Early clinical trial data suggests that topoisomerase-1 payload ADCs retain efficacy in patients previously treated with mirvetuximab. Because mirvetuximab has a different cytotoxic payload, this indicates that targeting the same receptor (FR-alpha) with a different type of toxin is a viable sequencing strategy.

As multiple new drugs like antibody-drug conjugates (ADCs) become available for SCLC, the critical research question will shift from *if* they work to *when* they should be used. Future biomarker strategies must focus on optimizing treatment sequences, considering factors like the drug's target and payload.

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.

Patients whose ovarian cancer progresses on the folate-targeted ADC mirvetuximab may still respond to a subsequent folate-targeted ADC with a different cytotoxic payload. This suggests that the folate receptor alpha target remains viable and that resistance may be payload-specific, opening new sequencing strategies.

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.

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.

Most new antibody-drug conjugates (ADCs) for ovarian cancer use the same topoisomerase-1 (Topo1) inhibitor payload. This similarity will likely prevent their sequential use due to cross-resistance, forcing clinicians into a "one-shot" scenario where they must choose the single best Topo1-based ADC upfront for a patient.

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.