Izalontamab brengitecan, an EGFR and HER3 bispecific antibody-drug conjugate, versus chemotherapy in heavily pretreated recurrent or metastatic nasopharyngeal carcinoma: a multicentre, randomised, open-label, phase 3 study in China.

[BACKGROUND] People with recurrent or metastatic nasopharyngeal carcinoma that progressed after chemotherapy and programmed cell death protein 1 (PD-1) and its ligand (PD-L1) inhibitors have few treatment options and a poor prognosis. We therefore aimed to investigate the efficacy and safety of the bispecific antibody-drug conjugate izalontamab brengitecan (iza-bren) in heavily pretreated individuals with recurrent or metastatic nasopharyngeal carcinoma.

[METHODS] This multicentre, randomised, open-label, phase 3 study was conducted at 55 hospitals in China. Eligible participants were aged 18-75 years with histologically or cytologically confirmed recurrent or metastatic nasopharyngeal carcinoma that had progressed after at least two lines of systemic chemotherapy including at least one platinum-containing regimen and PD-1 or PD-L1 inhibitors. Participants were randomly assigned (1:1) to receive either iza-bren at 2·5 mg/kg intravenously on days 1 and 8 of each 3-week cycle or chemotherapy. Random assignment was done through an interactive web-based response system, stratified by baseline Eastern Cooperative Oncology Group performance status (0 vs 1), liver metastases, and previous lines of platinum-based chemotherapy (one line vs two or more lines), with a variable block size. The dual primary efficacy endpoints were objective response rate (ORR) assessed by masked independent central review as per Response Evaluation Criteria in Solid Tumours version 1.1 criteria, and overall survival. Progression-free survival, duration of response, and safety were the secondary endpoints. This report is the first planned interim analysis. This trial is registered with ClinicalTrials.gov (NCT06118333) and is ongoing.

[FINDINGS] From Dec 4, 2023, to Feb 21, 2025, 522 patients were screened, of whom 386 were enrolled and randomly assigned to receive either iza-bren (n=191) or chemotherapy (n=195). At a median follow-up of 7·66 months for the iza-bren group and 7·10 months for the chemotherapy group, the ORR by masked independent central review was 54·6% (95% CI 45·2-63·8%) with iza-bren and 27·0% (19·1-36·0%) with chemotherapy (difference 27·9%, 95% CI 15·5-39·4%; p<0·0001). Overall survival data were not mature at data cutoff. Grade 3 or higher treatment-related adverse events occurred in 80% of patients receiving iza-bren and 62% of those receiving chemotherapy. The most common grade 3 or higher treatment-related adverse events in the iza-bren group were haematological, including anaemia (50% vs 10%), decreased white blood cell count (43% vs 44%), decreased platelet count (43% vs 7%), and decreased neutrophil count (38% vs 41%). Non-haematological treatment-related adverse events in the iza-bren group were mostly grade 1 or 2. Serious treatment-related adverse events occurred in 43% of patients receiving iza-bren and 27% of those receiving chemotherapy. Four (2%) treatment-related deaths occurred in the iza-bren group.

[INTERPRETATION] Iza-bren significantly improved the ORR compared with chemotherapy in individuals with heavily pretreated recurrent or metastatic nasopharyngeal carcinoma, with a manageable safety profile. These findings suggest iza-bren might represent a new therapeutic standard for this population. Further analysis will help to fully understand the benefit of this new therapy.

[FUNDING] Baili-Bio (Chengdu) Pharmaceutical.