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

Abstract

Background: 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. Methods: 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. Results: Among 3,436 studies, 23 randomized clinical trials (RCTs) met our selection criteria which included data from 12,876 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, p < 0.001; RR, 4.14, 95% CI: 1.82-9.42, p < 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, p < 0.001; RR, 2.11, 95% CI: 1.20-3.70, p < 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, p < 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, p < 0.001; RR 3.48, 95%CI: 1.10-11.02, p < 0.001). Conclusions: 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.

Keywords: immune checkpoint inhibitors; meta-analysis; pneumonia; pneumonitis; solid tumour.

Figure 1

Forest plot analysis of pneumonitis comparing PD-1/PD-L1/CTLA4 with control therapies. (A) PD-L1 inhibitor V.S. chemotherapy/placebo; (B) PD-1 inhibitor V.S. chemotherapy; (C) CTLA4 inhibitor V.S. chemotherapy/placebo; (D) PD-1 combined CTLA4 V.S. ICI. G1-5, grade 1-5; G3-5, grade 3-5, G5, death.

Figure 2

Forest plot analysis of pneumonia comparing PD-1/PD-L1/CTLA4 with control therapies. (A) PD-L1 inhibitor V.S. chemotherapy/placebo; (B) PD-1 inhibitor V.S. chemotherapy; (C) CTLA4 inhibitor V.S. chemotherapy/placebo; (D) PD-1 combined CTLA4 V.S. ICI. G1-5, grade 1-5; G3-5, grade 3-5, G5, death.

Figure 3

Forest plot analysis of pneumonitis comparing different ICIs with control therapies. Atezolizumab, atezolizumab V.S. chemotherapy; Nivolumab, nivolumab V.S. chemotherapy; Pembrolizumab, pembrolizumab V.S. chemotherapy; G1-5, grade 1-5; G3-5, grade 3-5, G5, death.

Figure 4

Forest plot analysis of pneumonia comparing different ICIs with control therapies. Atezolizumab, atezolizumab V.S. chemotherapy; Nivolumab, nivolumab V.S. chemotherapy; Pembrolizumab, pembrolizumab V.S. chemotherapy; G1-5, grade 1-5; G3-5, grade 3-5, G5, death.

Figure 5

Forest plot analysis of pneumonitis of different ICIs in different tumoral types. NSCLC, non-small cell lung cancer; Others, including MM, HNSCC, Prostate cancer, Mesothelioma. PD-L1, PD-L1 inhibitor V.S. chemotherapy/placebo; PD-1, PD-1 inhibitor V.S. chemotherapy; CTLA4, CTLA4 inhibitor V.S. chemotherapy/placebo; G1-5, grade 1-5; G3-5, grade 3-5, G5, death.

Figure 6

Forest plot analysis of pneumonia of different ICIs in different tumoral types. NSCLC, non-small cell lung cancer; Others, including MM, HNSCC, Prostate cancer, Mesothelioma PD-L1, PD-L1 inhibitor V.S. chemotherapy/placebo; PD-1, PD-1 inhibitor V.S. chemotherapy; CTLA4, CTLA4 inhibitor V.S. chemotherapy/placebo; G1-5, grade 1-5; G3-5, grade 3-5, G5, death.