Trastuzumab deruxtecan in non-breast solid tumors: Expanding indications, efficacy, and future directions

HER2 alterations occur across multiple malignancies beyond breast cancer, including gastric, non-small-cell lung, colorectal, gynecologic, salivary gland, biliary tract, and urothelial cancers. Trastuzumab deruxtecan (T-DXd), a next-generation antibody-drug conjugate, has transformed outcomes through its high drug-to-antibody ratio, potent topoisomerase I inhibitor payload, and membrane-permeable design enabling a bystander effect.

We reviewed clinical and translational evidence for T-DXd in non-breast solid tumors, focusing on efficacy, safety, biomarkers, and resistance mechanisms. Key data were derived from the DESTINY trial program, basket studies, and recent regulatory submissions.

Across tumor types, T-DXd has demonstrated clinically meaningful response rates: ∼55 % in HER2-mutant NSCLC, 42-51 % in gastric cancer, 37-45 % in colorectal cancer, 57 % in endometrial cancer, and ∼60 % in salivary duct carcinoma. Durable responses have also been observed in biliary and urothelial cancers. The most frequent adverse events are gastrointestinal and hematologic, while interstitial lung disease remains the most significant toxicity, occurring in ∼10-15 % of patients, with rare fatal cases. Predictive biomarkers vary by histology: HER2 mutation is most relevant in NSCLC, whereas amplification and overexpression define benefit in gastrointestinal and gynecologic malignancies. Resistance mechanisms include HER2 downregulation, bypass signaling activation, and impaired payload release.

T-DXd has emerged as a transformative therapy across HER2-driven malignancies, leading to histology-specific and tissue-agnostic approvals. Vigilant ILD monitoring is essential, and further research is warranted to refine biomarkers, address resistance, and explore rational drug combinations. T-DXd exemplifies the paradigm shift of antibody-drug conjugates toward pan-cancer precision oncology.