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

This study represents the first evaluation of the bispecific antibody-drug conjugate BL-B01D1 targeting EGFR and HER3 in metastatic esophageal squamous cell carcinoma (ESCC) patients, demonstrating robust antitumor activity and manageable adverse reactions. The research establishes a novel therapeutic option 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 targeting EGFR and HER3 in metastatic ESCC patients. The study demonstrates that BL-B01D1 at the recommended dose of 2.5 mg kg⁻¹ achieves favorable objective response rates and disease control rates in immunotherapy-pretreated ESCC patients.

Background Knowledge
Esophageal squamous cell carcinoma (ESCC) is the most prevalent global subtype of esophageal cancer, with limited treatment options particularly after immunotherapy resistance develops. EGFR and HER3, members of the epidermal growth factor receptor family, are co-expressed in tumor cells and associated with carcinogenesis and drug resistance. While EGFR-targeted therapies show efficacy in other cancers, their effectiveness in ESCC remains limited. Developing agents that simultaneously target both EGFR and HER3 has therefore become a research priority. This study evaluates BL-B01D1's recommended phase 2 dose, safety profile, and efficacy to guide future research.

 

 

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 for advanced or metastatic gastrointestinal tumors. In phase 1b, 82 previously treated ESCC patients were enrolled: 22 received 2.0 mg kg⁻¹ and 60 received 2.5 mg kg⁻¹. Primary endpoint was determination of recommended phase 2 dose (RP2D), with secondary endpoints including safety, tolerability, and efficacy evaluation through clinical objective response rate (cORR) and disease control rate (DCR). Safety analysis was based on adverse event (AE) data, while efficacy assessment followed RECIST v1.1 criteria.

Key Conclusions and Perspectives

• At the recommended dose of 2.5 mg kg⁻¹, cORR reached 39.6% and DCR achieved 79.2%, significantly outperforming the 2.0 mg kg⁻¹ cohort (cORR 15.0%, DCR 50.0%).
• Grade 3-4 treatment-related adverse events (TRAEs) occurred in 63.3% of patients at 2.5 mg kg⁻¹, with predominant events including anemia (28.3%), leukopenia (18.3%), thrombocytopenia (18.3%), and neutropenia (16.7%).
• Three patients (3.7%) developed interstitial lung disease (ILD): two receiving 2.5 mg kg⁻¹ recovered with steroid treatment, while one 2.0 mg kg⁻¹ patient refused treatment and died from ILD complications.
• Pharmacokinetic analysis revealed that total antibody, ADC, and toxin (Ed04) peak concentrations (Cmax) increased with dosage, with half-lives (T1/2) ranging 19.9–21.9 hours across 2.0–2.5 mg kg⁻¹ doses.
• EGFR and HER3 expression analysis confirmed nearly universal tumor expression of both targets in enrolled patients, though expression levels showed no significant correlation with antitumor responses.

Research Significance and Prospects
BL-B01D1 demonstrates promising antitumor activity through dual EGFR/HER3 blockade, particularly in immunotherapy-resistant ESCC patients. These findings support adoption of 2.5 mg kg⁻¹ as the recommended dose and have initiated phase 3 clinical trials (NCT06304974) for further efficacy and safety validation. Future research should explore more effective biomarkers to optimize patient selection and enhance therapeutic outcomes.

 

 

Conclusion
This study confirms BL-B01D1's safety and efficacy in metastatic ESCC patients, with 2.5 mg kg⁻¹ demonstrating robust antitumor activity and manageable safety profiles. While the drug shows effectiveness in resistant cases, further investigation into biomarkers and long-term safety remains necessary. These findings provide foundational clinical evidence for dual EGFR/HER3 targeting in ESCC treatment, paving the way for future precision medicine 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.