Nature Medicine | Application of a Bispecific Antibody-Drug Targeting EGFR and HER3 in Metastatic Esophageal Squamous Cell Carcinoma

This study is the first to evaluate the safety and efficacy of the bispecific antibody-drug conjugate BL-B01D1 targeting EGFR and HER3 in patients with metastatic esophageal squamous cell carcinoma (ESCC), demonstrating robust antitumor activity and manageable adverse reactions. The research provides a novel therapeutic option for advanced ESCC patients.

 

Literature Overview
The article, titled 'A bispecific antibody–drug conjugate targeting EGFR and HER3 in metastatic esophageal squamous cell carcinoma: a phase 1b trial', published in Nature Medicine, reviews and summarizes the clinical application, safety, and preliminary efficacy of BL-B01D1, a bispecific antibody-drug conjugate targeting EGFR and HER3, in metastatic esophageal squamous cell carcinoma (ESCC) patients. The article highlights that BL-B01D1 demonstrated favorable objective response rate and disease control rate at the recommended dose of 2.5 mg kg⁻¹ in ESCC patients previously treated with immunotherapy.

Background Knowledge
Esophageal squamous cell carcinoma (ESCC) is the most common type of esophageal cancer globally, with limited treatment options, particularly after immunotherapy resistance develops. EGFR and HER3 are members of the epidermal growth factor receptor family, whose co-expression is associated with tumor progression and drug resistance. While EGFR-targeted therapies have shown some efficacy in other cancers, their effectiveness in ESCC remains limited. Therefore, developing agents that simultaneously target both EGFR and HER3 has become a research hotspot. This study evaluates the recommended phase 2 dose, safety, and efficacy of BL-B01D1, providing direction for future investigations.

 

 

Research Methods and Experiments
The BL-B01D1-103 study (ClinicalTrials.gov: NCT05262491) is an open-label, multicenter, phase 1a/1b clinical trial assessing monotherapy with BL-B01D1 in advanced or metastatic gastrointestinal tumors. In phase 1b, 82 previously treated ESCC patients were enrolled, with 22 receiving the 2.0 mg kg⁻¹ dose and 60 receiving the 2.5 mg kg⁻¹ dose. The primary endpoint was the recommended phase 2 dose (RP2D), while secondary endpoints included safety, tolerability, and efficacy evaluation, such as confirmed objective response rate (cORR) and disease control rate (DCR). Safety analysis was based on adverse event (AE) data, and efficacy assessment followed RECIST v1.1 criteria.

Key Conclusions and Perspectives

• At the recommended dose of 2.5 mg kg⁻¹, cORR was 39.6% and DCR was 79.2%, significantly higher than the 2.0 mg kg⁻¹ group (cORR 15.0%, DCR 50.0%).
• Grade 3–4 treatment-related adverse events (TRAEs) occurred in 63.3% of the 2.5 mg kg⁻¹ group, with primary events including anemia (28.3%), leukopenia (18.3%), thrombocytopenia (18.3%), and neutropenia (16.7%).
• Three patients (3.7%) developed interstitial lung disease (ILD), including two receiving 2.5 mg kg⁻¹ who recovered after steroid treatment, and one receiving 2.0 mg kg⁻¹ who refused treatment and died from ILD-related complications.
• Pharmacokinetic analysis revealed that the maximum concentrations (Cmax) of total antibody, ADC, and toxin (Ed04) increased with dose, with half-lives (T1/2) ranging from 19.9 to 21.9 hours at 2.0–2.5 mg kg⁻¹ doses.
• Expression analysis of EGFR and HER3 demonstrated that nearly all patients' tumor tissues expressed both targets, though expression levels did not correlate with antitumor responses.

Research Significance and Prospects
BL-B01D1 demonstrates significant antitumor activity through dual targeting of EGFR and HER3, particularly in immunotherapy-resistant ESCC patients. The study supports 2.5 mg kg⁻¹ as the RP2D and a phase 3 trial (NCT06304974) has commenced to further validate its efficacy and safety. Future studies may focus on identifying more effective biomarkers to optimize patient selection and enhance therapeutic outcomes.

 

 

Conclusion
This study evaluated the safety and efficacy of BL-B01D1 in metastatic ESCC patients, showing robust antitumor activity and manageable safety at the 2.5 mg kg⁻¹ dose. The study highlights the need for further investigations into biomarkers and long-term safety. It provides preliminary yet critical clinical evidence for EGFR and HER3-targeted therapies in ESCC, laying the foundation for subsequent precision treatment strategies.

 

Chang Liu, Dan Liu, Yinghua Ji, Lin Shen, and Zhihao Lu. A bispecific antibody–drug conjugate targeting EGFR and HER3 in metastatic esophageal squamous cell carcinoma: a phase 1b trial. Nature Medicine.