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.

Dr. O'Malley avoids using multiple ADCs with the same TOPA-1 payload sequentially due to a lack of data. However, he will reuse a target if the subsequent ADC has a different, non-cross-resistant payload, such as an anti-microtubulin. This is a practical strategy to manage resistance in a data-sparse environment, prioritizing payload diversity over simply switching targets.

Retrospective data shows that using one Antibody-Drug Conjugate (ADC) after another, particularly those with the same class of payload like TOP1 inhibitors, results in a low response rate of 10-20%. This creates a significant unmet need and a major clinical challenge for patients who progress on a first-line ADC.

Experts question the efficacy of sequencing ADCs like EV (Nectin-4 target) and DV (HER2 target) because they share the same MMAE chemo payload. Since resistance is often tied to the payload, not the target antibody, switching targets may not overcome resistance, though anecdotal responses have been observed.

When planning treatment for patients who will receive multiple antibody-drug conjugates (ADCs), the prevailing clinical strategy is to focus on alternating the drug's payload (e.g., a tubulin inhibitor vs. a topoisomerase I inhibitor). This approach is believed to be more effective at overcoming resistance than alternating the cell-surface target.

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.

As more antibody-drug conjugates (ADCs) become available, a key concern is resistance to the cytotoxic payload. If a tumor develops resistance to a topoisomerase-1 inhibitor from one ADC, it may not respond to other ADCs using the same payload, regardless of their different antibody targets, complicating future treatment sequencing.

Contrary to concerns about cross-resistance between HER2 antibody-drug conjugates (ADCs), retrospective data shows TDM-1 remains effective after progression on TDXD. This suggests the different cytotoxic payloads are key, allowing for effective sequencing and challenging the assumption that progression on one ADC class member precludes using another.

In the absence of definitive data, a practical strategy is emerging to alternate ADC payloads, such as switching from a microtubule toxin to a topoisomerase inhibitor. This approach aims to avoid compounding toxicities like neuropathy and potentially circumvent drug resistance mechanisms.