Molecular Characterisation of Clinical Responses to Anti-PD-1 Therapy in Metastatic Gastric Cancer

Insight into the molecular features associated with response to pembrolizumab

The investigators from Samsung Medical Center in Seoul, Republic of Korea and Dana-Farber Cancer Institute, Boston, USA published on 16 July 2018 in Nature Medicine the findings from the study that provides insight into the molecular features associated with response to pembrolizumab in patients with metastatic gastric cancer with microsatellite instability-high and Epstein–Barr virus-positive tumours. The results point to biomarkers potentially relevant for the selection of patients who may derive greater benefit from PD-1 inhibition. 

Clinical studies support the efficacy of PD-1 targeted therapy in a subset of patients with metastatic gastric cancer. With a goal of identifying determinants of response, the study team led by Jeeyun Lee and Won Ki Kang performed molecular characterisation of tissues and circulating tumour DNA (ctDNA) from 61 patients with metastatic gastric cancer who were treated with pembrolizumab as salvage treatment in a prospective phase II clinical trial. 

In patients with microsatellite instability-high and Epstein–Barr virus-positive tumours, which are mutually exclusive, dramatic responses to pembrolizumab were observed; in particular, overall response rate (ORR) of 85.7% was recorded in microsatellite instability-high and 100% in Epstein–Barr virus-positive metastatic gastric cancer. 

In 55 patients PD-L1 combined positive score positivity was available (combined positive score cut-off value ≥1%), the ORR was significantly higher in PD-L1-positive gastric cancer when compared to PD-L1-negative tumours (50.0% vs 0.0%, p < 0.001). 

Changes in ctDNA levels at six weeks post-treatment predicted response and progression-free survival, and decreased ctDNA was associated with improved outcomes. 

This study provides biomarkers potentially relevant for the selection of patients with metastatic gastric cancer who may derive greater benefit from PD-1 inhibition. 

The study was supported by the MISP programme at Merck Sharp & Dohme Corp., USA, and a grant from the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (HI16C1990). 

Reference

Kim ST, Cristescu R, Bass AJ, et al. Comprehensive molecular characterization of clinical responses to PD-1 inhibition in metastatic gastric cancer. Nature Medicine; Published online 16 July2018. DOI: https://doi.org/10.1038/s41591-018-0101-z