Payload Diversification Overcomes Resistance and Guides Sequential Antibody–Drug Conjugate Therapy in Breast Cancer

Cross-resistance to sequential ADCs is primarily driven by shared payload mechanisms rather than loss of the target. Our data also suggest that the clinical benefit of sequential Topo1-based ADCs may be reduced following disease progression on a Topo1-based ADC, likely due to these shared resistance pathways. Importantly, switching to ADCs with non-cross-resistant payload classes may offer a more effective approach to guide ADC sequencing in patients with metastatic breast cancer, supporting payload diversification as a clinically actionable strategy.