한빛사 논문
C. G. Kim1,2,†, K. H. Kim1,3†, K.-H. Pyo2,4†, C.-F. Xin4, M. H. Hong2, B.-C. Ahn2, Y. Kim1, S. J. Choi1, H. I. Yoon3, J. G. Lee5, C. Y. Lee5, S. Y. Park5, S.-H. Park1, B. C. Cho2, H. S. Shim6,*, E.-C. Shin1,*, H. R. Kim2,*
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
† These authors contributed equally to this work.
* These authors contributed equally to this work as corresponding authors.
* Corresponding Authors :
Hye Ryun Kim, MD, PhD
Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine
Eui-Cheol Shin, MD, PhD
Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology
291 Daehak-ro, Yuseong-gu, Daejeon 34141, Republic of Korea
Hyo Sup Shim, MD, PhD
Department of Pathology, Yonsei Cancer Center, Yonsei University College of Medicine
50 Yonsei-ro, Seodaemun-gu, Seoul 03772, 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, tumor growth dynamics, PD-1/PD-L1 blockade, hyperprogressive disease, biomarkers
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