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


Ann Oncol. 2019;30(7):1104-1113. 

In This Article

Patients and Methods


Data from patients with recurrent and/or metastatic NSCLC treated with PD-1/PD-L1 inhibitors at the tertiary referral center were analyzed between April 2014 and November 2018 (N = 379). Patients were excluded if they did not undergo appropriate CT scans before the treatment (N = 23) or after the treatment (N = 17), had no target lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria (N = 49), or received other treatments combined with PD-1/PD-L1 blockade (N = 27). Total 263 patients were included in the final analysis. Data on the following variables were collected: age at PD-1/PD-L1 blockade initiation, sex, smoking history, Eastern Cooperative Oncology Group (ECOG) performance status, lactate dehydrogenase level, albumin level, neutrophil-to-lymphocyte ratio, metastatic sites, characteristics of previous treatments, tumor histology, and specific drugs for PD-1/PD-L1 blockade. Data regarding PD-L1 expression, EGFR driver mutation, ALK rearrangement, and ROS1 rearrangement were analyzed. Treatment responses were analyzed and classified based on RECIST 1.1 criteria. All patients provided written informed consent.

Definition of Tumor Growth Dynamics and HPD

Treatment response and tumor growth dynamics were assessed by treating medical oncologists and independent radiologists. All analyses regarding tumor growth dynamics were based on the serial CT scans. The reference period was defined as the time from 12 weeks before treatment to just before treatment initiation. Meanwhile, the experimental period was defined as the time from just after treatment initiation to 12 weeks after treatment. Tumor growth kinetics (TGK) and tumor growth rate (TGR) were defined based on previous reports.[10,11] Briefly, TGK was defined as the change in the sum of the longest diameters (SLD) of the target lesions according to RECIST 1.1 criteria per month. Similarly, TGR was defined as the log-scale calibrated change in the sum of the volumes of the target lesions according to RECIST 1.1 criteria per month. HPD based on TGK or TGR was defined as a more than twofold increase in TGK or TGR of the experimental period compared with that of the reference period in patients determined to have progressive disease (PD) by RECIST 1.1 at the first response evaluation after PD-1/PD-L1 blockade. In addition, HPD based on time to treatment failure (TTF) was defined as TTF <2 months as suggested in a previous report.[12]

Statistical Analysis

To compare the patient characteristics between two groups, χ 2 test and unpaired t-test were used for categorical and continuous variables, respectively. Progression-free survival (PFS) was defined as the time from the initiation of anti-PD-1/PD-L1 therapy until evidence of disease progression or death. Overall survival (OS) was defined as the time from the initiation of anti-PD-1/PD-L1 therapy until death from any cause. Logistic regression model was used to analyze the effect of specified variables on the occurrence of HPD. Kaplan–Meier method was used to depict survival distribution, and the log-rank test was used for comparison. Cox regression was used to analyze the hazard ratios for PFS and OS. Results were considered statistically significant at a P value of <0.05. All statistical analyses were carried out and visualized using GraphPad Prism version 6.0 (GraphPad Software).

See supplementary methods, available at Annals of Oncology online for more detail regarding prognostic score systems, biomarker analysis, and experiments regarding mechanism.