Hyperprogressive disease during PD-1/PD-L1 blockade in patients with non-small-cell lung cancer

C. G. Kim; K. H. Kim; K. H. Pyo; C. F. Xin; M. H. Hong; B. C. Ahn; Y. Kim; S. J. Choi; H. I. Yoon; J. G. Lee; C. Y. Lee; S. Y. Park; S. H. Park; B. C. Cho; H. S. Shim; E. C. Shin; H. R. Kim

doi:10.1093/annonc/mdz123

Hyperprogressive disease during PD-1/PD-L1 blockade in patients with non-small-cell lung cancer

C. G. Kim, K. H. Kim, K. H. Pyo, C. F. Xin, M. H. Hong, B. C. Ahn, Y. Kim, S. J. Choi, H. I. Yoon, J. G. Lee, C. Y. Lee, S. Y. Park, S. H. Park, B. C. Cho, H. S. Shim, E. C. Shin, H. R. Kim

Department of Internal Medicine

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

169 Citations (Scopus)

Abstract

Background: Immune checkpoint blockade with Programmed cell death 1 (PD-1)/PD-L1 inhibitors has been effective in various malignancies and is considered as a standard treatment modality for patients with non-small-cell lung cancer (NSCLC). However, emerging evidence show that PD-1/PD-L1 blockade can lead to hyperprogressive disease (HPD), a flair-up of tumor growth linked to dismal prognosis. This study aimed to evaluate the incidence of HPD and identify the determinants associated with HPD in patients with NSCLC treated with PD-1/PD-L1 blockade. Patients and methods: We enrolled patients with recurrent and/or metastatic NSCLC treated with PD-1/PD-L1 inhibitors between April 2014 and November 2018. Clinicopathologic variables, dynamics of tumor growth, and treatment outcomes were analyzed in patients with NSCLC who received PD-1/PD-L1 blockade. HPD was defined according to tumor growth kinetics (TGK), tumor growth rate (TGR), and time to treatment failure (TTF). Immunophenotyping of peripheral blood CD8⁺ T lymphocytes was conducted to explore the potential predictive biomarkers of HPD. Results: A total of 263 patients were analyzed. HPD was observed in 55 (20.9%), 54 (20.5%), and 98 (37.3%) patients according to the TGK, TGR, and TTF. HPD meeting both TGK and TGR criteria was associated with worse progression-free survival [hazard ratio (HR) 4.619; 95% confidence interval (CI) 2.868-7.440] and overall survival (HR, 5.079; 95% CI, 3.136-8.226) than progressive disease without HPD. There were no clinicopathologic variables specific for HPD. In the exploratory biomarker analysis with peripheral blood CD8⁺ T lymphocytes, a lower frequency of effector/memory subsets (CCR7^-CD45RA^- T cells among the total CD8⁺ T cells) and a higher frequency of severely exhausted populations (TIGIT⁺ T cells among PD-1⁺CD8⁺ T cells) were associated with HPD and inferior survival rate. Conclusion: HPD is common in NSCLC patients treated with PD-1/PD-L1 inhibitors. Biomarkers derived from rationally designed analysis may successfully predict HPD and worse outcomes, meriting further investigation of HPD.

Original language	English
Article number	mdz123
Pages (from-to)	1104-1113
Number of pages	10
Journal	Annals of Oncology
Volume	30
Issue number	7
DOIs	https://doi.org/10.1093/annonc/mdz123
Publication status	Published - 2019 Jul 1

Bibliographical note

Funding Information:
This work was supported by grants from the Basic Science Research Program through the National Research Foundation of Republic of Korea (grant numbers: NRF-2017R1A2A1A17069782, 2017R1D1A1B03029874, 2017M3A9E8029717, 2017M3A9E9072669, and 2016M3C9A4922809).

Funding Information:
The authors would like to thank Hyung-Don Kim, Ji Won Han, and Hoyoung Lee, members of the Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, for scientific advice and useful discussions. This work was supported by grants from the Basic Science Research Program through the National Research Foundation of Republic of Korea (grant numbers: NRF-2017R1A2A1A17069782, 2017R1D1A1B03029874, 2017M3A9E8029717, 2017M3A9E9072669, and 2016M3C9A4922809). National Research Foundation of Republic of Korea NRF-2017R1A2A1A17069782 2017R1D1A1B03029874 2017M3A9E8029717 2017M3A9E9072669 2016M3C9A4922809, The authors have declared no conflicts of interest.

Publisher Copyright:
© 2019 The Author(s) 2019.

