Integrating T-DXd in HER2+  Gynecologic Cancers: Impact on Treatment Decisions and Sequencing

In this part of the discussion, the clinicians focus on the clinical implications of the recent accelerated approval of trastuzumab deruxtecan (T-DXd) and how it influences treatment sequencing in HER2-expressing endometrial cancer. Although there is enthusiasm about new options, both experts acknowledge the lack of definitive data to guide sequencing strategies. They reference insights from other tumor types—such as the DREAMseq trial in melanoma—which showed that the sequence of immunotherapy and targeted therapy could impact overall outcomes. This raises the possibility that similar sequencing considerations may soon be necessary in gynecologic oncology, where treatment choices are expanding.

In practice, the sequencing of treatments such as T-DXd and lenvatinib plus pembrolizumab (Len-Pem) remains a point of uncertainty. One speaker explains that they often lean toward using T-DXd first in HER2-positive tumors due to its favorable toxicity profile, even though phase 3 data currently support Len-Pem. The concern is that starting with a more toxic regimen might prevent patients from tolerating subsequent therapies, thus reducing their overall treatment benefit. Others may prefer to begin with Len-Pem based on stronger overall survival data, especially in mismatch repair–proficient (pMMR) tumors where frontline immunotherapy is still controversial.

The conversation highlights the broader challenge of balancing efficacy, toxicity, and long-term treatment access. Both participants agree that treatment-related adverse effects often determine whether patients can continue therapy or receive future options. They also stress the need for data that help clarify whether prior treatments influence the effectiveness or safety of subsequent ones. With new antibody-drug conjugates on the horizon and little standardization yet in place, the field is poised for rapid evolution. As the participants note, ongoing trials and real-world experience will be critical in shaping how best to sequence therapies and personalize care for patients with gynecologic cancers.