Real-world data suggests that using one antibody-drug conjugate (ADC) immediately after another is often ineffective. A potential strategy to overcome this resistance is to administer a different class of chemotherapy before starting the second ADC.

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.

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.

Sequencing antibody-drug conjugates (ADCs) like enfortumab vedotin (EV) and disitamab vedotin is complicated because both use the same MMAE cytotoxic payload. If a tumor develops resistance to the MMAE from EV, it is unlikely to respond to a subsequent ADC using the same payload.

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.

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.

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.