Double immune checkpoint inhibitor therapy for unresectable pleural mesothelioma rarely induces hyperprogressive...

Use of immune checkpoint inhibitors (ICIs) is associated with new response types, such as hyperprogressive disease (HPD), whose definition is still being discussed. Some authors use dynamic indexes to define HPD. However, since the Checkmate-743 study, ICIs have been a first-line therapy for pleural mesothelioma (PM), thereby making use of dynamic indexes less appropriate. The aim of this study is to describe two cases of HPD and then discuss its definitions and implications.

Herein, we report two cases of PM HPD on first-line ICI therapy. A 67-year-old man with right unresectable epithelioid PM, without BAP1 or CDKN2A losses, high neutrophil/lymphocyte ratio and rapid-onset pulmonary and mediastinal HPD after two ICI cycles, died of respiratory failure 1 month after starting treatment. A 40-year-old woman with left unresectable epithelioid PM had HPD at first assessment after 4 ICI infusions with jugular thrombosis, liver metastases and more dismal biological parameters. There are multiple different ways to describe HPD, some not applicable to PM. Suspected mechanisms include macrophage reprogramming to M2 cells. There are no known predictive factors of HPD, and future works should focus on identifying them.

HPD is a mode of progression for ICI-treated PM patients. Further investigation is needed to better define and anticipate HPD in these patients.