Trastuzumab Rezetecan
Trastuzumab Rezetecan
Overview
Trastuzumab rezetecan is a novel HER2-targeted antibody-drug conjugate (ADC) designed to deliver cytotoxic payload selectively to tumor cells overexpressing or amplifying the human epidermal growth factor receptor 2 (HER2), encoded by the Erb-b2 receptor tyrosine kinase 2 (ERBB2) gene. Like other HER2-directed ADCs, trastuzumab rezetecan consists of a trastuzumab-based monoclonal antibody backbone conjugated to a cytotoxic small molecule via a chemical linker, enabling targeted intracellular drug delivery upon receptor-mediated internalization. Its development reflects the broader therapeutic rationale of exploiting HER2 overexpression — a validated oncogenic driver across multiple tumor types including gastric, gastroesophageal junction (GEJ), colorectal, breast, head/neck, melanoma, and prostate tumors — to achieve tumor-selective cytotoxicity while limiting systemic toxicity.
HER2-directed ADCs have emerged as a cornerstone of precision oncology following the clinical success of ado-trastuzumab emtansine (T-DM1) and, more recently, trastuzumab deruxtecan (T-DXd). Trastuzumab rezetecan represents a next-generation entry in this class, distinguished by its specific linker-payload architecture. Its evaluation across HER2-expressing gastrointestinal malignancies positions it within an active area of unmet clinical need, particularly as optimal ADC sequencing strategies and resistance mechanisms in HER2-positive disease remain incompletely defined.
Focus of Latest Publications
Recent publications on trastuzumab rezetecan have focused primarily on its early clinical evaluation as a HER2-targeted antibody-drug conjugate. In a multicenter, open-label phase I trial, the agent was assessed in patients with HER2-expressing advanced gastric or gastroesophageal junction adenocarcinoma and colorectal cancer, reflecting interest in its activity across multiple HER2-expressing solid tumors.
The broader recent literature also places trastuzumab rezetecan in the context of evolving HER2-directed treatment strategies and antibody-drug conjugate development. Several studies examined sequencing, comparative safety, and practical use of HER2-targeting ADCs, including trastuzumab deruxtecan and ado-trastuzumab emtansine, using pharmacovigilance databases and real-world cohorts. These reports addressed unresolved questions about adverse event profiles, prior treatment exposure, and optimal sequencing in HER2-positive metastatic breast cancer and HER2-positive advanced gastric cancer.
Other publications considered trastuzumab deruxtecan in specific clinical settings, including neoadjuvant treatment for high-risk HER2-positive early breast cancer, HER2 reassessment discordance in metastatic breast cancer, and management of interstitial lung disease in a patient with non-small cell lung carcinoma harboring a HER2 exon 20 insertion. One study also evaluated hospital in-use stability of reconstituted trastuzumab deruxtecan, reporting preserved physicochemical and affinity characteristics under the tested conditions for up to 4 weeks. Collectively, these studies underscore the rapid expansion of HER2-directed ADC research and the need for continued clinical characterization of trastuzumab rezetecan alongside related agents.