Association Between Mdm2/Mdm4 Amplification And Pd-1/Pd-L1 Inhibitors-Related Hyperprogressive Disease: A Pan-Cancer Analysis

2557 Background: Immune checkpoint inhibitors have demonstrated a clear survival benefit in various tumor types. However, accelerated disease progression, documented as hyperprogressive disease (HPD), was reported in a subset of patients treated with PD-1/PD-L1 inhibitors. Until now, the mechanisms underlying HPD have not been elucidated. Previous studies have demonstrated that MDM2/MDM4 amplification were associated with HPD. In the present study, we evaluated the relationship between MDM2/MDM4 amplification and HPD. Methods: We reviewed extensive clinical trials of PD-1/PD-L1 inhibitors in advanced solid tumor patients updated to January 2019, and estimated the incidence of HPD, which was defined as time-to-treatment failure (TTF) < 2 months, and > 50% increase in tumor burden compared with pre-immunotherapy imaging in this study. The proportions of MDM2/MDM4 amplification across different cancer types were obtained from The Cancer Genome Atlas (TCGA) and our own database respectively. Then we plotted the incidence of HPD and the corresponding proportion of MDM2/MDM4 amplification across various cancer types in TCGA. Results: Overall, 19 published clinical trials of 1318 patients treated with PD-1/PD-L1 inhibitors were included for analysis, covering 12 types of solid cancers. The incidences of HPD among these studies were ranging from 1.58% in renal clear cell carcinoma to 24.3% in sarcoma. Correspondingly, the proportions of MDM2/MDM4 amplification for these cancer types in TCGA were 0.74% in renal clear cell carcinoma to 20.38% in sarcoma. In our database, in total, 60 patients with MDM2/MDM4 amplification were identified in 2931 patients with the highest proportion of MDM2/MDM4 amplification in sarcoma (22 of 152, 14.5%). A significant correlation was detected between the incidence of HPD and the corresponding proportion of MDM2/MDM4 amplification in TCGA across various cancer types ( P < 0.001, R2 = 0.67). Conclusions: Our results suggest that MDM2/MDM4 amplification may be associated with rapid disease progression in patients receiving PD-1/PD-L1 inhibitors among various tumor types. The exact mechanisms underlying HPD are needed to be further evaluated.