On June 9, 2025 Daiichi Sankyo reported that the first patient has been dosed in the DESTINY- Endometrial01 phase 3 trial evaluating ENHERTU (trastuzumab deruxtecan) in combination with rilvegostomig or pembrolizumab versus platinum-based chemotherapy (carboplatin and paclitaxel) in combination with pembrolizumab as a first-line therapy in patients with HER2 expressing (IHC 3+/ 2+), mismatch repair proficient (pMMR) primary advanced or recurrent endometrial cancer (Press release, Daiichi Sankyo, JUN 9, 2025, View Source [SID1234653780]). DESTINY- Endometrial01 will be conducted in collaboration with The GOG Foundation, Inc. (GOG-F) and the European Network of Gynecological Oncological Trial (ENGOT).
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ENHERTU is a specifically engineered HER2 directed DXd antibody drug conjugate (ADC) discovered by Daiichi Sankyo (TSE: 4568) and being jointly developed and commercialized by Daiichi Sankyo and AstraZeneca (LSE/STO/Nasdaq: AZN).
Endometrial cancer that is recurrent or diagnosed in advanced stages has a median overall survival of up to 30 months.1 While there have been recent treatment advances, there is still a need to further improve outcomes for patients. HER2 expression (IHC 3+/2+) is associated with aggressive disease and is present in 18% to 56% of endometrial cancers.2,3,4,5,6 There currently are no HER2 directed medicines approved in the first-line endometrial cancer setting.
"Following the positive results in the endometrial cancer cohort of DESTINY-PanTumor02, 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 ENHERTU in the first-line setting of advanced endometrial cancer," said Mark Rutstein, MD, Head, Therapeutic Area Oncology Development, Daiichi Sankyo. "The DESTINY-Endometrial01 trial will help us better understand the role of ENHERTU 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."
About DESTINY-Endometrial01
DESTINY-Endometrial01 is a global, multicenter, randomized, open-label phase 3 trial evaluating the efficacy and safety of ENHERTU (5.4 mg/kg) in combination with rilvegostomig or pembrolizumab versus platinum-based chemotherapy (carboplatin and paclitaxel) in combination with pembrolizumab as a first-line therapy in patients with HER2 expressing (IHC 3+/2+), pMMR, primary advanced (stage III/IV) or first recurrent endometrial cancer of any histologic subtype except sarcoma. Patients will be randomized in a 1:1:1 ratio to receive either ENHERTU in combination with rilvegostomig, ENHERTU in combination with pembrolizumab or platinum-based chemotherapy in combination with pembrolizumab.
The primary endpoint is progression-free survival (PFS) as assessed by blinded independent central review (BICR). The key secondary endpoint is overall survival. Additional secondary endpoints include PFS as assessed by investigator, objective response rate, duration of response and safety.
DESTINY-Endometrial01 will enroll approximately 600 patients across multiple sites in Asia, Europe, North America, Oceania and South America. For more information about the trial, visit ClinicalTrials.gov.
Rilvegostomig is AstraZeneca’s PD-1/TIGIT bispecific antibody. The TIGIT component of rilvegostomig is derived from the clinical-stage anti-TIGIT antibody, COM902, developed by Compugen Ltd. (Nasdaq/TASE: CGEN). Pembrolizumab (KEYTRUDA) is Merck’s (known as MSD outside of the US and Canada) anti-PD-1 therapy.
