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.
NCCN guidelines for folate receptor alpha and HER2 in ovarian cancer allow treatment at lower expression levels than initial trials. This is driven not only by data showing activity in these groups but also by the fact that the original smaller biotech developers had limited resources for expansive trials beyond the highest-expressing cohorts, a commercial factor influencing current clinical guidance.
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.
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.