PURPOSE: Checkpoint inhibitors demonstrate salutary anti-cancer effects including long-term remissions. PD-L1 expression/amplification, high mutational burden and mismatch repair-deficiency correlate with response. We have, however, observed a subset of patients who appear to be "hyper-progressors," with a greatly accelerated rate of tumor growth and clinical deterioration compared to pre-therapy, which was also recently reported by Institut Gustave Roussy. The current study investigated potential genomic markers associated with "hyper-progression" after immunotherapy. METHOD: Consecutive stage IV cancer patients who received immunotherapies (CTLA-4, PD-1/PD-L1 inhibitors or other [investigational] agents) and had their tumor evaluated by next-generation sequencing were analyzed (N=155). We defined hyper-progression as time-to-treatment failure (TTF) <2 months, >50% increase in tumor burden compared to pre-immunotherapy imaging, and >2-fold increase in progression pace. RESULTS: Amongst 155 patients, TTF <2 months was seen in all six individuals with MDM2/MDM4 amplification. After anti-PD1/PDL1 monotherapy, four of these patients showed remarkable increases in existing tumor size (55% to 258%), new large masses, and significantly accelerated progression pace (2.3-, 7.1-, 7.2- and 42.3-fold compared to the two months before immunotherapy). In multivariate analysis, MDM2/MDM4 and EGFR alterations correlated with TTF<2 months. Two of 10 patients with EGFR alterations were also hyper-progressors (53.6% and 125% increase in tumor size; 35.7- and 41.7-fold increase). CONCLUSION: Some patients with MDM2 family amplification or EGFR aberrations had poor clinical outcome and significantly increased rate of tumor growth after single-agent checkpoint (PD-1/PD-L1) inhibitors. Genomic profiles may help to identify patients at risk for progression on immunotherapy. Further investigation is urgently needed.