Sequencing antibody-drug conjugates in metastatic cancer (Review)

The therapeutic landscape of metastatic solid tumors has been fundamentally reshaped by the rapid development and regulatory approval of multiple antibody-drug conjugates (ADCs) across breast, urothelial and lung cancers. As these targeted agents move into earlier lines of therapy, patients are experiencing prolonged survival and are increasingly becoming candidates for sequential ADC treatment. This evolution introduces a critical and complex clinical dilemma: The question of whether a second 'Trojan Horse' remains effective following the failure of a prior ADC, or whether shared resistance mechanisms undermine sequential efficacy. While the expanding ADC armamentarium provides new therapeutic opportunities, emerging real-world data suggest that sequential use is frequently complicated by cross-resistance, particularly when successive agents employ similar cytotoxic payloads such as topoisomerase I inhibitors. The present narrative review critically discusses the biological basis of resistance in the sequential ADC setting. The present review distinguishes between target-mediated resistance, in which antigen downregulation limits drug delivery, and payload-mediated resistance, in which intracellular mechanisms neutralize the cytotoxic component. By synthesizing clinical evidence from metastatic breast and urothelial carcinoma cohorts, the present review highlights the diminished efficacy often observed when changing targets without altering payload class. Therefore, a pragmatic sequencing framework emphasizing 'payload swapping' is proposed, prioritizing a change in cytotoxic mechanisms over antigen switching to optimize patient outcomes and minimize futile toxicity in this rapidly evolving therapeutic era.