Dr Waks on Key Questions Regarding the First-Line Use of T-DXd in HER2+ Breast Cancer

Adrienne G. Waks, MD, physician, associate director of Clinical Research, Dana-Farber Cancer Institute, instructor in medicine, Harvard Medical School, discusses key questions and potential implications for replacing the prior first-line standard of care (SOC) with fam-trastuzumab-deruxtecan-nxki (T-DXd) in HER2-positive breast cancer.

An important question in treating HER2-positive metastatic breast cancer is whether the frontline standard of care will shift from the CLEOPATRA regimen (NCT00567190) to T-DXd, depending on the results of the ongoing phase 3 DESTINY-Breast09 trial (NCT04784715), Waks begins. The CLEOPATRA regimen, which combines pertuzumab (Perjeta) with trastuzumab (Herceptin) and chemotherapy, typically involves 4 to 6 months of treatment with chemotherapy, followed by maintenance with HER2-directed therapy alone, she says. This approach significantly reduces toxicity and improves the quality of life for patients, allowing them to experience durable benefits and lead relatively normal lives with minimal adverse effects (AEs), Waks reports.

The DESTINY-Breast09 trial is assessing the upfront use of T-DXd alone or in combination with pertuzumab plus trastuzumab vs a taxane plus pertuzumab and trastuzumab in metastatic disease. If the DESTINY-Breast09 trial demonstrates positive results and T-DXd is moved into the front line, it will introduce a new treatment paradigm, she emphasizes. Currently, the treatment protocol in DESTINY-Breast09 involves continuing T-DXd until disease progression or unacceptable adverse events, which differs significantly from the dosing schedule for the CLEOPATRA regimen. Although T-DXd is highly effective, it is also associated with considerable toxicity, Waks elucidates. This raises concerns about the long-term sustainability of maintaining patients on such a regimen indefinitely, as patients may experience extended periods on a potentially toxic therapy, she adds

The key question that will emerge is how to optimize the use of T-DXd in the first-line setting to balance efficacy and quality of life, Waks continues. One potential strategy could involve an induction phase with T-DXd, followed by a maintenance phase with trastuzumab and pertuzumab. This approach would necessitate comprehensive studies to gather efficacy, safety, feasibility, and patient-reported outcome data to determine the best course of action, she states.

Research will also need to focus on the optimal duration of T-DXd therapy before transitioning to maintenance therapy, Waks expands. This would involve assessing how many cycles of T-DXd are necessary to achieve maximum benefit before switching to a less toxic regimen. Additionally, understanding the long-term effects of continuous T-DXd therapy on patients’ health and quality of life will be crucial, Waks concludes.