A multicenter, randomized phase 2 study evaluating the efficacy and safety of HLX43 (an anti-PD-L1 ADC) in recurrent/metastatic esophageal squamous cell carcinoma.

364 Background: Chemotherapy is the predominant treatment option for patients with advanced ESCC following disease progression on first-line chemoimmunotherapy, which has limited efficacy. HLX43 is a novel antibody-drug conjugate targeting the programmed cell death-ligand 1 (PD-L1). Its promising efficacy alongside good tolerability was demonstrated in patients with advanced solid tumors refractory to immune checkpoint inhibitors in a phase 1 trial. This phase 2 study evaluated the efficacy and safety of HLX43 in previously treated recurrent/metastatic ESCC. Methods: Patients with histologically or cytologically confirmed recurrent/metastatic ESCC who progressed on or are intolerant to first-line chemoimmunotherapy were enrolled and randomized 1:1:1 to receive intravenous HLX43 at 2 mg/kg, 2.5 mg/kg, or 3 mg/kg once every 3 weeks. The primary endpoints were investigator-assessed objective response rate (ORR) and progression-free survival per RECIST v1.1. Secondary endpoints included other efficacy endpoints, safety, pharmacokinetics, immunogenicity, and biomarker explorations. Results: As of data cutoff date Aug 26, 2025, 35 patients were randomized to and received HLX43 at 2 mg/kg (n = 11), 2.5 mg/kg (n = 12) and 3 mg/kg (n = 12) groups. Most enrolled patients had an Eastern Cooperative Oncology Group performance status score of 1 (85.7%). Patients received a median line of prior antitumor therapy of 2 (range, 1–4). Among the 7 response-evaluable patients in the 3 mg/kg group, ORR was 57.1% with 4 patients having achieved partial response and DCR was 100.0%; ORR was 60.0% for those with a PD-L1 combined positive score ≥ 1 (n = 5) in this dose group. Overall, treatment-emergent adverse events (TEAEs) occurred in 27 patients (77.1%; grade ≥3, 20.0%). Most common grade ≥3 TEAEs (≥5% in incidence) included anemia (8.6%), and lymphocyte count decreased (5.7%). Conclusions: HLX43 conferred promising efficacy, particularly at 3 mg/kg dose, along with a manageable safety profile in patients with previously treated recurrent/metastatic ESCC. Further investigation is warranted. Clinical trial information: NCT06769113 .