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.

Pulmonary complications of immune checkpoint inhibitors in patients with nonsmall cell lung cancer

“…, p=0.0001) for all grades and 3.3 (1.68-6.5, p=0.0006) for grades ⩾3, for ICIs versus chemotherapy and for all tumour types. In the third study [60], the relative risk of pneumonitis was 5.17 (2.82-9.47, p=0.001) for all grades and 4.14 (1.82-9.42, p=0.001) for grades ⩾3, for anti-PD-1 versus chemotherapy and for all tumour types. In the study focusing only on NSCLC, the relative risk of pneumonitis was 4.93 (2.35-10.34, p=0.001) for all grades and 4.19 (1.50-11.76, p=0.001) for grades ⩾3, for anti-PD-1 compared with chemotherapy.…”

“…In a similar study [52], the relative risk of ICI-P was 6.4 (3.2-12.7) with PD-1/PD-L1 inhibitors versus CTLA-4 inhibitors, with perhaps a greater risk with anti-PD-1 drugs and in cases of NSCLC or CRC compared to melanoma. However, in two other meta-analyses [55,60], the relative risk of ICI-P was higher with nivolumab and ipilimumab combotherapy than with nivolumab monotherapy for all toxicity grades (3.68, 1.59-8.50; p=0.001 and 3.47, 1.76-6.83; p=0.01) in both studies [55,60], yet for ICI-P grade ⩾3 only in the more recent study (3.48, 1.10-11.0; p=0.01) [60]. Another study [58] adjusted for tumour types revealed that the relative risk of ICI-P was higher for pembrolizumab than nivolumab (2.08, 1.52-2.85; p=0.0001) and atezolizumab (2.43, 1.24-4.76; p=0.07), and higher for nivolumab than atezolizumab (1.91, 0.94-3.87; p=0.09) for all toxicity grades, yet without any differences for ICI-P grade ⩾3.…”

“…In a meta-analysis including all cancer types and ICIs [51], ICI-P of all grades was observed in 2.6% of patients, representing the fifth cause of irAE after cutaneous, hepatic, thyroid and colic disorders. In another [55,60] Fatal ICI-P Primary cause of lethal irAEs (35% of deaths) 13% fatality rate [53,55] NSCLC: nonsmall cell lung carcinoma; PD-1: programmed cell death protein 1; PD-L1: programmed cell death ligand 1; CTLA: cytotoxic T-lymphocyte associated antigen.…”

“…Four meta-analyses focused specifically on the risk of pneumonitis with ICIs in all tumour types [55,58,60] and in NSCLC [59]. In the first study [55], the relative risk of pneumonitis with ICIs compared to chemotherapy was 3.96 (2.02-7.79, p=0.0001) for all toxicity grades and 2.87 (0.90-9.20, p=0.08) for grades 3-4, with no difference among cancer types, or between anti-PD-1 and ipilimumab used alone.…”

“…Clarifications provided by systematic reviews and meta-analyses on irAEs In December 2018, several systematic reviews conducted on irAEs [21,22,[50][51][52][53][54] and, more specifically, on respiratory adverse events including ICI-P [55][56][57][58][59][60], involved nine to 48 randomised controlled prospective trials including 3500-15 000 patients. These studies involved patients with either any cancer type [22, 50-55, 57, 58, 60] or only NSCLC [21,56,59], treated either with any ICI [22, 50-52, 55, 57, 60] or only anti-PD-1/PD-L1 inhibitors [21,53,54,56,58,59].…”