Meta-Analysis: ICI Adds Survival Benefit in HER2+ Gastric Cancer

Key Takeaways

• In advanced HER2-positive gastric or gastroesophageal junction adenocarcinoma, adding an immune checkpoint inhibitor to trastuzumab and chemotherapy was associated with longer pooled progression-free survival and overall survival than trastuzumab-based therapy alone, with median progression-free survival of 10.40 versus 8.27 months and median overall survival of 20.4 versus 17.2 months.
• Response outcomes were also higher with immune checkpoint inhibitor intensification in advanced HER2-positive gastric or gastroesophageal junction adenocarcinoma, with pooled odds ratios of 1.85 for objective response rate and 2.46 for disease control rate; all six pooled regimens used anti-PD-1 antibodies, and no PD-L1 inhibitors were included.
• Grade 3 or higher adverse events were not significantly different between groups, although diarrhea, hypothyroidism, abnormal liver function, and pneumonia were reported more often with immune checkpoint inhibitor plus trastuzumab and chemotherapy.

Adding an anti-PD-1–based immune checkpoint inhibitor to trastuzumab and chemotherapy in advanced HER2-positive gastric or gastroesophageal junction adenocarcinoma was associated with longer pooled progression-free survival than trastuzumab-based therapy alone, with a median of 10.40 versus 8.27 months and a hazard ratio of 0.6951 (95% CI 0.6012-0.8037; p<0.0001). In the systematic review and meta-analysis of immune checkpoint inhibitor intensification in HER2-positive gastric and gastroesophageal junction adenocarcinoma, the authors pooled six studies involving 1,097 patients, including 540 who received the triplet regimen, and also found longer overall survival. Grade 3 or higher adverse events were reported as similar between groups.

The analysis followed PRISMA methods and searched PubMed, Cochrane Library, Embase, and Scopus through December 29, 2025, for studies comparing immune checkpoint inhibitor plus trastuzumab and chemotherapy with trastuzumab-based therapy alone that reported at least one of progression-free survival, overall survival, or safety. To derive pooled time-to-event estimates, the authors digitized published Kaplan-Meier curves with WebPlotDigitizer and reconstructed individual participant data. In a compact PRISMA flow, 310 records were identified, 95 duplicates were removed, 129 articles remained after early exclusions, and 6 studies were ultimately included.

Efficacy favored immune checkpoint inhibitor intensification across survival and response measures. Objective response rate and disease control rate were each higher with the intensified regimen, with pooled odds ratios of 1.85 (p<0.00001) and 2.46 (p=0.006), respectively. The authors also noted that all six included regimens were anti-PD-1 monoclonal antibodies, with no PD-L1 inhibitors represented in the final pooled analysis. The observed benefit pattern extended across progression-free survival, overall survival, and tumor response outcomes.

The authors framed several limits on interpretation, including the small number of included studies, heterogeneous designs and patient populations, and the inability to analyze individual PD-1 agents separately. They also noted that reconstructed Kaplan-Meier data may deviate slightly from original datasets and that long-term survival outcomes and late-onset adverse events were not reported consistently across studies. Within those bounds, the pooled analysis described a favorable efficacy signal without a significant difference in severe toxicity rates.

Clinician Questions

What survival differences were reported when an immune checkpoint inhibitor was added to trastuzumab and chemotherapy in advanced HER2-positive gastric or gastroesophageal junction adenocarcinoma?

In advanced HER2-positive gastric or gastroesophageal junction adenocarcinoma, immune checkpoint inhibitor plus trastuzumab and chemotherapy was associated with a median progression-free survival of 10.40 months versus 8.27 months with trastuzumab-based therapy alone, with HR 0.6951 (95% CI 0.6012-0.8037; p<0.0001), and a median overall survival of 20.4 months versus 17.2 months, with HR 0.8104 (95% CI 0.7010-0.9369; p=0.0040).

Did immune checkpoint inhibitor plus trastuzumab and chemotherapy improve response outcomes in HER2-positive gastric or GEJ cancer?

In advanced HER2-positive gastric or gastroesophageal junction adenocarcinoma, the pooled analysis reported higher objective response rate and disease control rate with immune checkpoint inhibitor plus trastuzumab and chemotherapy, with odds ratios of 1.85 for objective response rate (p<0.00001) and 2.46 for disease control rate (p=0.006).

Was severe toxicity higher with immune checkpoint inhibitor intensification in advanced HER2-positive gastric or GEJ adenocarcinoma?

In advanced HER2-positive gastric or gastroesophageal junction adenocarcinoma, grade 3 or higher adverse events were not significantly different between groups in the pooled analysis, while diarrhea, hypothyroidism, abnormal liver function, and pneumonia were reported more frequently with immune checkpoint inhibitor plus trastuzumab and chemotherapy.

How was the meta-analysis of immune checkpoint inhibitor plus trastuzumab in HER2-positive gastric or GEJ cancer conducted?

The authors conducted a PRISMA-guided systematic review and meta-analysis in advanced HER2-positive gastric or gastroesophageal junction adenocarcinoma, searched PubMed, Cochrane Library, Embase, and Scopus through December 29, 2025, included six studies with 1,097 patients, and derived pooled time-to-event outcomes by digitizing published Kaplan-Meier curves with WebPlotDigitizer and reconstructing individual participant data.