1577P - Prior antibiotic administration disrupts outcomes of PD-1 blockade in advanced gastric cancer by altering gut microbiome and systemic immune response

Background

Antibiotic therapy has been known to disrupt microbiota homeostasis and systemic immune responses, both of which are linked to response to immune checkpoint blockade. We aim to investigate whether prior antibiotics (pATB) administration influences outcomes following treatment with programmed cell death protein-1 (PD-1) inhibitors or chemotherapy in patients with advanced gastric cancer (AGC).

Methods

We analysed data of patients with AGC who were treated with PD-1 inhibitors (retrospective exploratory cohort; n=152) or irinotecan (chemotherapy cohort; n=101). Patients were classified into two groups based on whether they had received pATB within 28 days prior to the treatment. Another independent retrospective validation cohort (n=123) and prospective validation cohort (n=30) treated with PD-1 inhibitors were further analysed. Distinct features in gut microbiome and circulating immune cells were analysed (experimental cohort; n=24).

Results

In the retrospective exploratory cohort, pATB administration was associated with poor 17 progression-free survival (PFS; hazard ratio [HR]=2.897, 95% confidence interval [CI]=2.043–4.109) and overall survival (OS; HR=2.294, 95% CI=1.622–3.242) but did not affect outcomes among patients treated with irinotecan. In the validation cohorts, pATB administration was associated with poor treatment outcomes following PD-1 blockade. Multivariate analysis of the overall patients treated with PD-1 inhibitors confirmed that pATB was an independent predictor of poor PFS (HR=3.243, 95% CI=2.427–4.333) and OS (HR=3.046, 95% CI= 2.358–3.935). Administration of pATB was associated with diminished gut microbiome diversity, reduced abundance of Lactobacillus gasseri, and disproportional enrichment of circulating exhaustive CD8⁺ T cells, all of which can hinder the efficacy of PD-1 blockade.

Conclusions

Considering the inferior treatment response and poor survival outcomes by pATB followed by PD-1 blockade, antibiotics should be prescribed with caution in patients with AGC planned to receive PD-1 inhibitors.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

National Research Foundation of Korea, Ministry of Science and ICT, Yonsei University College of Medicine.

Disclosure

All authors have declared no conflicts of interest.