Pulmonary Toxicity Associated with Immune Checkpoint Inhibitors-Based Therapy: Current Perspectives and Future Directions.

ABSTRACT

Immune checkpoint inhibitors (ICIs) have shown efficacy in tumor therapy. However, the risk of pulmonary toxicity from ICI-based treatment regimens remains unknown. We searched multiple databases and clinical trial websites from January 2015 to December 2021 and summarized the pulmonary toxicity profile and risk ranking of ICI-based treatments in cancer patients. We included a Phase III randomized clinical trial (RCT) in which the treatment group received at least one ICI and experienced pulmonary adverse events (PAEs). Our study, which included 104 RCTs, found the highest incidence of grades 1-2 and 3-5 treatment-associated PAEs (Tr-PAEs) in programmed death 1 (PD-1)+ chemotherapy and PD-1+ cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), respectively. The first incidence rates of grades 1-2 and 3-5 immune-mediated PAEs (Im-PAEs) were PD1+CTLA-4+ chemotherapy and PD-L1 + CTLA4, respectively. Cytotoxic T lymphocyte-associated antigen 4 + chemotherapy regimen and PD-L1+ targeted therapy drug (TTD)+ chemotherapy regimen had the highest risk of developing grades 1-2 and 3-5 Tr-PAEs. Programmed death-L1+ CTLA-4 has a higher risk of grade 3-5 Tr-PAEs than PD-L1. The risk of grade 1-2 pulmonary toxicity was significantly different in the high-dose and low-dose groups of nivolumab and atezolizumab. Nivolumab and atezolizumab induced dose-dependent grade 1-2 pulmonary toxicity. Among single-agent regimens, PD-1 showed the greatest grade 1-2 pulmonary toxicity. Programmed death-L1+ TTD+ chemotherapy showed the greatest grade 3-5 pulmonary toxicity in combination therapy. PD-L1+ TTD+ chemotherapy was associated with a higher risk of grade 3-5 Tr-PAEs and a lower risk of Im-PAEs. We recommend a targeted approach to managing PAE.