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Antibody-drug conjugate izalontamab brengitecan (iza-bren) improves survival as a second-line therapy in patients with recurrent or metastatic esophageal squamous cell carcinoma (ESCC), based on interim results of a phase 3 randomized trial.

Compared with chemotherapy, iza-bren reduced the risk for death by 36% and the risk for progression or death by half. It also nearly tripled the objective response rate.

These results support iza-bren as a new second-line standard of care for ESCC in China, said lead author Zhihao Lu, MD, on Monday, June 1, in an oral abstract session at the American Society of Clinical Oncology (ASCO) 2026 in Chicago.

Many patients with advanced ESCC develop resistance to first-line treatment with chemotherapy plus a checkpoint inhibitor, and second-line chemotherapy response rates sit below 10%, with a median overall survival (OS) of less than 6 months, said Lu, who is an oncologist at Peking University Cancer Hospital in Beijing, China.

Iza-bren, an antibody-drug conjugate that pairs an epidermal growth factor receptor-human epidermal growth factor receptor 3 (HER3) bispecific antibody with a topoisomerase I inhibitor payload via a cleavable linker, could potentially address this practice gap, he said. In early-phase testing, the agent demonstrated activity among patients with previously treated ESCC, prompting the current phase 3 trial.

Trial Design

The trial, which was conducted at 80 centers in China, enrolled 497 patients with recurrent or metastatic ESCC that had progressed after first-line treatment with a PD-1 or PD-L1 inhibitor plus platinum-based chemotherapy.

Explaining the rationale behind the requirement for prior checkpoint inhibitor exposure, Lu noted that HER3 expression is typically low in ESCC, but it increases with resistance to PD-1 blockade.

Participants were randomly assigned in a 1:1 ratio to receive either iza-bren (2.5 mg/kg on days 1 and 8 every 3 weeks) or physician’s choice of chemotherapy with irinotecan, paclitaxel, or docetaxel.

The dual primary endpoints were OS and progression-free survival (PFS).

Improved Survival and Response

After a median follow-up of approximately 8 months, median OS was 9.8 months for iza-bren vs 7.2 months for chemotherapy (hazard ratio, 0.64; P = .0004).

Median PFS and objective response rate also significantly favored iza-bren, at 4.2 months vs 2.0 months and 35.3% vs 13.1%, respectively.

These benefits were consistent across prespecified subgroups.

Grade 3 or higher treatment-related adverse events were predominantly hematologic and more common for iza-bren than for chemotherapy (85.1% vs 60.2%).

Most adverse events were managed with dose delays, dose reductions, and supportive care, allowing the majority of patients to continue treatment, Lu said.

Rates of treatment discontinuation (2.0% vs 3.3%) and treatment-related death (1.2% vs 1.6%) were similar between the arms.

A New Standard in China, With Open Questions

Sunnie S. Kim, MD, of the UCHealth Cancer Care in Aurora, Colorado, the session’s invited discussant, agreed that iza-bren represents a new standard of care for second-line ESCC in China.

Whether the results will translate beyond the study population, however, remains unclear, Kim added.

She outlined key differences between China and the US, including screening protocols, risk factors, and pharmacogenomics, and then pointed to previous second-line trials such as KEYNOTE-181 and RATIONALE-302, which reported different results by region.

US regulatory approval is therefore unlikely, based on these results alone, said Kim. The is because the FDA prefers to approve new agents based on more representative data, she explained.

Kim also pointed out that relatively fewer patients in the iza-bren arm went on to receive subsequent therapy (37.3% vs 53.7%), raising the possibility that iza-bren caused more toxicity than captured by the reported data; such toxicity may have kept some patients in the iza-bren cohort from receiving later treatments that could have further extended survival. She questioned whether additional growth-factor support might improve tolerability in this context.

Looking ahead, Kim suggested evaluating iza-bren in the first-line setting in a global study and predicted that patients in the US would likely tolerate and benefit from the drug. In the meantime, she called for patient-reported quality-of-life data.

The study was funded by Baili-Bio (Chengdu) Pharmaceutical, the developer of iza-bren. Lu reported having no relevant financial relationships; several co-authors reported being employees of Baili Biopharmaceutical or SystImmune. Kim disclosed serving consulting or advisory roles with Amgen, AstraZeneca, Merck, and others.