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.