medwireNews: Treatment with the antibody–drug conjugate trastuzumab deruxtecan leads to better survival outcomes than with ramucirumab plus paclitaxel in patients with HER2-positive metastatic gastric or gastroesophageal junction adenocarcinoma, suggests an interim analysis of the DESTINY-Gastric04 trial.
The results, which were presented at the 2025 ASCO Annual Meeting in Chicago, Illinois, USA, and simultaneously published in The New England Journal of Medicine, suggest that “trastuzumab deruxtecan may be the preferred second-line treatment option in patients whose tumors retain HER2 expression after progression occurs during a trastuzumab-containing regimen,” write Kohei Shitara (National Cancer Center Hospital East, Chiba, Japan) and colleagues.
The trial enrolled 494 patients with HER2-positive metastatic gastric or gastroesophageal junction adenocarcinoma confirmed on tumor biopsy conducted after the patient had progression while receiving trastuzumab-based therapy.
The investigators randomly assigned the patients to receive trastuzumab deruxtecan at a dose of 6.4 mg/kg every 21 days (n=246) or ramucirumab at 8 mg/kg on days 1 and 15 of each 28-day cycle plus paclitaxel at 80 mg/m2 on days 1, 8, and 15 (n=248).
The patients were a median of 63.2–64.3 years old, 79.4% were men, 49.8% were White, 61.1% had the primary tumor in the stomach, and 84.0% had a HER2 status of IHC 3+.
Shitara et al found that, at data cut-off, 50.4% of patients in the trastuzumab deruxtecan arm had died, as had 57.3% of those in the ramucirumab–paclitaxel arm. The former group had a significantly better overall survival – the primary endpoint of the trial – with a median duration of 14.7 months versus 11.4 months for those treated with ramucirumab–paclitaxel, giving a hazard ratio (HR) for death of 0.70.
The trastuzumab deruxtecan group showed a consistently higher survival rate than the ramucirumab–paclitaxel group at 6, 12, and 24 months, with corresponding rates of 83.5% versus 74.4%, 57.6% versus 48.9%, and 29.0% versus 13.9%.
Trastuzumab deruxtecan was also significantly superior to ramucirumab–paclitaxel with regard to two secondary endpoints. These were progression-free survival, with corresponding medians of 6.7 months versus 5.6 months and an HR for disease progression or death of 0.74, and confirmed objective response, at rates of 44.3% and 29.1%, respectively.
However, there was no significant difference between the two groups for the secondary endpoints of disease control, duration of response, or quality of life.
Adverse events (AEs) of grade 3 or higher occurred in a similar 50.0% of patients in the trastuzumab deruxtecan group and 54.1% of those in the ramucirumab–paclitaxel group, with the most common being neutropenia (28.7 and 35.6% of patients, respectively) and anemia (13.9 and 13.7%). Treatment was discontinued due to AEs in 11.5% and 13.3% of patients in the trastuzumab deruxtecan and ramucirumab–paclitaxel groups, respectively.
In all, there were six treatment-related deaths. The four in the trastuzumab deruxtecan arm were due to upper gastrointestinal hemorrhage, intestinal obstruction, sudden death syndrome, and one was not otherwise specified. The two in the ramucirumab–paclitaxel group were from gastric perforation and interstitial lung disease.
Meanwhile, incidences of other interstitial lung disease events and pneumonitis with trastuzumab deruxtecan, a known toxicity of the drug, were mainly of low grade.
Limitations of the study included an open-label design due to the different treatment schedules of the trial drugs, low power to assess subgroups, and intrapatient heterogeneity meaning the obtained tumor biopsy samples may not reflect the HER2 status of all metastases, the authors say.
“[A]fter the failure of other HER2-directed therapies in the context of second-line treatment of metastatic gastric cancer or gastroesophageal junction adenocarcinoma, the clinical benefit that was observed with trastuzumab deruxtecan over ramucirumab plus paclitaxel in our trial suggests that trastuzumab deruxtecan may be the preferred second-line treatment option” in this patient population, the researchers write.
They conclude that the results “warrant further evaluation of trastuzumab deruxtecan in the context of first-line therapy.”
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N Engl J Med 2025; doi:10.1056/NEJMoa2503119
2025 ASCO Annual Meeting; Chicago, Illinois, USA: 30 May–3 June