Comprehensive molecular characterization of clinical responses to PD-1 inhibition in metastatic gastric cancer

• Published in: Nature medicine Vol. 24; no. 9; pp. 1449 - 1458
• Main Authors: Kim, Seung Tae, Cristescu, Razvan, Bass, Adam J., Kim, Kyoung-Mee, Odegaard, Justin I., Kim, Kyung, Liu, Xiao Qiao, Sher, Xinwei, Jung, Hun, Lee, Mijin, Lee, Sujin, Park, Se Hoon, Park, Joon Oh, Park, Young Suk, Lim, Ho Yeong, Lee, Hyuk, Choi, Mingew, Talasaz, AmirAli, Kang, Peter Soonmo, Cheng, Jonathan, Loboda, Andrey, Lee, Jeeyun, Kang, Won Ki
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.09.2018; Nature Publishing Group
• Subjects: 631/67/1504/1829; 692/308/2779/109; 692/308/575; Apoptosis; Biochemistry; Biological markers; Biomarkers; Biomedical and Life Sciences; Biomedicine; Cancer; Cancer metastasis; Cancer patients; Cancer prevention; Cancer Research; Care and treatment; Cell death; Clinical trials; Deoxyribonucleic acid; DNA; Epstein-Barr virus; Gastric cancer; Genetic aspects; Health aspects; Infectious Diseases; Medical research; Medical schools; Metabolic Diseases; Metastases; Metastasis; Microsatellite instability; Molecular Medicine; Monoclonal antibodies; Neurosciences; Patients; PD-1 protein; PD-L1 protein; Pembrolizumab; Salvage; Stability; Stomach cancer; Targeted cancer therapy; Tumors; Viruses; South Korea
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/s41591-018-0101-z

Clinical studies support the efficacy of programmed cell death 1 (PD-1) targeted therapy in a subset of patients with metastatic gastric cancer (mGC). With the goal of identifying determinants of response, we performed molecular characterization of tissues and circulating tumor DNA (ctDNA) from 61 patients with mGC who were treated with pembrolizumab as salvage treatment in a prospective phase 2 clinical trial. In patients with microsatellite instability-high and Epstein–Barr virus-positive tumors, which are mutually exclusive, dramatic responses to pembrolizumab were observed (overall response rate (ORR) 85.7% in microsatellite instability-high mGC and ORR 100% in Epstein–Barr virus-positive mGC). For the 55 patients for whom programmed death-ligand 1 (PD-L1) combined positive score positivity was available (combined positive score cut-off value ≥1%), ORR was significantly higher in PD-L1(+) gastric cancer when compared to PD-L1(−) tumors (50.0% versus 0.0%, P value <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. Our findings provide insight into the molecular features associated with response to pembrolizumab in patients with mGC and provide biomarkers potentially relevant for the selection of patients who may derive greater benefit from PD-1 inhibition. Microsatellite instability and Epstein–Barr virus positivity represent novel biomarkers of clinical response to PD-1 blockade in patients with metastatic gastric cancer.