A first-in-human phase I study of FS118, an anti-LAG-3/PD-L1 bispecific antibody in patients with solid tumors that have progressed on prior PD-1/PD-L1 therapy.

Abstract

TPS2652 Background:PD-1/PD-L1 checkpoint inhibitors demonstrated remarkable anti-tumor activity, but only a minority of patients achieve full clinical benefit with deep and durable responses. Translational studies suggest resistance to cancer immunotherapy can be mediated by additional immune checkpoints e.g. lymphocyte-activation gene 3 (LAG-3). The combination of LAG-3 and PD-1 mAbs synergistically improved anti-tumor response in murine models and early clinical trials. In a small cohort, TIL LAG-3 expression enriched for responsiveness in PD-1/PD-L1 relapsed/refractory patients. FS118 is a novel bispecific antibody incorporating a LAG-3 binding Fc-region into a PD-L1-specific IgG1 antibody to potentially deliver superior anti-tumor efficacy while limiting immunotherapy-related adverse effects by dual targeting. Methods: The FiH study (NCT03440437) is being conducted in adult patients with solid tumors who failed prior PD-1/PD-L1 treatment. Primary objectives of the study are to determine safety, PK and the maximum tolerated/recommended Phase 2 dose of FS118. Secondary objectives include preliminary evidence of efficacy, immunogenicity, PD profile and exposure/response correlation. 50 subjects from four study sites in the USA are planned to enrol in dose escalation initiated with accelerated titration (5 single subject cohorts) followed by 3+3 design and expansion cohorts. FS118 is administered weekly IV in 21-day treatment cycles until progression, unacceptable toxicity, withdrawal, or death. Patients are followed for safety, overall survival and initiation of subsequent therapy. DLT clearance, dose escalation and cohort expansion (to further characterise safety, PK/PD or clinical efficacy) are supervised by a safety review committee (SRC). Translational studies assess PD-L1/LAG-3 receptor occupancy, soluble PD-L1/LAG-3 levels and the correlation of FS118 exposure with selected PD markers of target engagement and response. Translational endpoints include TIL analysis, transcriptomic profiles and target expression analyses on tumor tissues. Cohorts 1 through 6 have been completed, enrollment in cohort 7 began December 2018. Clinical trial information: NCT03440437.