On March 31, 2025 Daiichi Sankyo reported first patient has been dosed in the DESTINYGastric05 phase 3 trial evaluating ENHERTU (trastuzumab deruxtecan) in combination with a fluoropyrimidine chemotherapy (5-FU or capecitabine) and Merck’s (known as MSD outside of the US and Canada) anti-PD-1 therapy KEYTRUDA (pembrolizumab) versus trastuzumab in combination with platinum-based chemotherapy (cisplatin plus 5-FU or oxaliplatin plus capecitabine) and pembrolizumab in previously untreated patients with unresectable, locally advanced or metastatic HER2 positive (IHC 3+ or IHC 2+/ISH+) gastric or gastroesophageal junction (GEJ) cancer with PD-L1 CPS ≥1 (Press release, Daiichi Sankyo, MAR 31, 2025, View Source [SID1234651693]). An exploratory cohort of patients with PD-L1 CPS <1 will be randomized to either ENHERTU plus fluoropyrimidine or trastuzumab plus platinum-based chemotherapy.
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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).
Gastric cancer is associated with a poor prognosis, particularly in advanced stages of the disease where the five-year survival rate is 5% to 10%. 1 Current recommended first-line treatment for HER2 positive advanced gastric cancer with PD-L1 CPS ≥1 is trastuzumab in combination with platinum-based chemotherapy (cisplatin plus 5-FU or oxaliplatin plus capecitabine) and pembrolizumab. 2,3 New treatment strategies are needed to continue to improve survival, including additional HER2 directed treatment options.
"Following the positive overall survival results seen with DESTINY-Gastric04 in the second-line HER2 positive metastatic gastric cancer setting, the DESTINY-Gastric05 trial will explore the role of ENHERTU earlier in the metastatic setting as a first-line treatment," said Mark Rutstein, MD, Global Head, Oncology Clinical Development, Daiichi Sankyo. "With DESTINY-Gastric05, we are evaluating whether a potential platinum-free chemotherapy regimen of ENHERTU combined with immunotherapy and a fluoropyrimidine chemotherapy can further improve survival in patients with previously untreated HER2 positive metastatic gastric cancer."
ENHERTU is currently approved in more than 65 countries in the second-line or third-line metastatic setting of HER2 positive gastric cancer based on DESTINY-Gastric01, a randomized phase 2 trial, and DESTINYGastric02 and DESTINY-Gastric06, two single-arm phase 2 trials. KEYTRUDA is a registered trademark of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.
About DESTINY-Gastric05
DESTINY-Gastric05 is a global, multicenter, randomized, open-label, phase 3 trial evaluating the efficacy and safety of ENHERTU (5.4 mg/kg) in combination with a fluoropyrimidine-based chemotherapy (5-FU or capecitabine) and Merck’s (known as MSD outside of the US and Canada) anti-PD-1 therapy KEYTRUDA (pembrolizumab) versus trastuzumab in combination with platinum-based chemotherapy (cisplatin plus 5-FU or oxaliplatin plus capecitabine) and pembrolizumab in approximately 576 previously untreated patients with unresectable, locally advanced or metastatic HER2 positive (IHC 3+ or IHC 2+/ISH+) gastric or GEJ cancer with PD-L1 CPS ≥1.
The primary endpoint is progression-free survival (PFS) as assessed by blinded independent central review. The key secondary endpoint is overall survival. Additional secondary endpoints include PFS as assessed by investigator, objective response rate, duration of response and safety.
An exploratory cohort of 150 patients with PD-L1 CPS <1 will be randomized to either ENHERTU plus fluoropyrimidine (5-FU or capecitabine) or trastuzumab plus platinum-based chemotherapy (cisplatin plus 5- FU or oxaliplatin plus capecitabine).
DESTINY-Gastric05 will enroll patients across multiple sites in Asia, Europe, North America and South America. For more information about the trial, visit ClinicalTrials.gov.
About HER2 Positive Gastric Cancer
Gastric (stomach) cancer is the fifth most common cancer worldwide and the fifth leading cause of cancerrelated death.
4 Approximately one million cases were diagnosed in 2022.4 Gastric cancer is associated with a poor prognosis, particularly in advanced stages of the disease where the five-year survival rate is 5% to 10%.
HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumors, including gastric cancer.5 Approximately one in five gastric cancers globally are HER2 positive.Recommended first-line treatment for HER2 positive advanced gastric cancer with PD-L1 CPS ≥1 is trastuzumab in combination with platinum-based chemotherapy (cisplatin plus 5-FU or oxaliplatin plus capecitabine) and pembrolizumab.2,3 In patients with PD-L1 CPS <1 recommended first-line treatment is trastuzumab plus platinum-based chemotherapy (cisplatin plus 5-FU or oxaliplatin plus capecitabine). 2 New treatment strategies, including additional HER2 directed treatment options, are needed to continue to improve survival in patients with previously untreated advanced gastric cancer.