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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.

Key Publications

  • NEWJan Adverse Event Profiling and Comparative Analysis of HER2-targeting Antibody-drug Conjugates Using Pharmacovigilance Databases. (In vivo (Athens, Greece), 2026, PMID 42379740): "Therefore, we compared the adverse events for trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd) using the Japanese Adverse Drug Event Report (JADER) database and U.S. Food and Drug Administration Adverse Event Reporting System (FAERS)."
  • NEWJun Clinical implications of discordance in HER2 reassessment from HercepTest to 4B5 in metastatic breast cancer. (Breast cancer research and treatment, 2026, PMID 42329461): "HER2-low breast cancer has emerged as a therapeutic category following the DESTINY-Breast04 trial, where trastuzumab deruxtecan (T-DXd) improved survival."
  • Jun "Neoadjuvant trastuzumab deruxtecan for high-risk HER2-positive early breast cancer: Does the evidence support its use as a new standard-of-care?". (European journal of cancer (Oxford, England : 1990), 2026, PMID 42142430): "Recently, positive results from the Destiny Breast 011 (DB11) randomized clinical trial were reported, seemingly supporting T-DXd followed by paclitaxel, trastuzumab, and pertuzumab as a potential new neoadjuvant treatment option for high-risk, HER2-positive early breast cancer (eBC)."
  • May Tumor Microenvironment-Responsive Antibody Fragment-Cleavable PEGylated Drug Conjugates (AFCDC) for Improved Tumor Penetration and Antitumor Efficacy. (Journal of medicinal chemistry, 2026, PMID 42055598): "Under the evaluated regimen, AFCDC demonstrated enhanced activity over T-DXd in the NCI-N87 xenografts."
  • Jun Hospital in-use evaluation of the physical, chemical and affinity stability of the antibody-drug conjugate trastuzumab deruxtecan (Enhertu®). (European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences, 2026, PMID 42009233): "In the case of trastuzumab deruxtecan (Enhertu® or T-DXd), reconstituted vial leftovers are thrown away after 48 h, resulting in considerable economic losses."
  • Jun Antibody-drug conjugate sequencing in HER2-positive metastatic breast cancer: Real-world outcomes of trastuzumab deruxtecan with and without prior T-DM1 exposure. (Breast (Edinburgh, Scotland), 2026, PMID 41980521): "Optimal sequencing of trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd) in HER2 positive metastatic breast cancer (mBC) remains uncertain, and real-world evidence on the impact of prior T-DM1 exposure on subsequent T-DXd outcomes is limited."
  • May Impact of prior immune checkpoint inhibitor on trastuzumab deruxtecan in HER2-positive advanced gastric cancer: exploratory analysis of the EN-DEAVOR study. (Japanese journal of clinical oncology, 2026, PMID 41789591): "However, evidence suggesting an optimal sequence for nivolumab and trastuzumab deruxtecan (T-DXd) treatment is limited."
  • May Trastuzumab Rezetecan in Human Epidermal Growth Factor Receptor 2-Expressing Advanced Gastric Cancer or Gastroesophageal Junction Adenocarcinoma and Colorectal Cancer: A Multicenter, Open-Label, Phase I Trial. (Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2026, PMID 41779980): "We conducted a phase I trial to assess trastuzumab rezetecan, a novel HER2-targeted ADC, in HER2-expressing advanced GC/GEJ and CRC."
  • Jun Successful Rechallenge of Trastuzumab Deruxtecan Following Early Detection of ILD in a Patient with Non-small Cell Lung Carcinoma Harboring HER2 Exon 20 Insertion. (Internal medicine (Tokyo, Japan), 2025, PMID 41192915): "...who developed grade 1 trastuzumab deruxtecan (T-DXd)-induced interstitial lung disease (ILD) during third-line therapy."
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