Efficacy and safety of trastuzumab deruxtecan in the treatment of HER2-positive advanced or metastatic gastric or gastroesophageal cancer: a meta-analysis of single-arm trials.

BACKGROUND

Trastuzumab deruxtecan (T-DXd) has demonstrated clinical activity in HER2-positive advanced gastric and gastroesophageal junction (GEJ) adenocarcinoma following trastuzumab failure. However, variability across studies has limited a comprehensive assessment of its efficacy and safety.

METHODS

A systematic review and meta-analysis were conducted following PRISMA guidelines. PubMed, Scopus, and Cochrane databases were searched through September 2025. Prospective studies evaluating T-DXd in HER2-positive gastric or GEJ adenocarcinoma were included. Outcomes were pooled using a random-effects model and reported as proportions with 95% confidence intervals (CIs).

RESULTS

Eight trials (range of median follow-up 8.3-16.8 months) comprising 1,182 patients were included, with 77.9% treated in the second-line or later setting. The pooled objective response rate (ORR) was 42.7% (95% CI 36.9-48.6; I2 = 50%, p = 0.075), and the disease control rate (DCR) was 82.4% (95% CI 78.6-86.0; I2 = 0%, p < 0.001). Complete response occurred in 3.2% (95% CI 1.3-5.7; I2 = 52%, p = 0.062), partial response in 39.1% (95% CI 35.6-42.7; I2 = 13%, p = 0.33), and stable disease in 41.1% (95% CI 35.5-46.7; I2 = 55%, p = 0.049). Progressive disease was observed in 12.0% (95% CI 7.7-17.0; I2 = 71%, p = 0.004). Pooled overall survival was 54.5% (95% CI 43.5-65.3; I2 = 90%, p < 0.001) and progression-free survival was 73.4% (95% CI 60.5-84.5; I2 = 93%, p < 0.001). Grade ≥ 3 adverse events occurred in 46.7% (95% CI 32.5-61.2; I2 = 90%, p < 0.001), and interstitial lung disease in 2.1% (95% CI 0.2-5.6; I2 = 82%, p = 0.004).

CONCLUSIONS

T-DXd demonstrates meaningful antitumor activity and survival benefit in HER2-positive gastric and GEJ adenocarcinoma, with a clinically relevant toxicity profile requiring careful monitoring.