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

Key Points

Payload diversification improves effectiveness against resistance mechanisms, particularly in metastatic breast cancer.
Switching to non-cross-resistant antibody-drug conjugates shows potential for better outcomes after failure of Topo1-based ADCs.
Sequential therapy with Topo1-based ADCs may lead to reduced clinical benefits due to shared resistance pathways.
Diversifying payload classes may offer a clinically actionable strategy to optimize therapy and enhance patient outcomes.

Abstract

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.

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Cite This Study

Rampa et al. (Tue,) studied this question.

synapsesocial.com/papers/69a75a55c6e9836116a20056 https://doi.org/https://doi.org/10.1158/1078-0432.ccr-25-3321

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