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Application and Progress of Antibody-Drug Conjugates (ADCs) in the Treatment of Metastatic Triple-Negative Breast
Banghong Xie1,2, Chao Chen3, Haolin Cai1,2
1Department of Medical Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, Fujian, China.
Abstract:
Metastatic triple-negative breast cancer (TNBC) lacks actionable targets, and chemotherapy yields median progression-free survival (mPFS) of 4.6-9.7 months and median overall survival (mOS) of 12.6-26.3 months. Immune checkpoint inhibitors (ICIs) and poly (ADP-ribose) polymerase (PARP) inhibitors only help subsets (objective response rate [ORR] of ~ 5% and ~ 12%, respectively). Antibody-drug conjugates (ADCs) have emerged as a leading therapeutic strategy: sacituzumab govitecan extended mPFS to 5.6 months (ASCENT trial), SKB264 to 6.7 months, and datopotamab deruxtecan achieved an ORR of 79%. In Human epidermal growth factor receptor 2 (HER2)-low TNBC, trastuzumab deruxtecan prolonged OS to 18.2 months, while disitamab vedotin and SHR-A1811 achieved ORRs of 26% and 60%, respectively. ADCs targeting Human epidermal growth factor receptor 3 (HER3)-, Nectin-4-, LIV-1- and folate receptor α (FRα) showed responses in 22%-54% of cases. Resistance can arise via antigen loss, endocytic defects, lysosomal failure, and efflux pumps. Bispecific ADCs, linker optimization, and combination regimens (ICI, PARPi) are under investigation. Future efforts will focus on targeting epidermal growth factor receptor (EGFR) and FRα and on developing multimodal immunovascular strategies to sustain clinical benefit.
Insights
Metastatic triple-negative breast cancer (TNBC) treatments are improving with antibody-drug conjugates (ADCs). These targeted therapies show promising response rates and survival benefits, offering new hope for patients with limited options.
Area of Science:
- Oncology
- Medical Chemistry
- Immunotherapy
Background:
- Metastatic triple-negative breast cancer (TNBC) presents limited therapeutic targets, with chemotherapy offering modest survival benefits.
- Current treatments like immune checkpoint inhibitors (ICIs) and poly (ADP-ribose) polymerase (PARP) inhibitors benefit only specific patient subsets.
Purpose of the Study:
- To review the emerging role and efficacy of antibody-drug conjugates (ADCs) in treating metastatic triple-negative breast cancer (TNBC).
- To explore novel targets and resistance mechanisms for ADCs in TNBC treatment.
Main Methods:
- Review of clinical trial data for various ADCs in TNBC, including sacituzumab govitecan, SKB264, datopotamab deruxtecan, and trastuzumab deruxtecan.
- Analysis of response rates (ORR) and survival outcomes (mPFS, mOS) for ADCs targeting specific receptors like HER2, HER3, Nectin-4, LIV-1, and FRα.
- Examination of mechanisms of resistance to ADC therapy and investigation of novel therapeutic strategies.
Main Results:
- ADCs demonstrate significant improvements in progression-free survival and overall survival compared to traditional chemotherapy.
- Specific ADCs like datopotamab deruxtecan and trastuzumab deruxtecan have shown high objective response rates (ORR) in TNBC and HER2-low TNBC populations.
- ADCs targeting various receptors (HER3, Nectin-4, LIV-1, FRα) show response rates between 22%-54%.
Conclusions:
- Antibody-drug conjugates (ADCs) represent a leading and highly effective therapeutic strategy for metastatic triple-negative breast cancer (TNBC).
- Understanding resistance mechanisms is crucial for optimizing ADC therapy, with bispecific ADCs and combination regimens showing potential.
- Future research will focus on novel targets like EGFR and FRα, and multimodal immunovascular strategies to enhance long-term clinical benefits.
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