Antibody-drug conjugates in metastatic breast cancer: sequencing, combinations and resistances

Significant advancements have been made in treating metastatic breast cancer (MBC) with antibody drug conjugates (ADCs). However, due to the development of resistance, patients experience disease progression. The aim of this review is to summarize current evidence on ADCs sequencing strategies and combination approaches in the treatment of MBC.

Concerning HER2 positive MBC, current evidence on the optimal ADC-sequencing is primarily about T-DXd, which demonstrated therapeutic value when used post-T-DM1. Conversely, data are limited about the reverse sequence. Similarly, in HER2-negative MBC, recent studies evaluated the sequential use of Sacituzumab Govitecan and T-DXd, which was associated with poor responses. Retrospective analyses have not demonstrated an optimal sequencing strategy for ADCs, and it is still very unclear whether switching the payload or targeting a different antigen may represent the best approach. Combinations may better overcome ADC resistance: interesting data associating immunotherapy or tyrosine kinase inhibitors to ADCs appear promising, albeit data are still immature.

In MBC, ADCs have expanded treatment options but their sequential use requires further study. Evidence suggests that sequencing ADCs with similar payloads is ineffective, though current data are inconclusive. More research is needed to optimize treatment strategies, including potential combination therapies.