Izalontamab Brengitecan in Recurrent or Metastatic Esophageal Squamous Cell Carcinoma: The PANKU-Esophagus01 Randomized Clinical Trial

Importance Effective therapy remains lacking for patients with advanced esophageal squamous cell carcinoma (ESCC) whose disease progressed after standard treatment. Izalontamab brengitecan, an epidermal growth factor receptor and human epidermal growth factor receptor 3 bispecific antibody-drug conjugate with a topoisomerase I inhibitor, Ed-04, has shown clinical activity in ESCC in a phase 1b study. Objective To evaluate the efficacy and safety of izalontamab brengitecan compared with chemotherapy in patients with advanced ESCC who progressed after first-line programmed cell death 1 protein (PD-1)/programmed cell death 1 ligand 1 (PD-L1) inhibitor plus platinum-containing chemotherapy. Design, Setting, and Participants This phase 3, open-label, randomized clinical trial was conducted across 80 hospitals in China. Patients with recurrent or metastatic ESCC that had progressed with first-line PD-1/PD-L1 inhibitor plus platinum-containing chemotherapy were enrolled. Between March 19, 2024, and August 1, 2025 (final follow-up, October 17, 2025), a total of 704 patients were screened, and 497 were enrolled and randomized. Interventions Patients were randomly assigned (1:1) to receive either izalontamab brengitecan (n = 249; 2.5 mg/kg on days 1 and 8 every 3 weeks) or physician-selected chemotherapy (n = 248; irinotecan, paclitaxel, or docetaxel) every 3 weeks. Main Outcomes and Measures The dual primary end points were progression-free survival (PFS) assessed by blinded independent central review according to Response Evaluation Criteria in Solid Tumors version 1.1 and overall survival (OS). Results Of 497 patients who underwent randomization (median age, 61.0 years [range, 34-76]; 448 male patients [90.1%]), 493 received study treatment. At this interim analysis, izalontamab brengitecan demonstrated statistically significant improvement in both PFS and OS. Median PFS by blinded independent central review was 4.17 months (95% CI, 3.61-4.53 months) with izalontamab brengitecan vs 1.97 months (95% CI, 1.61-2.73 months) with chemotherapy (hazard ratio, 0.50; 95% CI, 0.40-0.63; log-rank P < .001). Median OS was 9.79 months (95% CI, 7.89-11.01 months) with izalontamab brengitecan vs 7.20 months (95% CI, 6.18-7.82 months) with chemotherapy (hazard ratio, 0.63; 95% CI, 0.48-0.82; log-rank P < .001). Grade 3 or higher treatment-related adverse events occurred in 212 of 249 patients (85.1%) with izalontamab brengitecan and 147 of 248 patients (59.3%) with chemotherapy and were predominantly hematologic. Conclusions and Relevance Izalontamab brengitecan significantly improved PFS and OS vs chemotherapy in patients with recurrent or metastatic ESCC whose disease had progressed after first-line treatment. These findings support izalontamab brengitecan as a new second-line treatment for this population in China. Trial Registration ClinicalTrials.gov Identifier: NCT06304974