A first-in-human (FiH) phase I study of GFS202A, a GDF15/IL-6 bispecific antibody, in advanced cancer patients (pts) with pre-cachexia or cachexia.

Abstract

12055 Background: Cachexia is a common syndrome in cancer pts, associated with weight loss, impaired quality of life, and poor treatment outcomes. GDF15, a pleiotropic factor of TGF-β super family, has been verified to be correlated with cancer cachexia and anorexia. IL-6 contributes to cancer cachexia progression via both central and peripheral pathways. GFS202A, a first-in-class bispecific antibody dual-targeting GDF15 and IL-6, improves symptoms in preclinical cachexia models with lean body mass and adipose tissue weight increased. Here, we report the preliminary data from the ongoing FiH study of GFS202A. Methods: This is the FiH phase I study (NCT06898255) of GFS202A in advanced cancer pts with pre-cachexia or cachexia. Eligible pts are required to have weight loss in the six months prior to the first dose and decreased appetite, with or without anticancer therapy. Enrolled pts will receive GFS202A Q3W at a starting dose of 5 mg for a 12-week treatment period, followed by a 12-week follow-up period. An accelerated titration design, combined with the Bayesian Optimal Interval (BOIN) and backfilling design, is employed. The primary objectives are to assess safety and determine the recommended dose ranges for future clinical studies. The secondary and exploratory objectives include characterization of PK profiles, PD biomarkers, preliminary efficacy and exploratory biomarkers. Results: Data cutoff at Dec 26, 2025, 14 pts had received at least one dose of GFS202A ranging from 5 to 400 mg Q3W (5mg: N=1; 25mg: N=4; 100mg: N=4; 200mg: N=4; 400mg: N=1). The overall safety profile was favorable. No DLT was observed. Adverse events (AEs) of any cause were reported in all pts. Six pts experienced at least one treatment-related AEs (TRAEs). Only one pt had G3 hypertension assessed related to GFS202A, which alleviated during the treatment. The pt did not experience any other cardiovascular events and had no clinically meaningful changes in lipid profiles. All other TRAEs were G1. No ≥ 2pt experienced an identical TRAE. GFS202A exposure was approximately dose-proportional from 5-200 mg, and the mean half-life was 82–138 hours. GDF15 was not detectable immediately at the end of infusion from the 5mg cohort, and durable inhibition of GDF15 was observed from the 100mg dosing cohorts during 21-day dosing interval. CRP decreased significantly post-infusion, with suppressions sustained through Week 6 in 12 out of 13 pts in 5-200 mg Q3W groups. Weight gain was observed across different dose groups, with least-squares mean increases of 1.8, 1.5 and 2.5 kg at Week 6 in the 25, 100, and 200 mg Q3W groups, respectively. Conclusions: GFS202A demonstrated favorable safety and encouraging efficacy with systemic inflammation alleviated and weight gain. The data support that dual-targeting GDF15 and IL-6 is a feasible way to mitigate cancer cachexia clinically. Future studies are warranted. Clinical trial information: NCT06898255 .