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

Abstract and Introduction


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 (CCR7CD45RA 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.


Immune evasion has been established as a fundamental hallmark of cancer.[1] Numerous studies have demonstrated the importance of the interaction between tumor cell and host immune system in modulating tumor growth.[2] Tumor cells exploit several mechanisms to evade immunosurveillance.[3] Among these, the interaction of immune checkpoint ligands on tumor cells and immune checkpoint receptors on immune cells constitutes a crucial component of the immune evasion process.[4]

Programmed cell death 1 (PD-1) is one of the inhibitory immune checkpoints expressed on T cells, B cells, NK cells, and some myeloid cells.[5] Currently, immune checkpoint inhibitors targeting the PD-1/PD-L1 pathway have revolutionized the treatment of several cancers and have become a standard treatment modality. In non-small-cell lung cancer (NSCLC), PD-1/PD-L1 blockade as monotherapy or combination treatment demonstrated a clear survival benefit.[6–9] However, despite these advantages, increasing evidence show that PD-1/PD-L1 blockade is associated with rapid disease progression, i.e. hyperprogressive disease (HPD).[10–14] In particular, initial inferior outcomes of PD-1/PD-L1 blockade compared with standard chemotherapy resulting in crossover of survival curves after elapsing a certain period were observed in some phase III studies.[15–18] However, whether the rapid progression only represents the natural history of tumor growth or is induced by immunotherapy is controversial. In addition, the definition of HPD varied in previous studies, and a comprehensive comparison of these definitions is lacking until now. Moreover, relevant mechanisms and biomarkers to explain and predict HPD in terms of adaptive immunity have not been addressed.

This study aimed to evaluate the incidence of HPD in patients with NSCLC treated with PD-1/PD-L1 blockade and investigate the association between clinicopathologic variables, treatment outcomes, and HPD. Toward this goal, tumor growth dynamics before and during PD-1/PD-L1 blockade were assessed, and exploratory biomarker analysis was also conducted to determine potential biomarkers and provide mechanistic insights.