Hyperprogression as a distinct outcome after immunotherapy

Cancer research is living a time of unparalleled expectations around immunotherapy, a therapeutic strategy that materializes the elegant idea of weaponizing our immune system to eradicate tumor cells. In an everchanging standard of care, a growing number of studies have shown that immunotherapy may accelerate tumor progression in a significant subset of patients ranging from 4% to 29% across multiple histologies. The identification of hyperprogression poses a challenge for RECIST criteria, which fail to capture pre- and post-treatment tumor growth kinetics at early times of disease. To this end, parameters such as the TGR (Tumor Growth Rate), TGK (Tumor Growth Kinetics), and TTF (Time to Treatment Failure) have been proposed. Although the definition of hyperprogression is not consistent among research groups, it may be depicted as a RECIST progression at the first on-treatment scan with at least a doubling in growth pace when comparing pre- and post-treatment periods. Unlike pseudoprogression, patients displaying hyperprogression present worse survival outcomes. This phenomenon has been independently associated to older age, higher metastatic load, and previous irradiation, but remarkably failed to show association to tumor burden or aggressive pre-treatment growth. Despite the pivotal interest of recognizing subjects at increased risk of hyperprogression, only MDM2 amplification and EGFR aberrations have been described as potential biomarkers and require further validation. In addition, tumor mutation burden and circulating DNA may be valuable to this purpose. This work provides an update on epidemiology, clinical predictors, biomarkers, and a plausible molecular rationale of hyperprogressive disease after immunotherapy.