Nature Medicine | A Bispecific Antibody–Drug Conjugate Targeting EGFR and HER3 Demonstrates Promising Efficacy in Metastatic Esophageal Squamous Cell Carcinoma

This study represents the first clinical evaluation of BL-B01D1, a bispecific antibody–drug conjugate targeting EGFR and HER3, in patients with metastatic esophageal squamous cell carcinoma (ESCC). The research demonstrates significant antitumor activity and manageable safety profiles, offering a novel therapeutic strategy for advanced ESCC patients.

 

Literature Overview
This 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 the clinical application, safety, and preliminary efficacy of BL-B01D1 in metastatic ESCC patients. It highlights that BL-B01D1 at the recommended dose of 2.5 mg kg⁻¹ exhibits robust objective response rate and disease control rate in ESCC patients who previously received immunotherapy.

Background Knowledge
Esophageal squamous cell carcinoma (ESCC) is the most common global subtype of esophageal cancer, with limited treatment options, particularly after immune therapy resistance develops. EGFR and HER3, members of the epidermal growth factor receptor family, are co-expressed in tumors and associated with oncogenesis and drug resistance. While EGFR-targeted therapies show efficacy in other cancers, their benefits in ESCC remain modest. Developing agents that simultaneously target EGFR and HER3 has thus become a research priority. This study evaluates the recommended phase 2 dose, safety, and efficacy of BL-B01D1, providing critical insights 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 BL-B01D1 monotherapy in advanced or metastatic gastrointestinal tumors. In phase 1b, 82 previously treated ESCC patients were enrolled, with 22 receiving 2.0 mg kg⁻¹ and 60 receiving 2.5 mg kg⁻¹. The primary endpoint was the recommended phase 2 dose (RP2D), while secondary endpoints included safety, tolerability, and efficacy metrics such as clinical objective response rate (cORR) and disease control rate (DCR). Safety was analyzed using adverse event (AE) data, and efficacy was evaluated per RECIST v1.1 criteria.

Key Conclusions and Perspectives

• At the recommended dose of 2.5 mg kg⁻¹, cORR reached 39.6% and DCR reached 79.2%, significantly outperforming the 2.0 mg kg⁻¹ cohort (cORR 15.0%, DCR 50.0%).
• The 2.5 mg kg⁻¹ cohort reported a 63.3% incidence of grade 3-4 treatment-related adverse events (TRAEs), including anemia (28.3%), leukopenia (18.3%), thrombocytopenia (18.3%), and neutropenia (16.7%).
• Three patients (3.7%) developed interstitial lung disease (ILD), with two at 2.5 mg kg⁻¹ resolving after steroid treatment and one at 2.0 mg kg⁻¹ resulting in ILD-related death due to treatment refusal.
• Pharmacokinetic analysis revealed that maximum concentration (Cmax) of total antibody, ADC, and toxin (Ed04) increased with dose, with half-life (T1/2) ranging from 19.9–21.9 hours at 2.0–2.5 mg kg⁻¹.
• EGFR and HER3 expression analysis showed co-expression in nearly all patient tumors, though expression levels did not correlate with antitumor response.

Research Significance and Prospects
BL-B01D1 demonstrates robust antitumor activity in ESCC patients with EGFR and HER3 co-expression, particularly those with immunotherapy resistance. The study confirms 2.5 mg kg⁻¹ as the RP2D and has initiated a phase 3 trial (NCT06304974) to validate these findings. Future research should identify predictive biomarkers to refine patient selection and enhance therapeutic outcomes.

 

 

Conclusion
This study establishes BL-B01D1 as a promising therapeutic agent for metastatic ESCC, showing favorable antitumor activity and manageable safety at 2.5 mg kg⁻¹. While efficacy is observed in resistant populations, further investigations into biomarker identification and long-term safety are warranted. These findings provide foundational clinical evidence for dual EGFR/HER3-targeted therapy in ESCC, guiding the development of precision oncology 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.