T-DXd to Be Explored in HER2-Expressing Advanced Endometrial Cancer
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The first patient with endometrial cancer has been dosed in the global, multicenter, randomized, open-label, phase 3 DESTINY-Endometrial01 trial (NCT06989112).1
This pivotal study will evaluate fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) in combination with rilvegostomig or pembrolizumab (Keytruda) as a first-line therapy for patients with HER2-expressing (IHC 3+/2+) primary advanced or recurrent endometrial cancer, comparing these regimens against the current standard of care, platinum-based chemotherapy (carboplatin and paclitaxel) in combination with pembrolizumab.
“Following the positive results in the endometrial cancer cohort of DESTINY-PanTumor02 [NCT04482309], which contributed to a tumor agnostic approval for previously treated patients with HER2-positive metastatic tumors in several regions, we are initiating this first phase 3 trial of [T-DXd] in the first-line setting of advanced endometrial cancer,” said Mark Rutstein, MD, head of Therapeutic Area Oncology Development, Daiichi Sankyo, in a press release. “The DESTINY-Endometrial01 trial will help us better understand the role of [T-DXd] in combination with immunotherapy as a potential treatment strategy to help improve outcomes compared to the current standard of care in this specific gynecological cancer setting.”
Endometrial cancer incidence and mortality rates are projected to rise significantly by 2050, underscoring the urgent need for more effective treatment strategies, particularly for advanced or recurrent disease, which carries a poor prognosis with a median overall survival of up to 30 months. HER2 expression, observed in 18% to 56% of endometrial cancers, is associated with aggressive disease characteristics.
T-DXd is a specifically engineered HER2-directed antibody-drug conjugate (ADC). Its mechanism of action involves the targeted delivery of a cytotoxic topoisomerase I inhibitor payload (DXd) to HER2-expressing cancer cells, leading to DNA damage and cell death. The drug has demonstrated efficacy in various HER2-positive malignancies, including breast and gastric cancers, and has received tumor-agnostic approval for previously treated HER2-positive metastatic tumors in several regions based on positive results from the DESTINY-PanTumor02 trial, which included an endometrial cancer cohort.
The DESTINY-Endometrial01 trial aims to enroll approximately 600 patients across sites in North America, South America, Australia, Europe, and Asia.2 The primary end point for the study is progression-free survival as assessed by blinded independent central review. Key secondary end points include overall survival, objective response rate, duration of response, and safety profiles of the treatment arms.1,2
To be eligible for enrollment, patients must have histologically confirmed epithelial endometrial carcinoma, primary advanced disease, no prior exposure to ADCs or immune checkpoint inhibitors, an ECOG performance status of 0 to 1, and adequate organ and bone marrow function. Those with a history of organ transplant, uncontrolled intercurrent illness, clinically active central nervous system metastases, a history of primary immunodeficiency, or a history of noninfectious interstitial lung disease or pneumonitis are not eligible for enrollment.2
Currently, standard first-line treatment for advanced or recurrent endometrial cancer often involves platinum-based chemotherapy, frequently in combination with immunotherapy agents like pembrolizumab, particularly in mismatch repair proficient (pMMR) tumors.1 The DESTINY-Endometrial01 trial's design directly compares T-DXd–based combinations against this established regimen, with a focus on HER2-expressing, pMMR tumors.
The initiation of DESTINY-Endometrial01 reflects a strategic effort to explore the role of HER2-targeted therapy earlier in the treatment paradigm for this specific patient population. The outcomes of this trial are anticipated to provide crucial insights into whether T-DXd combinations can offer a significant improvement in outcomes compared to existing first-line therapies for HER2-expressing primary advanced or recurrent endometrial cancer.
