SECOND-LINE treatment with trastuzumab deruxtecan has been shown to extend overall survival by more than 3 months in patients with advanced HER2-positive gastric or gastroesophageal junction adenocarcinoma (GEJA) following progression on first-line therapy, according to Phase III data from the DESTINY-Gastric04 trial presented at the ASCO 2025 Annual Meeting.
The international trial enrolled 494 patients across Asia, Europe, and South America with metastatic or unresectable HER2-positive gastric cancer or GEJA who had previously received trastuzumab-based regimens. Participants were randomized to receive either trastuzumab deruxtecan (n=246) or the standard second-line treatment of paclitaxel with ramucirumab (n=248). At a median follow-up of 16.8 months in the trastuzumab deruxtecan group and 14.4 months in the comparator arm, median overall survival was 14.7 months and 11.4 months, respectively, a difference of 3.3 months.
The targeted therapy reduced the risk of death by 30% and the risk of disease progression by 26%, with a progression-free survival of 6.7 months versus 5.6 months in the control group. Trastuzumab deruxtecan also achieved higher objective response (44.3% vs. 29.1%) and disease control rates (91.9% vs. 75.9%) compared to paclitaxel with ramucirumab.
Treatment-related adverse events were frequent in both arms, with Grade 3 or higher events occurring in 68.0% of patients receiving trastuzumab deruxtecan and 73.8% of those on standard therapy. Common side effects in the trastuzumab deruxtecan group included fatigue, neutropenia, nausea, and anemia. These events were consistent with the known safety profile of the drug.
The DESTINY-Gastric04 findings mark the first phase 3 evidence supporting a HER2-directed therapy over standard chemotherapy in this setting. Further trials, including DESTINY-Gastric05, DESTINY-Gastric03, and ARTEMIDE-Gastric01, are underway to explore its potential use in earlier lines of therapy.
Reference:
ASCO. Trastuzumab Deruxtecan Can Help Some People With Advanced Gastric Cancers Live About 3 Months Longer. May 31 2025. Available at: https://www.asco.org/about-asco/press-center/news-releases/trastuzumab-deruxtecan-can-help-some-people-advanced-gastric. Last accessed: 1 June 2025.
