Background OCI is a humanized monoclonal antibody (mAb) against T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) with high affinity and specificity, enabling Fc-mediated effector functions that induce antibody-dependent cellular cytotoxicity.¹ The Phase 1/1b open-label AdvanTIG-105 trial was designed to assess the safety and efficacy of OCI plus TIS (an anti-programmed cell death protein 1 mAb) in patients with advanced solid tumors (NCT04047862).² In the dose-escalation part, the combination was well tolerated, and preliminary antitumor responses were observed. Here, we report PD biomarker data from peripheral blood.

Methods Eligible patients had locally advanced/metastatic, unresectable solid tumors previously treated with standard systemic therapy or for which treatment was not available/tolerated, ECOG PS ≤1 and had received no prior anti-TIGIT therapy. Patients received five escalating doses of OCI (50–1800mg) intravenously (IV) on Cycle (C) 1 Day (D) 1 and TIS 200mg IV was initiated on C1D8. If tolerated, patients received OCI (50–1800mg) plus TIS 200mg on D29 (C2D1) and every three weeks thereafter until discontinuation. Peripheral blood samples were collected to monitor changes in total and TIGIT-expressing immune cell subsets pre- and post-treatment. Meso Scale Discovery V-plex panels were used to assess cytokine/chemokine release in plasma samples. Wilcoxon signed-rank test compared pre- and post-treatment cytokine/chemokine levels; p values are descriptive.

Results At data cutoff (09/01/2021), 32 patients had received ≥1 dose of OCI plus TIS. Total peripheral regulatory T cells (Tregs) decreased following OCI monotherapy (at C1D2 and C1D8) with doses of 900mg and 1800mg (not dose proportional), but not 450mg; the decrease was maintained with subsequent combination with TIS (at C1D15 and C2D1). CD4+ and CD8+ T-cell populations were not impacted at any OCI dose. TIGIT downregulation was observed on Tregs, CD4+, and CD8+ T cells at C1D8 with multiple OCI doses (not dose proportional); the reduction was sustained after combination with TIS. Plasma IL12/23p40 (p<0.001), CCL4 (p<0.05), and CXCL10 (p<0.05) were notably induced post-OCI (C1D8), and further elevated following combination with TIS (p<0.001, p<0.001, and p<0.0001, respectively) at C2D1. Plasma IFNγ and TNFα increased post-OCI at C1D8 and were dramatically induced post-combination at C2D1 (p<0.0001 and p<0.001, respectively).

Conclusions OCI, with or without TIS, led to Treg reduction at higher doses, TIGIT downregulation, and proinflammatory cytokine/chemokine release, reflecting the potential mechanism of action of OCI as an Fc-competent anti-TIGIT mAb.

Acknowledgements This study was sponsored by BeiGene, Ltd. Medical writing support, under the direction of the authors, was provided by Sophie Cook, PhD, of Ashfield MedComms, an Inizio company, and was funded by BeiGene, Ltd.

Trial Registration NCT04047862

References

1. Chen X, Xue L, Ding X, et al. A Fc-competent anti-human TIGIT blocking antibody BGB-A1217 elicits strong immune responses and potent anti-tumor efficacy in pre-clinical models. J Cancer Res. 2021 Abstract 1854;81(13 Supplement):1854–54

2. Frentzas S, Meniawy T, Kao S, et al. AdvanTIG-105: Phase 1 dose-escalation study of anti-TIGIT monoclonal antibody ociperlimab (BGB-A1217) in combination with tislelizumab in patients with advanced solid tumors. J Clin Oncol. 2021;15:2583.

Ethics Approval The protocol, informed consent forms, any information given to the patients, and relevant supporting information were submitted, reviewed, and approved by the Institutional Review Board and Independent Ethics Committee before this study was initiated. This study was conducted in full conformance with the International Council for Harmonization E6 guideline for Good Clinical Practice, the International Council for Harmonization E2A guideline for Clinical Safety Data Management, and the principles of the Declaration of Helsinki or the laws and regulations of the country in which the research was conducted.