Abstract

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.

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Acknowledgements

This work was supported by the MISP program 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) (to J.L. and K.-M.K.). We thank D. Kaufman for drafting the manuscript. We thank J. Park at Samsung Medical Information and Media Servces at Samsung Medical Center for dedicated support with image work.

Author information

Author notes

  1. These authors contributed equally: Seung Tae Kim, Razvan Cristescu, Adam J. Bass, Kyoung-Mee Kim, Justin I. Odegaard.

Affiliations

  1. Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

    • Seung Tae Kim
    • , Kyung Kim
    • , Mijin Lee
    • , Sujin Lee
    • , Se Hoon Park
    • , Joon Oh Park
    • , Young Suk Park
    • , Ho Yeong Lim
    • , Jeeyun Lee
    •  & Won Ki Kang
  2. Merck & Co., Inc., Kenilworth, NJ, USA

    • Razvan Cristescu
    • , Xiao Qiao Liu
    • , Xinwei Sher
    • , Hun Jung
    • , Peter Soonmo Kang
    • , Jonathan Cheng
    •  & Andrey Loboda
  3. Division of Molecular and Cellular Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    • Adam J. Bass
  4. Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

    • Kyoung-Mee Kim
  5. Department of Medical Affairs, Guardant Health, Redwood City, CA, USA

    • Justin I. Odegaard
    •  & AmirAli Talasaz
  6. Division of Gastroenterology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

    • Hyuk Lee
  7. Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

    • Mingew Choi

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Contributions

The concept and clinical design were performed by J.L., S.T.K., R.C., K.-M.K., and W.K.K. J.L., S.T.K., R.C., A.J.B., J.I.O., K.-M.K., and W.K.K. wrote the manuscript. All clinical data analyses were done by S.T.K., R.C., K.-M.K., J.I.O., K.K., and J.L. All genomic analyses were performed by R.C., A.J.B., J.I.O., K.K., X.Q.L., X.S., A.T., P.S.K., J.C., and A.L. Clinical trial protocol development and clinical trial procedures were done by H.J., M.L., S.L., S.H.P., J.O.P., Y.S.P., H.Y.L., H.L., M.C., W.K.K., and J.L. All authors read and approved the final manuscript.

Competing interests

R.C., X.Q.L., X.S., J.C., P.S.K., and A.L. are employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. J.I.O. and A.T. are employees of Guardant Health, USA.

Corresponding author

Correspondence to Jeeyun Lee.

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https://doi.org/10.1038/s41591-018-0101-z

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