Advancing antibody drug conjugates in gastrointestinal cancers.

Gastrointestinal (GI) cancers account for one fifth of all cancer cases and one third of all cancer related deaths worldwide. Despite this, the number of systemic treatment options for these cancers remains overall low compared to other cancer types. Antibody-drug conjugates (ADCs), which are composed of a cytotoxic payload attached to an antibody via a linker, have emerged as a promising class of drugs for cancer therapy over the last decade, leading to several approvals in solid tumours and haematological malignancies. However, their development has been delayed in GI cancers compared to other frequent cancers. Encouraging clinical activity has been recently reported with ADCs targeting Claudin 18.2, CEACAM5 and MET. Switching from tubulin inhibitor payloads to topoisomerase I inhibitor payloads in the last generation of ADCs seems to increase the overall activity in GI cancers, particularly in adenocarcinomas. This is notably evident for MET and CEACAM5, but seems also true for ADCs targeting other broadly prevalent targets. In this article we review the current landscape of ADCs development in GI cancers, highlight potential development hurdles and discuss emerging solutions to bring this new therapeutic modality to its full potential in GI oncology.