Clarification of Definitions of Hyperprogressive Disease During Immunotherapy for Non-Small Cell Lung Cancer

Question Are the different definitions used to assess hyperprogressive disease during immunotherapy for non-small cell lung cancer representative of the same tumoral behavior? Findings For this multicenter cohort study of 406 patients with advanced non-small cell lung cancer treated with programmed cell death 1/programmed cell death 1 ligand inhibitors, the 5 disease definitions assessed resulted in diverse incidences, different patient characteristics, and different associations with survival outcomes. A new criterion of difference in tumor growth rate of greater than 100 showed more accuracy in assessing hyperprogressive disease. Meaning These findings suggest that the 5 definitions assessed are not representative of the same tumoral behavior. Importance Hyperprogressive disease (HPD) is an aggressive pattern of progression reported for patients treated with programmed cell death 1 (PD-1)/programmed cell death 1 ligand (PD-L1) inhibitors as a single agent in several studies. However, the use of different definitions of HPD introduces the risk of describing different tumoral behaviors. Objective To assess the accuracy of each HPD definition to identify the frequency of HPD and the association with poorer outcomes of immune-checkpoint inhibitor (ICI) treatment in patients with advanced non-small cell lung cancer (NSCLC) and to provide an optimized and homogenized definition based on all previous criteria for identifying HPD. Design, Setting, and Participants This retrospective cohort study included 406 patients with advanced NSCLC treated with PD-1/PD-L1 inhibitors from November 1, 2012, to April 5, 2017, in 8 French institutions. Measurable lesions were defined using the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria on at least 2 computed tomographic scans before the initiation of ICI therapy and 1 computed tomographic scan during treatment. Data were analyzed from November 1, 2012, to August 1, 2019. Exposures Advanced NSCLC and treatment with PD-1/PD-L1 inhibitors. Main Outcomes and Measures Association of the definition with the related incidence and the HPD subset constitution and the association between each HPD definition and overall survival. All dynamic indexes used in the previous proposed definitions, such as the tumor growth rate (TGR) or tumor growth kinetics (TGK), were calculated before and during treatment. Results Among the 406 patients with NSCLC included in the analysis (259 male [63.8%]; median age at start of ICI treatment, 64 [range, 30-91] years), the different definitions resulted in incidences of the HPD phenomenon varying from 5.4% (n = 22; definition based on a progression pace >2-fold and a time to treatment failure of <2 months) to 18.5% (n = 75; definition based on the TGR ratio). The concordance between these different definitions (using the Jaccard similarity index) varied from 33.3% to 69.3%. For every definition, HPD was associated with poorer survival (range of median overall survival, 3.4 [95% CI, 1.9-8.4] to 6.0 [95% CI, 3.7-9.4] months). The difference between TGR before and during therapy (Delta TGR) was the most correlated with poor overall survival with an initial plateau for a larger number of patients and a slower increase, and it had the highest ability to distinguish patients with HPD from those with progressive disease not classified as HPD. In addition, an optimal threshold of Delta TGR of greater than 100 was identified for this distinction. Conclusions and Relevance The findings of this retrospective cohort study of patients with NSCLC suggest that the previous 5 definitions of HPD were not associated with the same tumor behavior. A new definition, based on Delta TGR of greater than 100, appeared to be associated with the characteristics expected with HPD (increase of the tumor kinetics and poor survival). Additional studies on larger groups of patients are necessary to confirm the accuracy and validate this proposed definition. This multicenter cohort study assesses the accuracy of each definition of hyperprogressive disease to identify the frequency and associations with poorer outcomes of immune-checkpoint inhibitor therapy in patients with advanced non-small cell lung cancer and offers an optimized and homogenized definition based on all previous criteria for identifying hyperprogressive disease.