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.

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.

An ADC may show better response rates than chemotherapy, but its true benefit is compromised if toxicities lead to treatment discontinuation. As seen with failed PARP/IO combinations, if patients cannot tolerate a drug long enough, the regimen's overall effectiveness can become inferior to standard therapy.

The failure of the TROPiCS-04 trial for sacituzumab govitecan may not indicate the TROP2 ADC class is ineffective. Experts suggest problems with dosing and toxicity management (e.g., neutropenia) during the trial could be the real culprit, arguing that the drug class still holds promise.

While TROP2-ADCs are currently approved for later-line lung cancer treatment, active clinical trials are already evaluating them as a potential replacement for traditional chemotherapy in the first-line setting. This represents a significant strategic ambition to shift the entire treatment paradigm for newly diagnosed patients with both non-small cell and small cell lung cancer.

The ocular toxicity seen with the folate-targeted ADC mirvetuximab is not due to folate receptors in the eye. It is theorized to be caused by micropinocytosis, an alternative mechanism where the drug is non-specifically taken up by normal corneal cells, representing an off-target, off-tumor toxicity.

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.

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.

The ADC Dato-DXD causes high rates of stomatitis and dry eye that are difficult to treat once they appear. Effective management requires aggressive, proactive prevention from the start of therapy using steroid mouthwash and lubricating eye drops, demanding significant patient engagement and vigilance.