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

Research output: Contribution to journalArticle

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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 languageEnglish
Article numbermdz123
Pages (from-to)1104-1113
Number of pages10
JournalAnnals of Oncology
Volume30
Issue number7
DOIs
Publication statusPublished - 2019 Jul 1

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Non-Small Cell Lung Carcinoma
Cell Death
Growth
T-Lymphocytes
Neoplasms
Biomarkers
Treatment Failure
Confidence Intervals
Immunophenotyping
Disease-Free Survival
Survival Rate

All Science Journal Classification (ASJC) codes

  • Hematology
  • Oncology

Cite this

Kim, C. G., Kim, K. H., Pyo, K. H., Xin, C. F., Hong, M. H., Ahn, B. 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
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. / Hyperprogressive disease during PD-1/PD-L1 blockade in patients with non-small-cell lung cancer. In: Annals of Oncology. 2019 ; Vol. 30, No. 7. pp. 1104-1113.
@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.}",
year = "2019",
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language = "English",
volume = "30",
pages = "1104--1113",
journal = "Annals of Oncology",
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Kim, CG, Kim, KH, Pyo, KH, Xin, CF, Hong, MH, Ahn, BC, Kim, Y, Choi, SJ, Yoon, HI, Lee, JG, Lee, CY, Park, SY, Park, SH, Cho, BC, Shim, HS, Shin, EC & Kim, HR 2019, 'Hyperprogressive disease during PD-1/PD-L1 blockade in patients with non-small-cell lung cancer', Annals of Oncology, vol. 30, no. 7, mdz123, pp. 1104-1113. https://doi.org/10.1093/annonc/mdz123

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

In: Annals of Oncology, Vol. 30, No. 7, mdz123, 01.07.2019, p. 1104-1113.

Research output: Contribution to journalArticle

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.

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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