Metastatic Triple-Negative Breast Cancer: First-Line Antibody-Drug Conjugates
In this article
Treatment of mTNBC, long dominated by chemotherapy, is changing dramatically. Three major Phase 3 trials presented in 2025 show antibody-drug conjugates (ADCs) beginning to replace chemotherapy in first-line treatment and establish a new standard.
Key Findings
- PD-L1-Positive Patients: Sacituzumab govitecan (SG) + Pembrolizumab significantly improved progression-free survival (PFS) over standard chemotherapy + pembrolizumab in ASCENT-04.
- Patients Ineligible for Immunotherapy: Both SG (ASCENT-03) and Datopotamab deruxtecan (Dato-DXd) (TROPION-Breast02) produced superior PFS compared with chemotherapy.
- Clinical Implication: TROP2-targeted ADCs are becoming a new first-line mTNBC standard by replacing chemotherapy.
1. How Has the Treatment Paradigm Changed?
Before immune checkpoint inhibitors (ICIs), chemotherapy was standard first-line mTNBC treatment, with median overall survival around 15.5 months. KEYNOTE-355 established adding pembrolizumab for PD-L1-positive disease.
ADCs have changed the landscape. TROP2-targeted agents such as Sacituzumab Govitecan (SG) and Datopotamab Deruxtecan (Dato-DXd) deliver cytotoxic payloads directly to tumor cells. Previously used in second and later lines, they now aim to replace first-line chemotherapy.
2. Summary of the Three Major Trials
The table summarizes these paradigm-changing trials, their populations and results:
*PFS: Progression-Free Survival; HR: Hazard Ratio; SG: Sacituzumab Govitecan; Dato-DXd: Datopotamab Deruxtecan.
3. Safety and Side Effect Management
Although more effective than chemotherapy, ADCs have distinctive side effects requiring careful management. No new safety signals appeared, but known effects include:
Sacituzumab Govitecan (SG)
- Neutropenia: The commonest severe adverse event (67%). The FDA recommends primary G-CSF prophylaxis for at-risk patients.
- Others: Nausea and alopecia (hair loss).
Datopotamab Deruxtecan (Dato-DXd)
- Stomatitis: Mouth sores (57%) are common but usually mild.
- Ocular Toxicity: Dry eyes (24%). Preventive eye drops and avoiding contact lenses are recommended.
4. Conclusion: Which Treatment for Which Patient?
These trials challenge chemotherapy's dominance in mTNBC. For PD-L1-positive patients, SG + Pembrolizumab is moving toward a new standard. SG and Dato-DXd are strong options for patients ineligible for immunotherapy. Selection should consider patient preferences, side effects, including neutropenia versus stomatitis/ocular toxicity, and treatment schedules.
References
- Tolaney SM, et al. J Clin Oncol. 2025;43:17s (ASCENT-04).
- Cortés J, et al. ESMO Congress 2025; LBA20 (ASCENT-03).
- Dent R, et al. ESMO Congress 2025; LBA21 (TROPION-Breast02).
- McCann K. "Using Antibody-Drug Conjugates in the Frontline Setting: Treatment Updates in Metastatic Triple-Negative Breast Cancer."
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