Sequencing antibody-drug conjugates in metastatic breast cancer: A systematic review

Antibody-drug conjugates (ADCs) have redefined the treatment landscape of metastatic breast cancer (mBC), offering durable responses across all subtypes. As multiple ADCs with similar payloads become available for the same patient over the course of the disease, determining the optimal sequencing strategy has become an urgent need, particularly given concerns about cross-resistance and reduced efficacy.

A literature search identified 1868 citations, of which 23 studies (n = 2934 patients) met the inclusion criteria, encompassing ten full-text publications and 13 abstracts. Data on clinical subtypes, sequencing strategies, efficacy outcomes, and real-world evidence (RWE) were extracted and analyzed.

In HER2-low mBC, initial ADC exposure produced higher response rates and longer PFS than subsequent ADCs, with median PFS declining from 5.1-7.6 months to 2.1-3.1 months and OS from 16.5-22.8 months to 5.6-8.0 months. In HER2-positive disease, clinical activity was partially preserved with the second ADC, particularly when T-DXd followed T-DM1, with sustained PFS. TNBC and HR+/HER2- cohorts showed a consistent decline in efficacy with second ADC exposure (PFS 2.5-3.1 months). Evidence indicates that switching ADC payloads mitigates cross-resistance, with improved ORR and PFS2 compared to same-payload sequences. Bridging chemotherapy between ADCs did not compromise efficacy and, in some cohorts, yielded a longer PFS than direct sequencing with another ADC with the same payload.

Emerging evidence indicates that sequential ADC use can be effective despite some cross-resistance, especially when distinct payload mechanisms are employed. Clinical use should consider payload type, timing, and breast cancer subtype, but toxicities remain critical for decision-making. Research providing insights into resistance mechanisms and biomarkers is needed for personalized approaches.