Gut microbiome to predict survival time in advanced gastric cancer treated with nivolumab

The DELIVER trial has been performed to discover novel host-related biomarkers for nivolumab treatment in advanced gastric cancer using faecal samples. Several genomic pathways and genera in the gut microbiome were significantly associated with survival time in patients with advanced gastric cancer treated with nivolumab. Furthermore, the nucleotide metabolism pathway may become a biomarker to predict the prognosis of nivolumab treatment in this setting.

Thus far, several studies revealed that the efficacy of anti-PD-1-based immunotherapy was associated with the composition of the gut microbiome in various types of cancers. However, little is known about gastric cancer. Therefore, the DELIVER trial was initiated to discover novel host-related biomarkers for nivolumab treatment in advanced gastric cancer using faecal samples. Previously, it was reported that the genomic pathway of bacterial invasion of epithelial cells may predict poor response to nivolumab in patients with advanced gastric cancer. Gastric cancer-specific gut microbiome was also identified as a potential clinical biomarker. At the 2021 ESMO World Congress on Gastrointestinal Cancer, the results of an analysis to investigate the associations between genomic pathway/ genus of gut microbiome and survival time of nivolumab treatment in advanced gastric cancer, were presented.

DELIVER study design

The multicentre, observational/translational DELIVER trial enrolled 501 patients with advanced gastric or gastrooesophageal junction (GEJ) cancer who received nivolumab alone in any line of treatment. Faecal samples for gut microbiome analysis and blood samples for gene expression, SNPs and metabolome analyses were collected prospectively and at the time of progression or intolerance to nivolumab to investigate the associations of genomic pathway and genus of the gut microbiome with efficacy of nivolumab. Genomic data were measured by genome shotgun sequence at a central lab. Biomarkers were analysed using a Cox regression model in the first 200 patients (training cohort). Then, the top 30 candidates in an ascending order of p-value were validated in the last 301 patients (validation cohort) using the Bonferroni method.

Results

One hundred ninety of 200 patients and 277 of 301 patients were available for massive metagenomic and survival analysis in the training cohort and validation cohort, respectively. Median age of enrolled patients was approximately 70 years and more than 60% of patients were diagnosed with advanced disease. The median PFS and OS were 1.79 and 5.78 months, respectively, for the training cohort and 1.84 and 5.95 months, respectively, for the validation cohort.

In the OS analysis, 24 pathways and 6 genera were detected within top 30 candidates with p-value of <0.05 in the training cohort. Then, two pathways and one genus were confirmed to be statistically significant in the validation cohort: purine metabolism (HR 0.31, p= 0.00064), peptidoglycan biosynthesis (HR 0.27, p= 0.00088), and Corynebacterium (HR 1.09, p<0.0001). Also the nucleotide metabolism pathway was associated with OS, although it was not statistically significant under the Bonferroni method (HR 0.53, p=0.0022). In the PFS analysis, 20 pathways, 9 genera, and 1 phylum were detected with p-value of <0.05 in the training cohort; of which nucleotide metabolism pathway (HR 0.39, p= 0.0013) and Porphyromonas (HR 3.37, p< 0.0001) were confirmed in the validation cohort.

Conclusion

The DELIVER translational study demonstrated that several genomic pathways and genera in the gut microbiome were significantly associated with survival time in patients with advanced gastric cancer treated with nivolumab. In addition, as the nucleotide metabolism pathway was associated with both OS and PFS, it may potentially become a biomarker to predict the prognosis of nivolumab treatment in advanced gastric cancer.

Reference

Sunakawa Y, et al. Gut microbiome to predict survival time in advanced gastric cancer treated with nivolumab: the DELIVER trial (JACCRO GC-08). Presented at 2021 ESMO World Congress on Gastrointestinal Cancer; Abstract O-13.