To combat payload-related resistance, clinicians are reluctant to use two ADCs with the same payload (e.g., a deruxtecan) consecutively. The preferred strategy is to 'sandwich' a different class of chemotherapy between the two ADCs, hoping to restore sensitivity to the payload.

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.

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.

Emerging data in urothelial cancer suggests a potential solution to the ADC sequencing problem. After treatment with a Nectin-4 targeted ADC, using a second Nectin-4 ADC with a different payload (topo-1 inhibitor instead of MMAE) still demonstrated efficacy.

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.

Rather than moving through distinct lines of therapy, a future strategy could involve an "ADC switch." When a patient progresses on an ADC-IO combination, the IO backbone would remain while the ADC is swapped for one with a different, non-cross-resistant mechanism, adapting the treatment in real-time.

A promising future strategy for ovarian cancer involves combining two different ADCs. The key to this approach is selecting agents with distinct payloads (e.g., an anti-microtubulin and a TOPA-1 inhibitor) whose side effect profiles do not overlap. This could maximize anti-tumor efficacy while maintaining a manageable toxicity burden for patients, offering a novel combination paradigm.

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.