z-bio 2025-11-18 3441

　　On October 19, 2025, Sun Yat-sen University Zhang Zhang's team published an online study in Lancet (IF=88.5) titled "Izalontamab brengitecan, an EGFR and HER3 bispecific antibody–drug conjugate, versus chemotherapy in heavily pretreated recurrent or metastatic nasopharyngeal carcinoma: a multicentre, randomized, open-label, phase 3 study in China" research paper, which reports the results of a phase 3 clinical trial of Izalontamab brengitecan (Iza-bren), an EGFR and HER3 bispecific antibody-drug conjugate, combined with chemotherapy in heavily pretreated recurrent or metastatic nasopharyngeal carcinoma. The study results showed that compared with chemotherapy, Iza-bren significantly improved the ORR in patients with heavily pretreated recurrent or metastatic nasopharyngeal carcinoma, with a controllable safety profile.

　　This is the world's first randomized phase 3 clinical study conducted in patients with advanced nasopharyngeal carcinoma who have failed multiple lines of treatment, and is also the first phase 3 clinical study to prove the clinical benefit of a bispecific ADC. The emergence of Iza-bren is expected to provide a new treatment option for patients with advanced nasopharyngeal cancer, and Iza-bren is expected to become a new standard treatment for previously treated advanced nasopharyngeal cancer.

　　Nasopharyngeal carcinoma is a malignant tumor with unique geographical, etiological and biological characteristics, mainly distributed in Southeast Asia, the Middle East and North Africa. Globally, an estimated 120,416 new cases and 73,476 deaths will be reported in 2022. Radiotherapy or chemoradiotherapy is the main treatment method for early-stage or locally advanced nasopharyngeal cancer, and the 5-year survival rate is about 85%. However, recurrent or metastatic nasopharyngeal carcinoma is a major therapeutic challenge. Although outcomes have improved with the introduction of platinum-based dual chemotherapy and inhibitors of programmed cell death protein 1 (PD-1) and its ligand (PD-L1), a significant proportion of individuals ultimately experience disease progression. For these individuals, there are few treatment options and the prognosis is poor. Conventional salvage chemotherapy often results in low response rates and short duration of benefit, emphasizing the urgent need for more effective and durable treatments.

　　Antibody-drug conjugates (ADCs) are a promising therapeutic class currently being studied in different cancers. Epidermal growth factor receptor (EGFR) is overexpressed in up to 85% of nasopharyngeal carcinoma tumors and is associated with poor prognosis. Izalontamab brengitecan (iza-bren; also known as BL-B01D1) is the first bispecific ADC targeting EGFR and human epidermal growth factor receptor 3 (HER3) conjugated to a novel topoisomerase I inhibitor (Ed-04) payload with a high drug-to-antibody ratio of 8.14. Iza-bren is designed to specifically bind to EGFR or HER3 on the tumor surface and is subsequently internalized via endocytosis. This process ultimately leads to the release of Ed-04 from lysosomes, which induces tumor cell death by hindering DNA replication and RNA synthesis. A previous Phase 1 study showed that iza-bren had encouraging anti-tumor activity in patients with heavily pretreated recurrent or metastatic nasopharyngeal carcinoma, with an observed objective response rate (ORR) of 59.5% (confirmed ORR of 37.8%).

　　Progression-free survival rate (picture from Lancet)

　　This randomized phase 3 clinical trial directly compared the efficacy and safety of iza-bren with chemotherapy in patients with heavily pretreated recurrent or metastatic nasopharyngeal carcinoma. The study showed that the objective response rate was as high as 54.6% in the Iza-bren treatment group, compared with only 27.0% in the chemotherapy group. This means that more than half of patients with refractory advanced nasopharyngeal cancer experience significant tumor shrinkage. Regarding safety, 80% of patients in the Iza-bren treatment group experienced grade 3 or higher treatment-related adverse events, compared with 62% in the chemotherapy group. The main side effects were hematologic toxicities, including anemia (50%), leukopenia (43%), thrombocytopenia (43%), and neutropenia (38%). This is the world's first randomized phase 3 clinical study conducted in patients with advanced nasopharyngeal carcinoma who have failed multiple lines of treatment, and is also the first phase 3 clinical study to demonstrate the clinical benefit of a bispecific ADC. The emergence of Iza-bren is expected to provide a new treatment option for patients with advanced nasopharyngeal cancer, and Iza-bren is expected to become a new standard treatment for previously treated advanced nasopharyngeal cancer.