This study is the first to evaluate the safety and efficacy of BL-B01D1, a bispecific antibody-drug conjugate targeting EGFR and HER3, in patients with metastatic esophageal squamous cell carcinoma (ESCC). The drug demonstrated promising antitumor activity in patients with prior treatment failure, particularly in the 2.5 mg kg⁻¹ dose group, achieving a confirmed objective response rate (cORR) of 39.6% and a disease control rate (DCR) of 79.2%. Additionally, the drug exhibited manageable safety profiles, with primary adverse events including anemia and leukopenia, providing critical foundations for future research.
Literature Overview
This article, titled 'A bispecific antibody–drug conjugate targeting EGFR and HER3 in metastatic esophageal squamous cell carcinoma: a phase 1b trial' and published in Nature Medicine, reviews clinical trial results of BL-B01D1, a bispecific antibody-drug conjugate targeting EGFR and HER3, in metastatic ESCC patients. The study assessed the drug's safety, tolerability, and antitumor activity in previously treated ESCC patients, establishing the recommended phase II dose (RP2D) of 2.5 mg kg⁻¹ administered on days 1 and 8 every 3 weeks. Results showed robust antitumor activity at this dose with manageable safety profiles, providing critical groundwork for subsequent trials.
Background Knowledge
Esophageal squamous cell carcinoma (ESCC) is the most common esophageal cancer globally, characterized by rapid progression and limited treatment options. While immune checkpoint inhibitors combined with platinum-based chemotherapy have become first-line therapies, most patients eventually develop resistance, and second-line treatments like irinotecan exhibit objective response rates (ORR) below 10%. Developing novel therapeutic strategies is therefore urgent. EGFR and HER3, as key members of the ErbB family, are frequently co-expressed in various gastrointestinal tumors and associated with tumorigenesis and progression. HER3 mediates resistance to EGFR-targeted therapies, suggesting that dual targeting of EGFR and HER3 may overcome resistance mechanisms. BL-B01D1 is a novel antibody-drug conjugate (ADC) comprising an EGFR×HER3 bispecific antibody linked to a cleavable topoisomerase I inhibitor (Ed-04), enabling tumor-targeted delivery of cytotoxic agents while leveraging Fc-region-mediated antibody-dependent cellular cytotoxicity (ADCC). While preliminary studies demonstrate its antitumor activity across multiple solid tumors, this trial represents the first application in ESCC patients. This study aims to validate its safety and efficacy in metastatic ESCC, providing a basis for phase II and III trials.
Research Methods and Experiments
This open-label, multicenter, phase 1b dose-escalation trial (BL-B01D1-103, ClinicalTrials.gov: NCT05262491) enrolled 82 patients with metastatic ESCC who had failed prior therapies. Twenty-two patients received the 2.0 mg kg⁻¹ dose, and 60 received the 2.5 mg kg⁻¹ dose, with intravenous infusions on days 1 and 8 of each 3-week cycle. The primary endpoint was determining the recommended phase II dose (RP2D), while secondary endpoints included safety, objective response rate (ORR), disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Safety analyses included all 82 patients, while efficacy was evaluated in 73 evaluable patients per RECIST v.1.1. Pharmacokinetic (PK) and biomarker analyses explored relationships between drug exposure and efficacy/safety, as well as correlations between EGFR/HER3 expression levels and antitumor responses.
Key Conclusions and Perspectives
Research Significance and Prospects
This study represents the first clinical evaluation of EGFR/HER3 dual-targeting antibody-drug conjugates (ADCs) in metastatic ESCC, confirming efficacy in immunotherapy-resistant patients. The RP2D of 2.5 mg kg⁻¹ (days 1 and 8 every 3 weeks) demonstrated superior efficacy and safety compared to the 2.0 mg kg⁻¹ dose, providing critical data for phase II/III trials. While EGFR/HER3 expression did not directly correlate with outcomes, the dual-targeting mechanism may overcome resistance mechanisms, warranting further investigation. Future studies should validate efficacy and safety in broader populations and identify predictive biomarkers to optimize patient selection. This drug's development also provides a framework for dual-targeting ADCs in other gastrointestinal malignancies, offering broad translational and personalized medicine potential.
Conclusion
BL-B01D1 demonstrated manageable safety and significant antitumor activity in patients with metastatic esophageal squamous cell carcinoma (ESCC), particularly at the recommended phase II dose (2.5 mg kg⁻¹) with a confirmed objective response rate (cORR) of 39.6% and disease control rate (DCR) of 79.2%. While interstitial lung disease (ILD) and hematologic toxicities were observed, most adverse events were manageable and resolved with steroid therapy. This study pioneers the clinical application of dual-specificity ADCs in immunotherapy-resistant ESCC, establishing a foundation for phase II/III trials. Future research will focus on validating efficacy in larger cohorts and identifying biomarkers to refine patient selection. Additionally, this work provides critical insights for dual-targeting ADC development in gastrointestinal oncology, with promising implications for translational medicine and personalized therapies.