About Endometrial Cancer
Endometrial cancer is the second most common gynecologic cancer and the sixth most common cancer among women worldwide.7 Approximately 420,000 endometrial cancer cases were diagnosed in 2022, with more than 97,000 deaths globally.8 Incidence and mortality rates of endometrial cancer are expected to increase by approximately 61% and 87% respectively by 2050.9 Patients with advanced or recurrent endometrial cancer have a poor prognosis, with a median overall survival of up to 30 months.1
Endometrial cancer comprises several molecular subtypes.10 Approximately 20% to 30% of all endometrial cancers exhibit high microsatellite instability (MSI) due to a defective mismatch repair system and are classified as MSI-high or MMR deficient (dMMR).10 The remaining 70% to 80% of cases are considered mismatch repair proficient (pMMR) tumors.10
HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumors.11 HER2 expression (IHC 3+/ 2+) is present in 18% to 56% of endometrial cancers and is associated with markers of aggressive disease.2,3,4,5,6 HER2 expression is observed almost exclusively in pMMR tumors.2
Standard of care first-line treatment of advanced or recurrent endometrial cancer has long included carboplatin plus paclitaxel.12 The treatment paradigm has recently evolved to incorporate an immune checkpoint inhibitor with carboplatin and paclitaxel, particularly for patients with dMMR endometrial cancer; however, the benefit of this treatment regimen in pMMR endometrial cancer is less pronounced.13,14,15,16 There currently are no HER2 directed medicines approved in the first-line endometrial cancer setting.
About ENHERTU
ENHERTU (trastuzumab deruxtecan; fam-trastuzumab deruxtecan-nxki in the U.S. only) is a HER2 directed ADC. Designed using Daiichi Sankyo’s proprietary DXd ADC Technology, ENHERTU is the lead ADC in the oncology portfolio of Daiichi Sankyo and the most advanced program in AstraZeneca’s ADC scientific platform. ENHERTU consists of a HER2 monoclonal antibody attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers.
ENHERTU (5.4 mg/kg) is approved in more than 80 countries worldwide for the treatment of adult patients with unresectable or metastatic HER2 positive (immunohistochemistry [IHC] 3+ or in-situ hybridization (ISH)+) breast cancer who have received a prior anti-HER2-based regimen, either in the metastatic setting or in the neoadjuvant or adjuvant setting, and have developed disease recurrence during or within six months of completing therapy based on the results from the DESTINY-Breast03 trial.
ENHERTU (5.4 mg/kg) is approved in more than 80 countries worldwide for the treatment of adult patients with unresectable or metastatic HER2 low (IHC 1+ or IHC 2+/ISH-) breast cancer who have received a prior systemic therapy in the metastatic setting or developed disease recurrence during or within six months of completing adjuvant chemotherapy based on the results from the DESTINY-Breast04 trial.
ENHERTU (5.4 mg/kg) is approved in more than 30 countries for the treatment of adult patients with unresectable or metastatic hormone receptor (HR) positive, HER2 low (IHC 1+ or IHC 2+/ISH-) or HER2 ultralow (IHC 0 with membrane staining) breast cancer, as determined by a locally or regionally approved test, that has progressed on one or more endocrine therapies in the metastatic setting based on the results from the DESTINY-Breast06 trial.
ENHERTU (5.4 mg/kg) is approved in more than 60 countries worldwide for the treatment of adult patients with unresectable or metastatic NSCLC whose tumors have activating HER2 (ERBB2) mutations, as detected by a locally or regionally approved test, and who have received a prior systemic therapy based on the results from the DESTINY-Lung02 and/or DESTINY-Lung05 trials. Continued approval in China and the U.S. for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
ENHERTU (6.4 mg/kg) is approved in more than 70 countries worldwide for the treatment of adult patients with locally advanced or metastatic HER2 positive (IHC 3+ or IHC 2+/ISH+) gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen based on the results from the DESTINY-Gastric01, DESTINY-Gastric02 and/or DESTINY-Gastric06 trials. Continued approval in China for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
ENHERTU (5.4 mg/kg) is approved in Brazil, Israel, Russia, Saudi Arabia, Switzerland, Taiwan, U.K. and the U.S. for the treatment of adult patients with unresectable or metastatic HER2 positive (IHC 3+) solid tumors who have received prior systemic treatment and have no satisfactory alternative treatment options based on efficacy results from the DESTINY-PanTumor02, DESTINY-Lung01 and DESTINY-CRC02 trials. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
About the ENHERTU Clinical Development Program
A comprehensive global clinical development program is underway evaluating the efficacy and safety of ENHERTU as a monotherapy or in combination or sequentially with other anti-cancer therapies across multiple HER2 targetable cancers.