The current ADC landscape is saturated with similar drugs using topo-isomerase-1 inhibitors. This creates a market opportunity and an ethical imperative to develop new payloads with different mechanisms of action to treat patients who will inevitably develop resistance to the current generation of therapies.

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.

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.

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.

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.

With 18 of 19 ADCs in development for SCLC using a topoisomerase-1 inhibitor payload, there's a significant risk that patients may not respond to a second ADC after progressing on a first. This highlights a critical need to develop ADCs with alternative payloads to provide more therapeutic options and overcome resistance.

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.