Most approved ADCs for breast cancer utilize a topoisomerase-1 inhibitor payload. This common mechanism raises a critical question about cross-resistance, making the sequencing of these agents a significant clinical challenge without clear data to guide decisions on their subsequent use after progression.
Patients with triple-negative breast cancer (TNBC) who recur after standard neoadjuvant chemo-immunotherapy (per the KEYNOTE-522 trial) represent a new, challenging population. There is virtually no clinical data to guide treatment, particularly on whether re-challenging with immunotherapy alongside an ADC is effective.
For metastatic TNBC patients with both a germline BRCA mutation and PD-L1 positivity, experts favor initiating treatment with an ADC-immunotherapy combination. The rationale is that while PARP inhibitors are superior to chemo, there is no evidence they outperform a highly effective ADC, making the combo the preferred upfront choice.
Experts are more cautious about sequencing ADCs back-to-back in triple-negative breast cancer (TNBC) compared to less aggressive subtypes. A sobering 50% of TNBC patients do not receive treatment beyond the first line, making it critical to use the most effective therapy upfront rather than saving options for later.
With two newly approved, effective ADCs (Sacituzumab govitecan and Datopotamab deruxtecan) for first-line PD-L1 negative TNBC, clinicians face a state of "equipoise." Lacking head-to-head data, treatment selection hinges on physician experience and patient factors like side effect tolerance and schedule, not superior efficacy.