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.

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.

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 TROPION-PanTumor01 study showed that patients who progressed on the TROP2-ADC sacituzumab govitecan still achieved responses to a second TROP2-ADC, Dato-DXD. This suggests that targeting the same antigen with a different payload can overcome initial resistance, informing future treatment sequencing.

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.

A subtle finding in the DESTINY-Breast11 trial, where TDXD alone underperformed TDXD followed by THP, suggests that taxane-based chemotherapy might remain effective even after a patient's HER2-positive cancer becomes resistant to the antibody-drug conjugate TDXD.

A significant clinical challenge is the sequencing of antibody-drug conjugates (ADCs). Retrospective data from large databases indicates that using a second TROP2-targeted ADC after a first one provides very limited efficacy, highlighting an urgent need for prospective trials to define optimal sequencing strategies and overcome resistance.

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.

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.