated at 300mg in combination had SD for 13 months. Biomarkers data suggested evidence of PD effect with a trend for dose response through sustained increase of proliferative CD8+ T-cells in blood at the highest W0180 exposures and increased density of tumor-infiltrating lymphocytes in 10 out of 16 pts. These changes were independent of tumor VISTA expression level and correlated to high PD-L1 expression (CPS&gt;5) for 4 pts at baseline.
Conclusions: Analysis is ongoing to assess the RDE of W0180 + pembro and collect additional evidence of proof of mechanism in pts with solid tumors. NCT04564417
Citation Format: Carlos Gomez-Roca, Stéphane Champiat, Philippe Cassier, David Jegou, Marie Primard, Aurélie Pétain, Geneviève Gueguen-Dorbes, Claire Fabre, Ignacio Melero, Aurélien Marabelle. First-in-human phase I of anti-VISTA monoclonal antibody W0180 with and without anti-PD-1 pembrolizumab in patients with locally advanced or metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT181.