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.

A trial for a new Nectin-4 ADC was amended to include mandatory, prospective CYP2D6 genotyping after a few patients experienced life-threatening toxicities. This highlights the growing importance of pharmacogenomics for ensuring the safety of novel ADCs.

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.

When sequencing antibody-drug conjugates, clinical experience suggests that resistance to the chemotherapy payload is a primary driver of failure. Therefore, oncologists tend to avoid using another ADC with the same payload consecutively, preferring to switch both target and payload if possible.

The primary reason Antibody-Drug Conjugates (ADCs) stop working is payload resistance, a shift from the traditional belief that failure stems from tumors losing the target antigen. This insight drives development of multi-payload ADCs to overcome this resistance mechanism.

When sequencing antibody-drug conjugates (ADCs) for SCLC, resistance may be driven more by the cytotoxic payload (e.g., a topoisomerase 1 inhibitor) than the antibody's target antigen. This suggests prior exposure to a similar payload class could predict non-response, even when using an ADC with a different target.

Emerging data shows that a second ADC, particularly one with the same payload, often has limited efficacy. This suggests clinicians must be highly strategic in selecting the first ADC, as it may be their most impactful opportunity for this class of drugs.

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.