Definition, Incidence, and Challenges for Assessment of Hyperprogressive Disease during Cancer Treatment with Immune Checkpoint Inhibitors: A Systematic Review and Meta-analysis

Abstract

Importance: Hyperprogressive disease (HPD) is a recognized pattern of rapid tumor progression during immune checkpoint inhibitor (ICI) treatment. Definitions of HPD have not been standardized, posing the risk of capturing different tumoral behaviors. Objectives: To provide a systematic summary of definitions and the incidence of HPD in patients undergoing ICI treatment and discuss the challenges of current assessment of HPD. Data Sources: Articles that evaluated HPD published before March 3, 2020, were identified from MEDLINE and EMBASE. Study Selection: Clinical trials and observational studies providing the incidence and definition of HPD from patients with cancer treated with ICIs. Data Extraction and Synthesis: Factors included in the analysis comprised authors, year of publication, cancer type, ICI type, number of previous treatment lines, definition of HPD, time frame used to assess HPD, number of patients with HPD, onset of HPD, and prognosis of patients with HPD. Quantitative and qualitative syntheses for the incidence of HPD were performed. Main Outcomes and Measures: Definitions of HPD were categorized and the range of incidence of HPD was evaluated. Subgroup analysis on the incidence of HPD according to the category was performed and the challenges associated with current HPD assessment were evaluated. Results: Twenty-four studies with 3109 patients were analyzed. The incidence of HPD varied from 5.9% to 43.1%. The definitions were divided into 4 categories based on the calculation of tumor growth acceleration: tumor growth rate ratio (pooled incidence of HPD, 9.4%; 95% CI, 6.9%-12.0%), tumor growth kinetics ratio (pooled incidence, 15.8%; 95% CI, 8.0%-23.7%), early tumor burden increase (pooled incidence, 20.6%; 95% CI, 9.3%-31.8%), and combinations of the above (pooled incidence, 12.4%; 95% CI, 7.3%-17.5%). Hyperprogressive disease could be overestimated or underestimated if the assessment was limited to tumor growth rate or tumor growth kinetics ratio, target lesions, or response evaluation criteria in solid tumors (RECIST)-defined progressors, or if the assessment time frame conformed to RECIST. Study results on clinical outcome were heterogeneous on discriminating patients with HPD from those with natural progressive disease. Conclusions and Relevance: Definitions of HPD appear to be diverse, with the incidence of HPD varying from 5.9% to 43.1% across studies examined in this meta-analysis. Varying incidence and definitions of HPD indicate the need for establishing its uniform and clinically relevant criteria based on currently available evidence.