All Science Journal Classification (ASJC) codes

Hematology
Oncology

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1093/annonc/mdz123

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Kim, C. G., Kim, K. H., Pyo, K. H., Xin, C. F., Hong, M. H., Ahn, B. C., Kim, Y., Choi, S. J., Yoon, H. I., Lee, J. G., Lee, C. Y., Park, S. Y., Park, S. H., Cho, B. C., Shim, H. S., Shin, E. C., & Kim, H. R. (2019). Hyperprogressive disease during PD-1/PD-L1 blockade in patients with non-small-cell lung cancer. Annals of Oncology, 30(7), 1104-1113. [mdz123]. https://doi.org/10.1093/annonc/mdz123

@article{9147ac038de24633bf499efcb199b298,

title = "Hyperprogressive disease during PD-1/PD-L1 blockade in patients with non-small-cell lung cancer",

abstract = "Background: Immune checkpoint blockade with Programmed cell death 1 (PD-1)/PD-L1 inhibitors has been effective in various malignancies and is considered as a standard treatment modality for patients with non-small-cell lung cancer (NSCLC). However, emerging evidence show that PD-1/PD-L1 blockade can lead to hyperprogressive disease (HPD), a flair-up of tumor growth linked to dismal prognosis. This study aimed to evaluate the incidence of HPD and identify the determinants associated with HPD in patients with NSCLC treated with PD-1/PD-L1 blockade. Patients and methods: We enrolled patients with recurrent and/or metastatic NSCLC treated with PD-1/PD-L1 inhibitors between April 2014 and November 2018. Clinicopathologic variables, dynamics of tumor growth, and treatment outcomes were analyzed in patients with NSCLC who received PD-1/PD-L1 blockade. HPD was defined according to tumor growth kinetics (TGK), tumor growth rate (TGR), and time to treatment failure (TTF). Immunophenotyping of peripheral blood CD8+ T lymphocytes was conducted to explore the potential predictive biomarkers of HPD. Results: A total of 263 patients were analyzed. HPD was observed in 55 (20.9%), 54 (20.5%), and 98 (37.3%) patients according to the TGK, TGR, and TTF. HPD meeting both TGK and TGR criteria was associated with worse progression-free survival [hazard ratio (HR) 4.619; 95% confidence interval (CI) 2.868-7.440] and overall survival (HR, 5.079; 95% CI, 3.136-8.226) than progressive disease without HPD. There were no clinicopathologic variables specific for HPD. In the exploratory biomarker analysis with peripheral blood CD8+ T lymphocytes, a lower frequency of effector/memory subsets (CCR7-CD45RA- T cells among the total CD8+ T cells) and a higher frequency of severely exhausted populations (TIGIT+ T cells among PD-1+CD8+ T cells) were associated with HPD and inferior survival rate. Conclusion: HPD is common in NSCLC patients treated with PD-1/PD-L1 inhibitors. Biomarkers derived from rationally designed analysis may successfully predict HPD and worse outcomes, meriting further investigation of HPD.",

author = "Kim, {C. G.} and Kim, {K. H.} and Pyo, {K. H.} and Xin, {C. F.} and Hong, {M. H.} and Ahn, {B. C.} and Y. Kim and Choi, {S. J.} and Yoon, {H. I.} and Lee, {J. G.} and Lee, {C. Y.} and Park, {S. Y.} and Park, {S. H.} and Cho, {B. C.} and Shim, {H. S.} and Shin, {E. C.} and Kim, {H. R.}",

note = "Funding Information: This work was supported by grants from the Basic Science Research Program through the National Research Foundation of Republic of Korea (grant numbers: NRF-2017R1A2A1A17069782, 2017R1D1A1B03029874, 2017M3A9E8029717, 2017M3A9E9072669, and 2016M3C9A4922809). Funding Information: The authors would like to thank Hyung-Don Kim, Ji Won Han, and Hoyoung Lee, members of the Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, for scientific advice and useful discussions. This work was supported by grants from the Basic Science Research Program through the National Research Foundation of Republic of Korea (grant numbers: NRF-2017R1A2A1A17069782, 2017R1D1A1B03029874, 2017M3A9E8029717, 2017M3A9E9072669, and 2016M3C9A4922809). National Research Foundation of Republic of Korea NRF-2017R1A2A1A17069782 2017R1D1A1B03029874 2017M3A9E8029717 2017M3A9E9072669 2016M3C9A4922809, The authors have declared no conflicts of interest. Publisher Copyright: {\textcopyright} 2019 The Author(s) 2019.",

year = "2019",

month = jul,

day = "1",

doi = "10.1093/annonc/mdz123",

language = "English",

volume = "30",

pages = "1104--1113",

journal = "Annals of Oncology",

issn = "0923-7534",

publisher = "Oxford University Press",

number = "7",

}

TY - JOUR

T1 - Hyperprogressive disease during PD-1/PD-L1 blockade in patients with non-small-cell lung cancer

AU - Kim, C. G.

AU - Kim, K. H.

AU - Pyo, K. H.

AU - Xin, C. F.

AU - Hong, M. H.

AU - Ahn, B. C.

AU - Kim, Y.

AU - Choi, S. J.

AU - Yoon, H. I.

AU - Lee, J. G.

AU - Lee, C. Y.

AU - Park, S. Y.

AU - Park, S. H.

AU - Cho, B. C.

AU - Shim, H. S.

AU - Shin, E. C.

AU - Kim, H. R.

