C G Kim1, K H Kim2, K-H Pyo3, C-F Xin4, M H Hong5, B-C Ahn5, Y Kim6, S J Choi6, H I Yoon7, J G Lee8, C Y Lee8, S Y Park8, S-H Park6, B C Cho5, H S Shim9, E-C Shin10, H R Kim11. 1. Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon; Division of Medical Oncology, Department of Internal Medicine. 2. Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon; Department of Radiation Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul. 3. Division of Medical Oncology, Department of Internal Medicine; JE-UK Institute for Cancer Research, JEUK Co. Ltd, Gumi. 4. JE-UK Institute for Cancer Research, JEUK Co. Ltd, Gumi. 5. Division of Medical Oncology, Department of Internal Medicine. 6. Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon. 7. Department of Radiation Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul. 8. Department of Thoracic and Cardiovascular Surgery. 9. Department of Pathology, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea. Electronic address: shimhs@yuhs.ac. 10. Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon. Electronic address: ecshin@kaist.ac.kr. 11. Division of Medical Oncology, Department of Internal Medicine. Electronic address: nobelg@yuhs.ac.
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.
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 NSCLCpatients 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.
Authors: Amaia Martinez-Usatorre; Ece Kadioglu; Gael Boivin; Chiara Cianciaruso; Alan Guichard; Bruno Torchia; Nadine Zangger; Sina Nassiri; Ioanna Keklikoglou; Martina Schmittnaegel; Carola H Ries; Etienne Meylan; Michele De Palma Journal: Sci Transl Med Date: 2021-08-11 Impact factor: 17.956