Data from a novel Nectin-4 ADC trial showed zero responses in patients with prior topoisomerase therapy. This strongly suggests that payload resistance, not just the ADC target, is a critical mechanism that will dictate future treatment sequencing.

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.

Drawing lessons from T-DXD, experts treat newer exatecan-payload ADCs like RDXD as highly emetogenic from the first dose. Instead of a 'wait and see' approach, they recommend aggressive premedication with a triple-drug antiemetic regimen to prevent nausea and maintain quality of life.

Combining two payloads in an Antibody-Drug Conjugate (ADC) introduces a major risk: new, synergistic toxicities not seen with either agent alone. This complicates dose-finding and safety assessment, requiring developers to anticipate and monitor for entirely novel side effects.

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.

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.

Clinicians should avoid directly comparing the toxicity profiles of new ADCs, as the data often comes from different trial stages. A drug in a Phase 1 expansion cohort may appear more toxic than one with mature Phase 2 randomized data, making definitive safety assessments premature.

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.