Antibody-drug conjugates (ADCs) have rapidly emerged as one of the most transformative therapeutic agents in modern oncology. Their rational design enables selective drug delivery to tumor cells while limiting systemic exposure, resulting in meaningful clinical benefit across a wide range of malignancies. Technological advances in antibody engineering, linker stability, and payload chemistry have driven a marked expansion of approved ADCs and accelerated their transition from later treatment lines into first-line and potentially curative settings. Despite these advances, tumor heterogeneity, variable antigen expression, impaired internalization, and the emergence of intrinsic and acquired resistance mechanisms frequently limit the durability of response. In parallel, on-target off-tumor toxicities and cumulative treatment-related adverse events pose increasing concerns as ADCs are introduced earlier in the disease course and administered for longer durations. To address these limitations, extensive clinical and translational research efforts have focused on rational combination and sequencing strategies. Combinations with immune checkpoint inhibitors, targeted therapies, and monoclonal antibodies have demonstrated the potential to enhance antitumor activity, overcome resistance, and improve patient outcomes, while requiring careful management of overlapping toxicities. In parallel, sequencing strategies and emerging biomarker-driven approaches are beginning to inform optimal treatment algorithms in settings where multiple ADCs with overlapping targets or payloads are available. Finally, next-generation ADC platforms, including bispecific and dual-payload constructs, are being developed to better address tumor heterogeneity and resistance.
Etessami et al. (2026) studied this question.