The effective molecular characteristics of PD-1 inhibitor combination regimen as the first-line treatment for Chinese patients with HER2-positive gastric cancer: a real-world retrospective analysis study.

Background: The prognosis of gastric cancer (GC) patients with human epidermal growth factor receptor 2 (HER2) positive was poor. To illustrate the underlying effective and distinctive molecular characteristics of programmed cell death protein 1 (PD-1) blockade in the treatment of GC with HER2 positive, we analyzed the survival outcome of PD-1 inhibitors combination regimen as the first-line treatment for GC patients with HER2-positive in China.

Methods: This retrospective real-world study compared the prognoses of first-line systemic treatment of PD-1 inhibitors combined with trastuzumab and chemotherapy (PTC group) and trastuzumab and chemotherapy (TC group) in Chinese patients with HER2-positive GC, and then further to identify the specific and molecular characteristics of PD-1 inhibitors treatment by hierarchical analysis. The patients were matched using propensity score matching (PSM). Overall survival (OS) and progression-free survival (PFS) were used as the primary and secondary endpoints of the study.

Results: A total of 95 patients with HER2-positive GC receiving first-line treatment at Zhongshan Hospital of Fudan University from January 2019 to September 2022 were included. The median OS (24.67 vs. 16.00 months, P=0.01) and median PFS (15.57 vs. 7.57 months, P=0.008) of patients with HER2-positive GC who received PTC regimen were longer than those treated by TC regimen as first-line systemic treatment after PSM analysis. In hierarchical analysis, we discovered that programmed cell death ligand 1 (PD-L1) positive expression in tumor tissues was not a predictor of PD-1 inhibitors in HER2-positive GC. However, PD-L1 was an indicator of better survival outcomes by combined trastuzumab treatment in all GC patients. Furthermore, in the subgroup analysis, we found that the median OS for the PTC group was longer by nearly 8 months than the TC group in patients with HER2 gene copy number [HER2 fluorescence in situ hybridization (FISH) test] more than six, while the median OS for the PTC group was longer by approximately 12 months than the TC group in patients with HER2-positive GC with TP53 mutations.

Conclusions: The results suggested that patients with HER2-positive GC could benefit from PD-1 inhibitors combination with trastuzumab and chemotherapy, especially patients with HER-2 FISH more than six and TP53 mutations.