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Molecular Insights in Clinical Responses to PD-1 Inhibition in Metastatic Gastric Cancer

Potentially relevant biomarkers uncovered for selection of patients who may derive greater benefit from anti-PD-1 therapy
28 Aug 2018
Gastrointestinal cancers;  Cancer Immunology and Immunotherapy

Molecular characterisation of tissues and circulating tumour DNA (ctDNA) from 61 patients with metastatic gastric cancer who were treated with anti-PD-1 monoclonal antibody pembrolizumab as salvage treatment in a prospective phase II clinical trial provides insight into the features associated with response to the therapy. Korean researchers of the Samsung Medical Center in Seoul published the findings in the Nature Medicine.

A group of investigators led by Jeeyun Lee and Won Ki Kang described in background that clinical studies support the efficacy of PD-1 targeted therapy in a subset of patients with metastatic gastric cancer. However, identification of determinants of response prompted them to perform the current analysis.

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

For the 55 patients for whom 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% versus 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.

The authors concluded that their findings provide insight into the molecular features associated with response to pembrolizumab in patients with metastatic gastric cancer and provide biomarkers potentially relevant for the selection of patients who may derive greater benefit from PD-1 inhibition.

This work 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).

Among authors, six are employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. and two authors are employees of Guardant Health, USA. 


Kim ST, Cristescu R, Bass AJ, et al. Comprehensive molecular characterization of clinical responses to PD-1 inhibition in metastatic gastric cancerNature Medicine, Published online 16 July 2018. doi: 10.1038/s41591-018-0101-z.

Last update: 28 Aug 2018

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