Nature Medicine | 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 effects. The research provides new therapeutic options for patients with advanced ESCC.

 

Literature Overview
This article, '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 targeting EGFR and HER3, in patients with metastatic ESCC. The study reveals that BL-B01D1 at the recommended dose of 2.5 mg kg⁻¹ demonstrates favorable objective response rates and disease control rates 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 moderate efficacy in other cancers, their effectiveness in ESCC remains limited. Therefore, developing dual-targeting agents against 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 trials.

 

 

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 as a monotherapy for advanced or metastatic gastrointestinal tumors. In the phase 1b portion, 82 previously treated ESCC patients were enrolled, with 22 receiving a dose of 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 assessments such as clinical objective response rate (cORR) and disease control rate (DCR). Safety analysis was based on adverse event (AE) data, and efficacy was evaluated using 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%).
• The 2.5 mg kg⁻¹ group experienced a 63.3% incidence of grade 3-4 treatment-related adverse events (TRAEs), with major AEs 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 cases at 2.5 mg kg⁻¹ that resolved with steroid treatment and one case at 2.0 mg kg⁻¹ resulting in ILD-related death due to treatment refusal.
• Pharmacokinetic analysis showed that total antibody, ADC, and toxin (Ed04) maximum concentration (Cmax) increased with higher doses, with half-life (T1/2) ranging from 19.9 to 21.9 hours at 2.0–2.5 mg kg⁻¹ doses.
• EGFR and HER3 expression analysis revealed that nearly all patient tumor tissues expressed both targets, though expression levels showed no clear correlation with antitumor response.

Research Significance and Prospects
BL-B01D1 demonstrates robust antitumor activity through dual EGFR and HER3 blockade, particularly in ESCC patients with immunotherapy resistance. The study establishes 2.5 mg kg⁻¹ as the recommended dose and has initiated a phase 3 clinical trial (NCT06304974) to further validate efficacy and safety. Future research should explore 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, demonstrating its favorable antitumor activity and manageable safety profile at a dose of 2.5 mg kg⁻¹. While the drug showed promising efficacy in resistant patients, further investigation of biomarkers and long-term safety remains necessary. The research provides preliminary but critical clinical evidence for EGFR and HER3-targeted therapy 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.