trastuzumab deruxtecan + azenosertib

**Trastuzumab deruxtecan + azenosertib** is an investigational combination therapy pairing trastuzumab deruxtecan (T-DXd, Enhertu), an antibody-drug conjugate (ADC) developed by Daiichi Sankyo and AstraZeneca, with azenosertib (ZN-c3), an oral small molecule WEE1 kinase inhibitor from Zentalis Pharmaceuticals (now with GSK involvement). T-DXd targets **HER2** (human epidermal growth factor receptor 2) via a humanized monoclonal antibody conjugated to a topoisomerase I inhibitor payload (deruxtecan) through a cleavable tetrapeptide-based linker, enabling selective delivery and DNA damage in HER2-expressing tumor cells. Azenosertib selectively inhibits **WEE1** (serine/threonine-protein kinase WEE1), abrogating the G2/M DNA damage checkpoint to sensitize cancer cells to DNA-damaging agents like the T-DXd payload, promoting replication stress and apoptosis. This synergy is being evaluated in a Phase 1 dose-escalation/expansion trial (NCT06364410) for **HER2-expressing/amplified solid tumors**, including gastric/gastroesophageal junction adenocarcinoma and others that are locally advanced, metastatic, or unresectable.[1][4][5]

Brand names

Enhertu + azenosertib