Hyperprogression and Immune Checkpoint Inhibitors: Hype or Progress?

Abstract

There are currently seven approved immune checkpoint inhibitors (ICIs) for the treatment of various cancers. These drugs are associated with profound, durable responses in a subset of patients with advanced cancers. Unfortunately, in addition to individuals whose tumors show resistance, there is a minority subgroup treated with ICIs who demonstrate a paradoxical acceleration in the rate of growth or their tumors-hyperprogressive disease. Hyperprogressive disease is associated with significantly worse outcomes in these patients. This phenomenon, though still a matter of dispute, has been recognized by multiple groups of investigators across the globe and in diverse types of cancers. There are not yet consensus standardized criteria for defining hyperprogressive disease, but most commonly time to treatment failure less than 2 months and an increase in pace of progression of at least twofold between pre-immunotherapy and on-treatment imaging has been used. In some patients, the change in rate of progression can be especially dramatic-up to 35- to 40-fold. MDM2 amplification and EGFR mutations have been suggested as genomic correlates of increased risk of hyperprogression, but these correlates require validation. The underlying mechanism for hyperprogression is not known but warrants urgent investigation.

Keywords: Cancer clinical trials; Hyperprogressive disease; Immune checkpoint inhibitors; Immunotherapy.

Figure 1

Potential outcomes after initiation of immunotherapy with immune checkpoint inhibitors for the treatment of various cancers over time. (Green): Durable response to treatment in which target lesions shrink on imaging and remain attenuated. (Purple): Nondurable response in which lesions initially response to therapy, but on subsequent surveillance imaging, lesions become resistant and increase in size. (Orange): Disease progression in which target lesions grow >20% from previous imaging. (Blue): Pseudoprogression in which tumors enlarge on imaging initially followed by decrease in size seen. (Red): Hyperprogressive disease in which rapid growth occurs after initiating immune checkpoint inhibitors.