Abstract 2129: Predictive response biomarkers from Phase I clinical trial of a SIRPalpha inhibitor BI765063, stand-alone and in combination with ezabenlimab, a PD1 inhibitor, in patients with advanced solid tumors

Abstract

Background: Signal Regulatory Protein α [SIRPα] is an inhibitory membrane receptor expressed by myeloid cells (macrophages and myeloid-derived suppressor cells, MDSCs) and specifically binds to CD47. BI765063 is a selective anti-SIRPα monoclonal antibody acting as a checkpoint inhibitor of SIRPα/CD47 axis, promoting anti-tumor immunity through increase of dendritic cells antigen presentation, enabling MDSC differentiation, potentiating macrophage phagocytic/inflammatory properties and reinstating myeloid cell chemokine secretion and human T cell migration1. The escalation phase I study in advanced solid tumor patients (pts) showed preliminary efficacy as monotherapy (MONO), and in combination with PD-1 inhibitor ezabenlimab (COMBO). Our goal was to investigate BI765063 predictive response markers. Methods: A total of 68 patients (50 in MONO arm, 18 in COMBO arm) have been enrolled. Receptor occupancy (RO) was determined on peripheral CD14+ monocytes. Tumor biopsies were collected before treatment from 44 pts (62%) representative of overall population. Tumor microenvironment (TME) was analysed using a Brightplex® IHC panel comprised of CD68+ macrophages, CD11b+myeloid cells, SIRPα, and CD47. NanoString tumor profiling used PanCancer IO360 panel. Results: One partial response (PR) in MONO (Hepatocellular carcinoma HCC), and 4 PRs in COMBO (2 endometrial cancer, 1 HCC, 1 iRecist PR in MSS CRC) were observed2. BI 765063 full RO saturation was achieved in V1/V1 pts treated with doses of 6 mg/kg and higher, while V1/V2 patients showed a more heterogeneous RO ranging between 40-80%, reaching an apparent saturation at doses of 12 mg/kg and higher. Comparison of pts by best response showed that baseline tumor SIRPα+ expression in CD68+ macrophages and in CD11b+ myeloid cells were higher in PR versus PD pts. High percentage of CD11b+SIRPα+ myeloid cells at baseline significantly correlated with better OS (p=0.023), while CD68+SIRPα+ macrophages high expression in TME showed a trend for a better OS but did not reach statistical significance. The CD47 tumor expression did not correlate with the OS. Responder signature based on the top deregulated genes in responders versus non-responders at baseline was devised to sort relevant TCGA cohorts and showed strong positive correlation with TME MDSC infiltration (p≤0.0001). Conclusions: High levels of CD11b+SIRPα+ myeloid cells in TME at baseline, but not CD47 tumor expression, correlates with longer survival while MDSC signature in TME at baseline correlates with clinical response. Thus, suggesting that MDSCs expressing SIRPα in TME could represent a predictive efficacy biomarker. References: 1. Gauttier V. et al., 2020. J. Clin. Invest. 130: 6109; 2. Kotecki N. et al., 2021. ESMO meeting, abstract #983P Citation Format: Stéphane Champiat, Philippe A. Cassier, Nuria Kotecki, Carlos Gomez-Roca, Iphigenie Korakis, Ouali Kaissa, Antoine Italiano, Mabrouk M. Elgadi, Thomas Vandewalle, Isabelle Girault, Nina Salabert-Le Guen, Donogh O’Brien, Nicolas Poirier, Bérangère Vasseur, Dominique Costantini, Claudia Fromond, Françoise Bono, Jean-Pierre Delord. Predictive response biomarkers from Phase I clinical trial of a SIRPalpha inhibitor BI765063, stand-alone and in combination with ezabenlimab, a PD1 inhibitor, in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2129.

Blockade of SIRPα-CD47 axis by anti-SIRPα antibody enhances anti-tumor activity of DXd antibody-drug conjugates

“…For instance, in blood cancer, agents targeting CD47 such as magrolimab, evorpacept, and ontorpacept, and those targeting SIRPα such as CC-95251 have shown anti-cancer activity in monotherapy or combination with the standard of care [ 6 , 16 , 40 , 41 ]. In solid tumors, however, the anti-tumor activity of SIRPα-CD47 blockers remains to be improved [ 6 , 21 , 42 – 44 ]. The combination therapy proposed in this study might enhance anti-tumor activity by two mechanisms as follows.…”