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Ann Oncol. 2019 Apr 12. pii: mdz123. doi: 10.1093/annonc/mdz123. [Epub ahead of print]

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

Author information

1
Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.
2
Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea.
3
Department of Radiation Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea.
4
JE-UK Institute for Cancer Research, JEUK Co. Ltd., Gumi, Republic of Korea.
5
Department of Thoracic and Cardiovascular Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
6
Department of Pathology, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.

Abstract

BACKGROUND:

Immune checkpoint blockade with 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 was no clear relationship between clinicopathologic variables and 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.

KEYWORDS:

NSCLC; PD-1/PD-L1 blockade; biomarkers; hyperprogressive disease; tumor growth dynamics

PMID:
30977778
DOI:
10.1093/annonc/mdz123

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