Dose-escalation results from a phase I study of FZ-AD004, a TROP2-directed ADC, in patients with advanced solid tumors.

Abstract

8523 Background: FZ-AD004 is an ADC (antibody-drug conjugate) targeting Trop-2 (trophoblast cell-surface antigen 2), an intracellular calcium signaling transducer overexpressed on many epithelial tumors. It delivers the topoisomerase inhibitor DXd. This first-in-human study evaluated the safety and efficacy in patients(pts) with advanced solid tumors, mainly in non–small-cell lung cancer (NSCLC). Methods: PTs with unresectable, treatment-refractory or relapsed solid tumors received FZ-AD004 intravenously on days 1 of 21-day cycles. The primary objectives were to determine maximum tolerated dose (MTD), safety, and tolerability; secondary objectives included efficacy, pharmacokinetics, and immunogenicity of FZ-AD004. Pts were eligible regardless of TROP2 level. Results: As of November 28, 2025, 22 pts were treated with ≥1 dose of FZ-AD004 (median age: 61.5 years [range from 45-75], male: 77.3%, EOCG PS 1: 100%, prior lines of anticancer treatment ≥ 2: 77.3%). Diagnoses included NSCLC (n=21) and SCLC (n=1). Doses evaluated were at 3.2 (n=3), 5.6 (n=3), 6.4 (n=3), 8.0 (n=4), 10.0 (n=3), and 12.0 mg/kg (n=6). No dose-limiting toxicity (DLT) was observed across all dose levels.19 pts (86.4%) discontinued (15 (68.2%) due to disease progression per RECIST v1.1). Treatment emergent adverse events (TEAEs) regardless of causality were reported in all of 22 pts (100%; 10 pts [45.5%] experienced ≥grade 3, 5 pts [22.7%] had serious adverse events). Treatment-related AEs (TRAEs) occurred in all pts (100%; grade ≥3 in 36.4%; serious TRAEs in 13.6%). Grade ≥3 TRAEs included stomatitis (13.6%), decreased lymphocyte count (9.1%), nausea (4.5%), hypokalemia (4.5%), and keratitis (4.5%).Among 12 efficacy-evaluable pts at doses ≥8.0 mg/kg, the objective response rate (ORR) was 50.0% and the disease control rate (DCR) was 83.3%. Responses were observed in pts harboring KRAS G12C (n=1), EGFR mutations (n=3), and without AGA mutations (n=2). The longest duration treatment was 11.4 months. Conclusions: FZ-AD004 demonstrated a manageable safety profile with no DLTs observed up to 12.0 mg/kg and promising antitumor activity in heavily pretreated NSCLC patients, particularly at doses of 8.0 and 10.0 mg/kg. These doses are being further explored in the expansion phase. Clinical trial information: NCT05914545 .