C. G. Kim^1,2,†, K. H. Kim^1,3†, K.-H. Pyo^2,4†, 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. Shim^6,*, E.-C. Shin^1,*, H. R. Kim<sup>2,*

1</sup> 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

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