Antibody-drug conjugates (ADCs) have emerged as one of the most exciting modalities in oncology. Among them, HER2-targeted ADCs have undergone a dramatic transformation with the arrival of Daiichi Sankyo and AstraZeneca’s Enhertu, sparking what is often called the “second ADC boom.” In this first part of our feature, we explore the breakthrough achieved by Enhertu and how pharmacological differentiation is shaping the competitive landscape of HER2 ADCs.
The Birth of Enhertu: Heralding the Second ADC Boom
In 2013, Roche’s Kadcyla (trastuzumab emtansine, T-DM1) became the first HER2 ADC to win FDA approval, offering new hope for HER2-positive breast cancer. However, its clinical impact was modest and left room for improvement. The breakthrough came with Enhertu (trastuzumab deruxtecan, T-DXd), designed with a topoisomerase I inhibitor payload, high DAR, and membrane-permeable properties enabling the bystander effect. This unique mechanism allowed Enhertu to achieve activity not only in HER2-high tumors but also in HER2-low cases. The DESTINY-Breast03 trial highlighted its superiority, extending progression-free survival by an impressive 22 months compared to Kadcyla.
Kadcyla’s Limitations vs. Enhertu’s Superiority
Kadcyla represented a first-generation ADC with a microtubule inhibitor payload (DM1). While it provided meaningful benefit, its lack of a bystander effect and limited activity in tumors with heterogeneous HER2 expression constrained its use.
Enhertu, by contrast, leveraged its payload and advanced linker technology to expand the treatment population, firmly establishing itself as the torchbearer of the second ADC boom.
Key Pharmacological Differentiation Points
- Payload innovation: From microtubule inhibitors (Kadcyla) to DNA-damaging topoisomerase I inhibitors (Enhertu).
- Advanced linker design: Stable in circulation but cleavable within the tumor microenvironment, reducing systemic toxicity.
- Bystander effect: Effective even against HER2-low and heterogeneously expressing tumors.
- Expanded indications: From breast cancer to gastric, lung, and other solid tumors.
My Perspective: Outlook Ahead (Part 1 Summary)
From a pharmacological standpoint alone, Enhertu has redefined the standard of HER2 ADC therapy. Kadcyla’s role is fading, while new challengers like BioNTech and DualityBio’s BNT323 are rising. Yet, with its bystander effect and broad applicability, Enhertu’s dominance is likely to continue for now.
In the next installment (Part 2), we will dive into intellectual property strategies, patent lifespans, and the intense global competition that will determine the future of the HER2 ADC market. Stay tuned for insights into how this crowded race may evolve.
This article was edited by the Morningglorysciences team.
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