Abstract 1993: Biomarker analyses from the Phase I clinical trial of the first-in-class SIRPa immune checkpoint inhibitor BI765063 in patients with advanced solid tumors

Abstract Background: BI 765063 (OSE-172) is a humanised IgG4 monoclonal antibody which binds selectively to the V1 allele of Signal Regulatory Protein α [SIRPα] blocking the SIRPα/CD47 “don't eat me” pathway. Preclinical studies showed that SIRPα blockage led to macrophage and T-cell recruitment into tumor xenografts, and induced upregulation of chemokines, cytokines and adaptive immune function genes in human tumor explants (Gauttier et al., 2020). The goal of the biomarker analyses was to characterize the BI 765063 impact on peripheral blood immune cells (PBMCs) and the tumor microenvironment (TME). Methods: Fifty patients (26 V1/V1, 24 V1/V2) received BI 765063 IV from 0.02 mg/kg to 36 mg/kg every 3 weeks. Paired tumor biopsies were collected before and 2 weeks after first BI 765063 infusion. PBMCs were collected before, then 4 h, 1, 14, and 21 days after first infusion. BI 765063 receptor occupancy (RO) was determined on peripheral CD14+ monocytes. Immunophenotyping of PBMCs was performed by flow-cytometry. TME was analysed with a Brightplex® IHC panel including CD8+ T-cells, CD68+ macrophages, SIRPα, CD47, and PD-L1. Tumor gene expression profiling was performed using the Pan Cancer Immune gene set. Results: BI 765063 full RO saturation was achieved at trough levels (C2D1, pre-dose) in V1/V1 patients treated with doses of 6 mg/kg and higher, while V1/V2 patients showed a more heterogeneous RO ranging from 40-80%, reaching an apparent saturation at ≥ 12 mg/kg. An increase of activated CD80+/CD14+ and CD40+/CD14+ monocytes in PBMCs was observed at 24 h post-treatment in both, V1/V1 and V1/V2 patients. In paired tumor biopsies, IFNγ, MHCII antigen presentation gene pathways, and CCL7 transcripts appeared to be upregulated at C1D15 in patients with a systemic exposure of ≥ 100 µg/ml. One patient with hepatocellular carcinoma (HCC) and liver and lung metastases treated with BI 765063 monotherapy at 24 mg/kg achieved partial response (Champiat et al., ASCO, 2021). Baseline tumor biopsy of that patient showed that 66% of HCC tumor cells were CD47+ and 87% of CD68+ macrophages were SIRPα+. Furthermore, high levels of CD8+ T-cells were observed at baseline. At C1D15 increased CD68+ macrophage infiltration, sustained CD8 T-cell tumor accumulation and higher PD-L1 CPS (48% at baseline vs 75% at C1D15) were observed. Analysis of paired tumor biopsies in other patients showed that often, increased levels of tumor CD68+ macrophages were accompanied by CD8+ T-cell infiltration. Conclusion: This early biomarker analysis in patients with a wide range of solid tumors and treated with the first-in-class SIRPa inhibitor BI 765063 show encouraging signs of potentially mode-of-action related changes, both in peripheral blood and the TME. These early signals will be further evaluated in similar samples from the ongoing expansion cohorts in more homogeneous patient populations. Citation Format: Stephane Champiat, Philippe A. Cassier, Nuria Kotecki, Carlos Gomez-Roca, Aurélien Marabelle, Armelle Vinceneux, Christiane Jungels, Mabrouk Elgadi, Ralph Graeser, Thomas Vandewalle, Isabelle Girault, Nina Salabert-Le Guen, Nicolas Poirier, Bérangère Vasseur, Dominique Costantini, Claudia Fromond, Jean-Pierre Delord. Biomarker analyses from the Phase I clinical trial of the first-in-class SIRPa immune checkpoint inhibitor BI765063 in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1993.