Multicenter phase 3 trial of izalontamab brengitecan for recurrent or metastatic esophageal squamous cell carcinoma

There is no effective therapy for patients with advanced esophageal squamous cell carcinoma (ESCC) with progression after standard treatment. Izalontamab brengitecan (iza-bren) is a EGFR-HER3 targeted bispecific antibody-drug conjugate with a topoisomerase I inhibitor payload. The phase 3 PANKU-Esophagus01 trial, at 80 centers in China, evaluated iza-bren compared with chemotherapy among patients with advanced ESCC and progression after first-line PD-(L)1 inhibitor plus platinum-containing chemotherapy. Patients were randomized 1:1 to iza-bren (n=249; 2.5 mg/kg on days 1 and 8 every 3 weeks) or physician-selected chemotherapy every 3 weeks (n=248; irinotecan, paclitaxel, or docetaxel). Treatment continued until disease progression or unacceptable toxicity. The dual primary endpoints were progression-free survival (PFS) assessed by blinded independent cental review and overall survival (OS). At the now-reported interim analysis, iza-bren demonstrated statistically significant improvement in both PFS and OS. Median PFS was 4.17 months (95% CI 3.61-4.53) with iza-bren versus 1.97 months (1.61-2.73) with chemotherapy (HR 0.50; p<0.001) whereas median OS was 9.79 months (7.89-11.01) versus 7.20 months (6.18-7.82) (HR 0.63: p<0.001). Grade 3 or higher treatment-related adverse events occurred in 85.1% of patients with iza-bren and 59.3% of patients with chemotherapy. The authors conclude that iza-bren significantly improved PFS and OS versus chemotherapy in patients with recurrent or metastatic ESCC whose disease had progressed after first-line treatment.