The international phase 3 DESTINY-Gastric04 clinical trial found that second-line treatment with trastuzumab deruxtecan can help people with advanced HER2-positive gastric cancers that have grown during first-line treatment live about 3 months longer. These findings further support the use of trastuzumab deruxtecan in the second-line setting for these patients.

The research was presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting,

People with metastatic gastric cancer often have a poor prognosis, with a 5-year survival rate ranging from 5% to 10%. About 5% to17% of these cancers are HER2-positive.

For people with metastatic HER2-positive gastric cancer or GEJA that has progressed during first-line treatment, a standard second-line treatment option is paclitaxel with ramucirumab. Historically, there have not been any treatments that directly target the HER2 protein for people with metastatic HER2-positive gastric cancer in the second-line setting.

Trastuzumab deruxtecan is a targeted therapy drug that directly targets the HER2 protein on cancer cells.

Based on results from previous phase 2 clinical trials, trastuzumab deruxtecan has been approved in more than 65 countries for people with advanced HER2-positive gastric cancer or GEJA who have previously received treatment with a trastuzumab-based regimen.

The DESTINY-Gastric04 clinical trial is the first phase 3 clinical trial to directly compare trastuzumab deruxtecan against paclitaxel with ramucirumab in the second-line setting for these patients.

“If disease progression occurs in the first-line metastatic setting of HER2-positive gastric cancer, there historically have been no HER2-directed medicines that have demonstrated a survival benefit in a phase 3 clinical trial in the second-line setting. The results of DESTINY-Gastric04 show that second-line treatment with HER2-directed trastuzumab deruxtecan can extend survival compared to a chemotherapy-based regimen,” said lead study author Kohei Shitara, MD, National Cancer Center Hospital East, Kashiwa, Japan.

Key Findings

DESTINY-Gastric04 included 494 patients with metastatic or unresectable HER2-positive gastric cancer or GEJA that had progressed during or after treatment with a trastuzumab-based regimen. The median age of the patients was about 64 years old, and most of the patients were from Western Europe or Asia.

The patients were randomly assigned to receive either trastuzumab deruxtecan (246 patients) or paclitaxel with ramucirumab (248 patients). About 60% of the patients in each treatment group had gastric cancer, and about 40% in each group had GEJA.

After a median follow-up of 16.8 months for the trastuzumab deruxtecan group and 14.4 months for the standard treatment group, researchers found that:

• Trastuzumab deruxtecan helped patients live 3.3 months longer. The median overall survival was 14.7 months for patients who received trastuzumab deruxtecan vs. 11.4 months for patients who received paclitaxel with ramucirumab.
• Trastuzumab deruxtecan reduced the risk of death by 30% for patients.
• The median progression-free survival for the trastuzumab deruxtecan group was 6.7 months vs. 5.6 months in the standard treatment group.
• For the patients in the trastuzumab deruxtecan group, their risk of disease progression was reduced by 26%.
• The objective response rate (ORR), or percentage of patients whose cancer shrank following treatment, was 44.3% In the trastuzumab deruxtecan group vs. 29.1% in the standard treatment group.
• The disease control rate (DCR), or percentage of patients whose cancer either shrank or stabilized following treatment, was 91.9% in the trastuzumab deruxtecan group vs. 75.9% for the standard treatment group.

All of the patients in the trastuzumab deruxtecan group experienced side effects, as did nearly all of the patients in the standard treatment group (97.9%).

For most patients in both groups, these side effects were grade 3 or higher (68% in the trastuzumab deruxtecan group vs. 73.8% in the standard treatment group). Overall, the side effects experienced by the patients in the trastuzumab deruxtecan group were consistent with the previously known side effects of the drug. The most common side effects of trastuzumab deruxtecan included fatigue (48% of patients), neutropenia (48%), nausea (44.3%) and anaemia (31.1%).

Researchers will continue to study the safety and efficacy of trastuzumab deruxtecan for people with HER2-positive gastric cancer in the first-line setting in three separate clinical trials: DESTINY-Gastric05, DESTINY-Gastric03, and ARTEMIDE-Gastric01.

“Trastuzumab deruxtecan is approved for patients with metastatic HER2-positive gastric cancer or gastroesophageal junction adenocarcinoma who received a prior trastuzumab-based regimen based on previous phase 2 studies. The improvement in overall survival with trastuzumab deruxteacan compared to ramucirumab with paclitaxel seen in this study validates the role of trastuzumab deruxtecan in the second-line setting,” said Pamela Kunz MD, PhD, Director of the Center for Gastrointestinal Cancers at Smilow Cancer Hospital and Yale Cancer Center and an ASCO Expert in gastrointestinal cancers.

Source: ASCO