Trastuzumab-deruxtecan in breast cancer treatment: Balancing the triad of efficacy, safety and accessibility

Trastuzumab deruxtecan (T-DXd), an anti-human epidermal growth receptor 2 (HER2) antibody-drug conjugate (ADC), has emerged as a transformative therapy for metastatic breast cancer (MBC), demonstrating efficacy across the full spectrum of HER2 expression including HER2 positive, HER2 low and HER2 ultralow disease.1-4 This novel ADC consists of trastuzumab linked via an enzymatically cleavable disulfide linker to deruxtecan, a potent topoisomerase I inhibitor. Its high drug-to-antibody ratio (approximately 8) and membrane-permeable payload enable a bystander effect, contributing to its pronounced antitumour activity. The DESTINY-Breast03 trial redefined expectations in HER2-positive MBC, achieving a median overall survival of only over 50 months in the second-line setting, which far exceeds the 30-month benchmark set by previous gold standard therapy trastuzumab emtansine, underscoring a paradigm shift in the therapeutic landscape of this disease. While T-DXd is generally well-tolerated and allows most patients to preserve quality of life, its use is tempered by toxicities including alopecia, nausea and fatigue. The main long-term concern is interstitial lung disease (ILD), which requires careful monitoring. Despite its impressive clinical activity, the widespread adoption of T-DXd is constrained by its high cost and toxicity profile that can be clinically significant for some patients. These challenges underscore the need for strategies that enhance its generalisability, ensuring that more patients can benefit from its therapeutic potential without compromising safety or affordability.