Antibody–drug conjugates: Smart chemotherapy delivery across tumor histologies

As distinct cancer biomarkers have been discovered in recent years, a need to reclassify tumors by more than their histology has been proposed, and therapies are now tailored to treat cancers based on specific molecular aberrations and immunologic markers. In fact, multiple histology-agnostic therapies are currently adopted in clinical practice for treating patients regardless of their tumor site of origin. In parallel with this new model for drug development, in the past few years, several novel antibody–drug conjugates (ADCs) have been approved to treat solid tumors, benefiting from engineering improvements in the conjugation process and the introduction of novel linkers and payloads. With the recognition that numerous surface targets are expressed across various cancer histologies, alongside the remarkable activity of modern ADCs, this drug class has been increasingly evaluated as suitable for a histology-agnostic expansion of indication. For illustration, the anti-HER2 ADC trastuzumab deruxtecan has demonstrated compelling activity in HER2-overexpressing breast, gastric, colorectal, and lung cancer. Examples of additional novel and potentially histology-agnostic ADC targets include trophoblast cell-surface antigen 2 (Trop-2) and nectin-4, among others. In the current review article, the authors summarize the current approvals of ADCs by the US Food and Drug Administration focusing on solid tumors and discuss the challenges and opportunities posed by the multihistological expansion of ADCs.