AUTHOR=Su Qiang , Zhu Emily C. , Wu Jing-bo , Li Teng , Hou Yan-li , Wang Di-ya , Gao Zu-hua 

TITLE=Risk of Pneumonitis and Pneumonia Associated With Immune Checkpoint Inhibitors for Solid Tumors: A Systematic Review and Meta-Analysis

JOURNAL=Frontiers in Immunology

VOLUME=10

YEAR=2019

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2019.00108

DOI=10.3389/fimmu.2019.00108

ISSN=1664-3224

ABSTRACT=<p><bold>Background:</bold> We performed a systematic review and meta-analysis to evaluate the risk of pneumonitis and pneumonia associated with immune checkpoint inhibitors (ICIs) for solid tumors.</p><p><bold>Methods:</bold> The following keywords were used in searching the Embase and PubMed database: pneumonitis, pneumonia, and immune checkpoint inhibitors. The data was analyzed by using the R software and Metafor package.</p><p><bold>Results:</bold> Among 3,436 studies, 23 randomized clinical trials (RCTs) met our selection criteria which included data from <bold>12,876</bold> patients. Compared with chemotherapy, PD-1 inhibitors showed significant increase in grade 1-5 and grade 3-5 pneumonitis (RR, 5.17, 95% CI: 2.82–9.47, <italic>p</italic> &lt; 0.001; RR, 4.14, 95% CI: 1.82–9.42, <italic>p</italic> &lt; 0.001), but not in pneumonia. PD-L1 inhibitors showed significant increase in grade 1-5 pneumonitis and pneumonia (RR, 3.25, 95% CI: 1.61–6.57, <italic>p</italic> &lt; 0.001; RR, 2.11, 95% CI: 1.20–3.70, <italic>p</italic> &lt; 0.001). There was no significant difference in any grade pneumonitis and pneumonia in cytotoxic T lymphocyte-associated protein 4 (CTLA4) inhibitors subgroup. Programmed cell death protein 1 (PD-1) inhibitor (nivolumab and pembrolizumab) both showed significant increase in grade 1-5 pneumonitis, and pembrolizumab specially tended to increase grade 3-5 pneumonitis. (RR, 5.64 95% CI: 1.94–16.38, <italic>p</italic> &lt; 0.001). Compared with PD-1 inhibitor (nivolumab) or CTLA-4 inhibitor (ipilimumab) monotherapy, PD-1 inhibitor, and CTLA-4 inhibitor (nivolumab plus ipilimumab) combination therapies showed significant increase in grade 1-5 and grade 3-5 pneumonitis (RR 3.47, 95%CI:1.76–6.83, <italic>p</italic> &lt; 0.001; RR 3.48, 95%CI: 1.10–11.02, <italic>p</italic> &lt; 0.001).</p><p><bold>Conclusions:</bold> PD-1/PD-L1 inhibitors treatment could increase the risk of all-grade pneumonitis. CTLA4 inhibitor ipilimumab treatment alone could not increase the risk of pneumonitis but could augment the risk of pneumonitis in PD-1/PD-L1 inhibitor treated patients. There was no significant increase in the risk of pneumonia after either PD-1/PDL-1inhibitor or CTLA4 inhibitor treatment alone or in combination.</p>