Hyperprogressive Disease upon Immune Checkpoint Blockade: Focus on Non–small Cell Lung Cancer

Purpose of Review: Describe the controversial aspects of hyperprogressive disease (HPD) definition, mechanisms, and biomarkers. Recent Findings: Although immune checkpoint inhibitors (ICIs) demonstrated a survival benefit in non–small cell lung cancer (NSCLC), an acceleration of tumor growth during ICI, defined as HPD, was reported in ~ 13–26% of NSCLC patients and correlated with worse survival compared with conventional progression. Different criteria have been used for HPD definition. The main limitation for the use of tumor growth rate and tumor growth kinetics variations is its inapplicability for patients without a pre-baseline imaging or progressing on non-measurable lesions. On the contrary, time to treatment failure and clinical criteria (i.e., worsening of performance status, presence of new lesions, or metastatic spread to different sites) can be useful in the above-mentioned settings but do not consent an assessment of tumor growth before ICI initiation. Several mechanisms of HPD have been proposed so far, involving both adaptive and innate immunity or based on cell-autonomous signals of cancer growth triggered by ICI. The characterization of HPD biomarkers and the identification and validation on large series of one or more mechanistic explanations for the HPD phenomenon are of paramount significance to avoid detrimental immunotherapy in a subgroup of patients and exploit novel therapeutic targets for future immunotherapy combinations. Summary: HPD occur in a subgroup of NSCLC patients treated with ICI. Several definitions and mechanisms have been proposed and a consensus on HPD criteria and biological bases is currently lacking.