Instead of a single cure, the goal is to create a "cancer treatment framework." This involves sequencing different ADCs with varied mechanisms of action to overcome resistance as it develops. This approach aims to transform cancer from a terminal diagnosis into a manageable, long-term condition.

The modern pipeline of antibody-drug conjugates in solid tumors has largely moved away from older microtubule toxin payloads (like DM4 or MMAE). The majority of ADCs currently in development, and the focus of clinical excitement, utilize camptothecin-based payloads, specifically topoisomerase-1 inhibitors like deruxtecan, reflecting a major technological evolution in the field.

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.

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.

As effective antibody-drug conjugates (ADCs) move into earlier treatment lines for ovarian cancer, a new clinical challenge arises: treating patients who progress after receiving them. The field is just beginning to develop these 'post-ADC' therapies, highlighting a critical and urgent need for innovation in areas like DNA repair mechanism inhibitors (e.g., V1, CDK2) for this emerging patient population.

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.

Nearly all promising antibody-drug conjugates (ADCs) in late-stage development for small cell lung cancer utilize a topoisomerase-1 (Topo-1) inhibitor payload. This overlap raises a critical clinical question: if a patient develops resistance to one ADC, will they respond to another? This creates a significant challenge for treatment sequencing and patient selection.