# Deeper Analysis to Identify the True Benefit of ICIs Immunotherapy in First-Line Treatment for Non-HER2-Positive/HER2-Negative Advanced or Metastatic Advanced or Metastatic Gastric Cancer (GC) or Gastroesophageal Junction Cancer (GEJC)

## TL;DR

This study finds that immune checkpoint inhibitors combined with chemotherapy improve survival in gastric cancer patients with high PD-L1 expression but not in those with low or negative expression.

## Contribution

The study provides the largest pooled analysis to date on ICI efficacy in gastric cancer based on PD-L1 expression levels.

## Key findings

- Patients with high PD-L1 CPS scores (CPS ≥ 10) showed significant OS and PFS benefits with ICI plus chemotherapy.
- Low or negative PD-L1 expression subgroups did not benefit significantly from adding ICIs to chemotherapy.
- Combining immunotherapy with induction chemotherapy followed by maintenance therapy may be more effective than continuous chemotherapy.

## Abstract

This study investigates the true benefit of immune checkpoint inhibitors (ICIs) in first-line treatment for advanced or metastatic gastric cancer (GC) and gastroesophageal junction cancer (GEJC) based on PD-L1 expression. By analyzing data from several phase 3 clinical trials, we found that ICIs combined with chemotherapy significantly improve overall survival (OS) and progression-free survival (PFS) in patients with high PD-L1 CPS scores (CPS ≥ 10). However, the benefits are less clear in patients with low or negative PD-L1 expression. Our findings suggest that first-line immunotherapy combined with induction chemotherapy followed by maintenance therapy may be more effective than continuous chemotherapy. This study provides valuable insights for optimizing treatment strategies and identifying patients who will most benefit from ICIs in clinical practice.

Purpose: Immune checkpoint inhibitors (ICIs) have improved survival outcomes in patients with advanced or metastatic gastric cancer (GC) or gastroesophageal junction cancer (GEJC) in the first-line setting. However, who will truly benefit from ICIs based on PD-L1 expression in different segments remains controversial, lacking high-level evidence. Methods: We performed a pooled analysis of several approved phase 3 trials as first-line immunotherapy for non-HER2-positive/HER2-negative advanced or metastatic GC or gastroesophageal junction cancer (GEJC) based on PD-L1 expression in segments with different expression levels. Kaplan–Meier curves and hazard ratios for overall survival (OS) were extracted. KMSubtraction-derived survival data for unreported subgroups and one-stage pooled analyses were used to estimate the efficacy of the ICI regimens. The primary outcome was OS, and the secondary outcome was progression-free survival across different PD-L1-expression subgroups. Results: This study is the largest global-sample-size pooled analysis to date, which involved a total of 4807 patients, with 2407 (50.1%) in the ICI-plus-chemotherapy group and 2400 (49.9%) in the chemotherapy-only group. Overall, the evidence demonstrates that adding ICIs to chemotherapy may not provide additional OS or PFS benefits in the negative-PD-L1-expression (CPS < 1) or PD-L1-low subgroups (CPS 1–4/TAP < 5%) compared with chemotherapy alone. Patients with high PD-L1 CPS scores (CPS ≥ 10) had significant OS and PFS benefits, whereas patients with moderate PD-L1 CPS scores (CPS 5–9) showed unclear OS and PFS benefits. Our analysis indicated that first-line immunotherapy combined with induction chemotherapy, followed by maintenance therapy, may be more suitable for practical clinical applications than immunotherapy combined with continuous chemotherapy. Conclusions: These findings can provide stronger evidence to identify patients who truly benefit from first-line ICI immunotherapy based on PD-L1 expression in different segments and offer a basis for optimal treatment and research in advanced or metastatic GC or GEJC.