Sequencing Antibody-Drug Conjugates (ADCs) in HR+/HER2-Low Metastatic Breast Cancer

The conversation shifts to the optimal sequencing of antibody-drug conjugates (ADCs) in metastatic HR+/HER2-low breast cancer after progression on capecitabine. Two ADCs are currently approved in this setting: trastuzumab deruxtecan (T-DXd) based on the DESTINY-Breast04 trial and sacituzumab govitecan (SG) from the TROPICS-02 study.

Spring tends to favor T-DXd over SG in HER2-low disease given the impressive results from DESTINY-Breast04, which showed statistically significant and clinically meaningful improvements in progression-free and overall survival compared to physician's choice chemotherapy, regardless of hormone receptor status.

Bhave agrees and typically uses T-DXd first followed by SG in HER2-low patients. However, the optimal sequencing of ADCs and whether to add other therapies in between remains an open question due to lack of data on resistance mechanisms related to the target antigen versus the payload.

Both acknowledge the limitations of current retrospective data exploring ADC sequencing and the need for prospective trials. Spring has been using ADCs sequentially based on their superior efficacy over chemotherapy and the rationale of switching targets. She notes the ongoing development of datopotamab deruxtecan, a second Trop-2-directed ADC, which has shown promising activity but a different toxicity profile than SG, with more ocular toxicity and stomatitis but less gastrointestinal side effects.

Bhave highlights the importance of toxicity management strategies like prophylactic dexamethasone mouthwash to mitigate stomatitis. Differences in dosing schedules between ADCs may also factor into treatment decisions.

Overall, the optimal sequencing of ADCs in metastatic HR+/HER2-low breast cancer remains an active area of investigation, but having multiple effective options is an exciting development for patients.

This summary was AI-generated and edited for clarity.