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

Seung Tae Kim; Razvan Cristescu; Adam J. Bass; Kyoung Mee Kim; Justin I. Odegaard; Kyung Kim; Xiao Qiao Liu; Xinwei Sher; Hun Jung; Mijin Lee; Sujin Lee; Se Hoon Park; Joon Oh Park; Young Suk Park; Ho Yeong Lim; Hyuk Lee; Mingew Choi; Amir Ali Talasaz; Peter Soonmo Kang; Jonathan Cheng; Andrey Loboda; Jeeyun Lee; Won Ki Kang

doi:10.1038/s41591-018-0101-z

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

Seung Tae Kim, Razvan Cristescu, Adam J. Bass, Kyoung Mee Kim, Justin I. Odegaard, Kyung Kim, Xiao Qiao Liu, Xinwei Sher, Hun Jung, Mijin Lee, Sujin Lee, Se Hoon Park, Joon Oh Park, Young Suk Park, Ho Yeong Lim, Hyuk Lee, Mingew Choi, Amir Ali Talasaz, Peter Soonmo Kang, Jonathan ChengAndrey Loboda, Jeeyun Lee, Won Ki Kang

Department of Internal Medicine

Research output: Contribution to journal › Article › peer-review

1155 Scopus citations

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.

Original language	English
Pages (from-to)	1449-1458
Number of pages	10
Journal	Nature Medicine
Volume	24
Issue number	9
DOIs	https://doi.org/10.1038/s41591-018-0101-z
State	Published - 1 Sep 2018

Bibliographical note

Funding Information:
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.

Publisher Copyright:
© 2018, The Author(s).

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Kim, S. T., Cristescu, R., Bass, A. J., Kim, K. M., Odegaard, J. I., Kim, K., Liu, X. Q., Sher, X., Jung, H., Lee, M., Lee, S., Park, S. H., Park, J. O., Park, Y. S., Lim, H. Y., Lee, H., Choi, M., Talasaz, A. A., Kang, P. S., ... Kang, W. K. (2018). Comprehensive molecular characterization of clinical responses to PD-1 inhibition in metastatic gastric cancer. Nature Medicine, 24(9), 1449-1458. https://doi.org/10.1038/s41591-018-0101-z

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title = "Comprehensive molecular characterization of clinical responses to PD-1 inhibition in metastatic gastric cancer",

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.",

author = "Kim, {Seung Tae} and Razvan Cristescu and Bass, {Adam J.} and Kim, {Kyoung Mee} and Odegaard, {Justin I.} and Kyung Kim and Liu, {Xiao Qiao} and Xinwei Sher and Hun Jung and Mijin Lee and Sujin Lee and Park, {Se Hoon} and Park, {Joon Oh} and Park, {Young Suk} and Lim, {Ho Yeong} and Hyuk Lee and Mingew Choi and Talasaz, {Amir Ali} and Kang, {Peter Soonmo} and Jonathan Cheng and Andrey Loboda and Jeeyun Lee and Kang, {Won Ki}",

note = "Funding Information: 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. Publisher Copyright: {\textcopyright} 2018, The Author(s).",

year = "2018",

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doi = "10.1038/s41591-018-0101-z",

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Kim, ST, Cristescu, R, Bass, AJ, Kim, KM, Odegaard, JI, Kim, K, Liu, XQ, Sher, X, Jung, H, Lee, M, Lee, S, Park, SH, Park, JO, Park, YS, Lim, HY, Lee, H, Choi, M, Talasaz, AA, Kang, PS, Cheng, J, Loboda, A, Lee, J & Kang, WK 2018, 'Comprehensive molecular characterization of clinical responses to PD-1 inhibition in metastatic gastric cancer', Nature Medicine, vol. 24, no. 9, pp. 1449-1458. https://doi.org/10.1038/s41591-018-0101-z

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AU - Kim, Seung Tae

AU - Cristescu, Razvan

AU - Bass, Adam J.

AU - Kim, Kyoung Mee

AU - Odegaard, Justin I.

AU - Kim, Kyung

AU - Liu, Xiao Qiao

AU - Sher, Xinwei

AU - Jung, Hun

AU - Lee, Mijin

AU - Lee, Sujin

AU - Park, Se Hoon

AU - Park, Joon Oh

AU - Park, Young Suk

AU - Lim, Ho Yeong

AU - Lee, Hyuk

AU - Choi, Mingew

AU - Talasaz, Amir Ali

AU - Kang, Peter Soonmo

AU - Cheng, Jonathan

AU - Loboda, Andrey

AU - Lee, Jeeyun

AU - Kang, Won Ki

N1 - Funding Information: 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. Publisher Copyright: © 2018, The Author(s).

PY - 2018/9/1

Y1 - 2018/9/1

N2 - 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.

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

Abstract

Bibliographical note

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