A bispecific antibody–drug conjugate targeting EGFR and HER3 in metastatic esophageal squamous cell carcinoma: a phase 1b trial
Chang Liu, Dan Liu, Yinghua Ji, Meili Sun, Shegan Gao, Xuelei Ma, Diansheng Zhong, Ji Zhu, Yanshuo Cao, Changsong Qi, Miao Zhang, Panpan Zhang, Ran Xue, Zhi Peng, Jun Zhou, Sai Ge, Ming‐De Lu, Jiajia Yuan, Yakun Wang, Zhenghang Wang, Jian Li, Xiaotian Zhang, Yi Zhu, Hong Zhu, Sa Xiao, Jifang Gong, Lin Shen, Zhihao Lu
Abstract
Research on patients with advanced esophageal squamous cell carcinoma (ESCC) who have progressed on immunotherapy remains limited. BL-B01D1 is a first-in-class antibody–drug conjugate consisting of an EGFR–HER3 bispecific antibody bound to a topoisomerase I inhibitor (Ed-04) payload via a cleavable linker. Here, we present safety and efficacy data from a phase 1 study of BL-B01D1, in 82 patients previously treated for ESCC. The primary endpoint was the recommended phase 2 dose. Administered doses were 2.0 (n = 22) and 2.5 (n = 60) mg kg−1 D1D8 infusion every 3 weeks (Q3W). The confirmed objective response rate (cORR) was 29.3% (24 of 82) in all patients and 32.9% (24 of 73) among evaluable patients. For patients dosed at 2.5 mg kg−1, cORR was 39.6% (21 of 53) and disease control rate was 79.2% (42 of 53). In the 2.0 mg kg−1 group, cORR was 15.0% (3 of 20), and the disease control rate was 50.0% (10 of 20). The phase 2 dose was established at 2.5 mg kg−1 D1D8 Q3W. The incidence of G3 treatment-related adverse events at 2.5 mg kg−1 was 63.3%; most common adverse events were anemia (28.3%), leukopenia and thrombocytopenia (18.3%, each), and neutropenia (16.7%). Two cases of ≥G3 interstitial lung disease were observed. Overall, BL-B01D1 demonstrated promising efficacy and manageable safety in patients with metastatic ESCC. A further phase 3 clinical trial has already been initiated. ClinicalTrials.gov registration: NCT05262491 . In the dose-expansion cohort of this phase 1b trial, the EGFR×HER3 bispecific antibody–drug conjugate BL-B01D1 given to patients with metastatic esophageal squamous cell carcinoma led to encouraging clinical response rates, which need to be confirmed in larger efficacy trials.