Trastuzumab deruxtecan (TDXD) and datopotamab deruxtecan (Dato-DXd) share the same cytotoxic payload, yet Dato-DXd has a much lower rate of interstitial lung disease (ILD). This indicates the toxicity is driven by the antibody-antigen interaction, not the payload itself.

The varying outcomes of two similar Lilly ADCs (LY405/LY410) demonstrated that how a patient's body metabolizes the drug's payload is a critical factor. Absence of the CYP2D6 enzyme, crucial for a Topo-one payload, led to severe toxicity and death, highlighting a key variable beyond the linker and target.

Different TROP2-targeted ADCs using the same class of payload (topo-1 inhibitor) display distinct primary toxicities, such as diarrhea versus stomatitis. This highlights that subtle differences in drug-to-antibody ratio and linker technology create unique pharmacological profiles, making the drugs clinically distinct despite their apparent similarities.

Despite targeting the same protein (Trope-2), different ADCs like sacituzumab govitecan (SG) and sacituzumab tirumotecan (sac-TMT) exhibit unique toxicity profiles due to their different linker-payloads. Clinicians must be prepared for diarrhea with SG versus oral mucositis with sac-TMT, requiring distinct mitigation strategies for drugs that otherwise seem very similar.

With multiple ADCs available, an emerging sequencing strategy is to alternate between different mechanisms of action, such as following a microtubule toxin-based ADC with a topoisomerase-1 inhibitor payload. This approach aims to avoid compounding specific toxicities, like neuropathy, and potentially circumvent resistance, though it is a strategy born from logic rather than clinical trial data.

Despite both being Trop-2 targeted antibody-drug conjugates, Sacituzumab Govitecan and Datopotomab duroxotein have distinct side effects due to different linkers and payloads. Sacituzumab causes neutropenia and diarrhea, while Datopotomab is linked to stomatitis and ocular issues, requiring unique management strategies.

A key principle for clinicians is that an antibody-drug conjugate's adverse events are primarily dictated by its linker-payload (e.g., deruxtecan, vedotin), not its specific antibody target. This allows for anticipating toxicities like neuropathy or GI issues based on the payload class, creating a predictable framework for management across different ADCs.

The differing efficacy and toxicity profiles of TROP2 ADCs like sacituzumab govitecan and Dato-DXD suggest that the drug's linker and payload metabolism are crucial determinants of clinical outcome. This indicates that focusing solely on the target antigen is an oversimplification of ADC design and performance.

Despite being advanced targeted therapies, TROP2-directed ADCs present complex safety profiles. Oncologists must manage classic chemotherapy side effects like nausea and cytopenias alongside unique, serious toxicities including stomatitis, ocular issues, and potentially fatal interstitial lung disease, requiring specialized patient monitoring and counseling.