N1 - Funding Information: This work was supported by grants from the Basic Science Research Program through the National Research Foundation of Republic of Korea (grant numbers: NRF-2017R1A2A1A17069782, 2017R1D1A1B03029874, 2017M3A9E8029717, 2017M3A9E9072669, and 2016M3C9A4922809). Funding Information: The authors would like to thank Hyung-Don Kim, Ji Won Han, and Hoyoung Lee, members of the Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, for scientific advice and useful discussions. This work was supported by grants from the Basic Science Research Program through the National Research Foundation of Republic of Korea (grant numbers: NRF-2017R1A2A1A17069782, 2017R1D1A1B03029874, 2017M3A9E8029717, 2017M3A9E9072669, and 2016M3C9A4922809). National Research Foundation of Republic of Korea NRF-2017R1A2A1A17069782 2017R1D1A1B03029874 2017M3A9E8029717 2017M3A9E9072669 2016M3C9A4922809, The authors have declared no conflicts of interest. Publisher Copyright: © 2019 The Author(s) 2019.

PY - 2019/7/1

Y1 - 2019/7/1

N2 - Background: Immune checkpoint blockade with Programmed cell death 1 (PD-1)/PD-L1 inhibitors has been effective in various malignancies and is considered as a standard treatment modality for patients with non-small-cell lung cancer (NSCLC). However, emerging evidence show that PD-1/PD-L1 blockade can lead to hyperprogressive disease (HPD), a flair-up of tumor growth linked to dismal prognosis. This study aimed to evaluate the incidence of HPD and identify the determinants associated with HPD in patients with NSCLC treated with PD-1/PD-L1 blockade. Patients and methods: We enrolled patients with recurrent and/or metastatic NSCLC treated with PD-1/PD-L1 inhibitors between April 2014 and November 2018. Clinicopathologic variables, dynamics of tumor growth, and treatment outcomes were analyzed in patients with NSCLC who received PD-1/PD-L1 blockade. HPD was defined according to tumor growth kinetics (TGK), tumor growth rate (TGR), and time to treatment failure (TTF). Immunophenotyping of peripheral blood CD8+ T lymphocytes was conducted to explore the potential predictive biomarkers of HPD. Results: A total of 263 patients were analyzed. HPD was observed in 55 (20.9%), 54 (20.5%), and 98 (37.3%) patients according to the TGK, TGR, and TTF. HPD meeting both TGK and TGR criteria was associated with worse progression-free survival [hazard ratio (HR) 4.619; 95% confidence interval (CI) 2.868-7.440] and overall survival (HR, 5.079; 95% CI, 3.136-8.226) than progressive disease without HPD. There were no clinicopathologic variables specific for HPD. In the exploratory biomarker analysis with peripheral blood CD8+ T lymphocytes, a lower frequency of effector/memory subsets (CCR7-CD45RA- T cells among the total CD8+ T cells) and a higher frequency of severely exhausted populations (TIGIT+ T cells among PD-1+CD8+ T cells) were associated with HPD and inferior survival rate. Conclusion: HPD is common in NSCLC patients treated with PD-1/PD-L1 inhibitors. Biomarkers derived from rationally designed analysis may successfully predict HPD and worse outcomes, meriting further investigation of HPD.

AB - Background: Immune checkpoint blockade with Programmed cell death 1 (PD-1)/PD-L1 inhibitors has been effective in various malignancies and is considered as a standard treatment modality for patients with non-small-cell lung cancer (NSCLC). However, emerging evidence show that PD-1/PD-L1 blockade can lead to hyperprogressive disease (HPD), a flair-up of tumor growth linked to dismal prognosis. This study aimed to evaluate the incidence of HPD and identify the determinants associated with HPD in patients with NSCLC treated with PD-1/PD-L1 blockade. Patients and methods: We enrolled patients with recurrent and/or metastatic NSCLC treated with PD-1/PD-L1 inhibitors between April 2014 and November 2018. Clinicopathologic variables, dynamics of tumor growth, and treatment outcomes were analyzed in patients with NSCLC who received PD-1/PD-L1 blockade. HPD was defined according to tumor growth kinetics (TGK), tumor growth rate (TGR), and time to treatment failure (TTF). Immunophenotyping of peripheral blood CD8+ T lymphocytes was conducted to explore the potential predictive biomarkers of HPD. Results: A total of 263 patients were analyzed. HPD was observed in 55 (20.9%), 54 (20.5%), and 98 (37.3%) patients according to the TGK, TGR, and TTF. HPD meeting both TGK and TGR criteria was associated with worse progression-free survival [hazard ratio (HR) 4.619; 95% confidence interval (CI) 2.868-7.440] and overall survival (HR, 5.079; 95% CI, 3.136-8.226) than progressive disease without HPD. There were no clinicopathologic variables specific for HPD. In the exploratory biomarker analysis with peripheral blood CD8+ T lymphocytes, a lower frequency of effector/memory subsets (CCR7-CD45RA- T cells among the total CD8+ T cells) and a higher frequency of severely exhausted populations (TIGIT+ T cells among PD-1+CD8+ T cells) were associated with HPD and inferior survival rate. Conclusion: HPD is common in NSCLC patients treated with PD-1/PD-L1 inhibitors. Biomarkers derived from rationally designed analysis may successfully predict HPD and worse outcomes, meriting further investigation of HPD.

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Hyperprogressive disease during PD-1/PD-L1 blockade in patients with non-small-cell lung cancer

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