Pneumonitis and pneumonitis-related death in cancer patients treated with programmed cell death-1 inhibitors: a systematic review and meta-analysis

PURPOSE We conducted a meta-analysis of published clinical trials to determine the relationship between the risks of pneumonitis and pneumonitis-related death and programmed cell death-1 (PD-1) inhibitor treatment in patients with cancer. MATERIALS AND METHODS We examined clinical trials from the Medline and Google Scholar databases. Data from original studies and review articles were also cross-referenced and evaluated. Randomized Phase II and Phase III trials of pembrolizumab and nivolumab treatment in patients with cancer were eligible for the analysis. Information about the participants, all-grade and high-grade pneumonitis, and pneumonitis-related death was extracted from each study and analyzed. RESULTS After the exclusion of ineligible studies, 12 clinical trials were included in the analysis. The odds ratio (OR) for all-grade pneumonitis after PD-1 inhibitor treatment was 4.59 (95% confidence interval [CI]: 2.51-8.37; P<0.00001), and the OR for high-grade pneumonitis after PD-1 inhibitor treatment was 3.83 (95% CI: 1.54-9.48; P=0.004). The OR for pneumonitis-related death after PD-1 inhibitor treatment was 2.47 (95% CI: 0.41-14.81; P=0.32). Moreover, the OR for all-grade pneumonitis after nivolumab/ipilimumab combination therapy versus nivolumab monotherapy was 3.54 (95% CI: 1.52-8.23; P=0.003), and that for high-grade pneumonitis after nivolumab/ipilimumab combination therapy versus nivolumab monotherapy was 2.35 (95% CI: 0.45-12.13; P=0.31). Treated cancer appeared to have no effect on the risk of pneumonitis. CONCLUSION Our data showed that PD-1 inhibitors were associated with increased risks of all-grade and high-grade pneumonitis compared with chemotherapy or placebo controls in patients with cancer. However, we noted no significant difference between patients treated with a PD-1 inhibitor and patients treated with control regimens with respect to the risk of pneumonitis-related death.