Izalontamab brengitecan (iza-bren) versus chemotherapy in patients with recurrent or metastatic esophageal squamous cell carcinoma (ESCC): A multicenter, randomized, open-label, phase III study.

Abstract

4008 Background: Chemotherapy plus a PD-1/PD-L1 inhibitor is the standard first-line treatment for PD-L1 expressing advanced ESCC. However, most patients (pts) inevitably develop resistance to first-line therapy, and second-line chemotherapy shows an ORR of less than 10% and a median OS of less than 6 mo, highlighting the urgent need for novel therapeutics. Iza-bren is a potentially first-in-class ADC consisting of an EGFR-HER3 bispecific antibody conjugated to a potent topoisomerase I inhibitor Ed-04 via a cleavable linker. Iza-bren has shown promising clinical activity in previously treated ESCC pts in phase I study. Here, we present results from a phase III, randomized, open-label, multicenter study conducted in China evaluating the efficacy and safety of iza-bren versus chemotherapy as second line treatment for advanced ESCC. Methods: Pts with recurrent or metastatic ESCC who had progressed after first-line treatment with a PD-1/PD-L1 inhibitor plus platinum-based chemotherapy were randomized (1:1) to receive iza-bren (2.5 mg/kg at D1D8 Q3W) or physician’s choice of chemotherapy (irinotecan, paclitaxel, or docetaxel Q3W). Dual primary endpoints were OS and PFS by Blinded Independent Central Review (BICR) per RECIST v1.1. Results: As of Oct 17, 2025, a total of 497 pts were randomized to iza-bren (n = 249) or chemotherapy (n = 248). Baseline characteristics were balanced between the two groups. At interim analysis, median follow-up for OS was 7.8 mo in the iza-bren group and 7.6 mo in the chemotherapy group. Iza-bren has demonstrated statistically significant and clinically meaningful improvement in both OS and PFS by BICR compared with chemotherapy. The median OS was 9.8 mo (95% CI, 7.9 to 11.0) with iza-bren and 7.2 mo (95% CI, 6.2 to 8.2) with chemotherapy (HR, 0.64; 95% CI, 0.49 to 0.83; P = 0.0004). The median PFS by BICR was 4.2 mo (95% CI, 3.6 to 4.5) with iza-bren and 2.0 mo (95% CI, 1.6 to 2.7) with chemotherapy (HR, 0.50; 95% CI, 0.40 to 0.63; P < 0.0001). ORR by BICR was 35.3% for iza-bren and 13.1% for chemotherapy. Grade≥3 TRAEs, which were predominantly hematologic in nature, occurred in 85.1% in the iza-bren group and 60.2% in the chemotherapy group. TRAEs leading to drug discontinuation were 2.0% in the iza-bren group and 3.3% in the chemotherapy group. TRAEs leading to death were 1.2% in the iza-bren group and 1.6% in the chemotherapy group. Conclusions: The study met both dual primary endpoints at prespecified interim analysis. Iza-bren demonstrated statistically significant and clinically meaningful improvements in OS and PFS compared with chemotherapy in pts with recurrent or metastatic ESCC who had progressed after first line PD-1/PD-L1 inhibitor plus platinum-based chemotherapy. The safety profile was manageable. The results support iza-bren as a new second-line standard of care for ESCC. Clinical trial information: NCT06304974 .