Outcome and risk factor of immune-related adverse events and pneumonitis in patients with advanced or postoperative recurrent non-small cell lung cancer treated with immune checkpoint inhibitors

Abstract

Background: Non-small cell lung cancer (NSCLC) patients with pre-existing respiratory diseases have been excluded in clinical trials of immune checkpoint inhibitor (ICI) therapy, and it is unknown whether the same degree of response can be expected as that in patients without pre-existing respiratory diseases and if they are associated with increased risk for various immune-related adverse events (irAEs) and ICI pneumonitis. This study aimed to evaluate predictive factors of clinical response, prognostic factors, risk factors of irAEs, and ICI pneumonitis in NSCLC patients with or without pre-existing respiratory diseases.

Methods: We conducted a retrospective study of 180 NSCLC patients who received ICI monotherapy of nivolumab, pembrolizumab, or atezolizumab from 1 January 2016 to 31 March 2019.

Results: A total of 119 patients had pre-existing respiratory diseases, including 20 with pre-existing idiopathic interstitial pneumonias (IIPs). A total of 85 patients experienced irAEs, of which ICI pneumonitis was the most frequent adverse event, occurring in 27 patients. Of the three patients who died from irAEs, all from ICI pneumonitis, two had pulmonary emphysema and one had pre-existing IIP. In multivariate analyses, irAEs were associated with objective response rate (ORR) and favorable OS, and IIPs were associated with increased risk for ICI pneumonitis. However, IIPs were not associated with low ORR or poor OS.

Conclusions: Pre-existing IIPs were a risk factor for ICI pneumonitis. However, this study showed that ICI therapy can be offered to patients with pre-existing respiratory diseases with the expectation of the same degree of response as that in patients without pre-existing respiratory diseases.

Key points: Significant findings of the study: Pre-existing IIPs were a risk factor for ICI pneumonitis, but objective response rate and prognosis of patients with IIPs were similar to those of other patients.

What this study adds: In patients with pre-existing IIPs, ICI pneumonitis should be noted. However, ICI therapy can be offered to patients with pre-existing respiratory diseases with the expectation of the same degree of response as that in patients without pre-existing respiratory diseases.

Keywords: Immune checkpoint inhibitor; immune-related adverse event; lung cancer; pneumonitis.

Figure 1

Kaplan‐Meier curves showing irAE free survival and irAE free survival rate at 30 days, 60 days, 90 days, 120 days, 150 days, 180 days and 365 days. CI, confidence interval; IIPs, idiopathic interstitial pneumonias; ILD, interstitial lung disease; irAE, immune‐related adverse event; NR, not reached; NSIP, nonspecific interstitial pneumonia; PE, pulmonary emphysema; UIP, usual interstitial pneumonia.

Figure 2

Kaplan‐Meier curves showing (a) surOS stratified by pre‐existing respiratory diseases; (b) OS stratified by radiographic pattern of IIPs; and (c) OS stratified by type of ICI in non‐small cell lung cancer patients treated with immune checkpoint inhibitors. The log‐rank test of the difference between survival curves of patients with and without pre‐existing respiratory disease was not significant. On the other hand, the log‐rank test revealed a significant survival benefit in patients treated with pembrolizumab compared to those treated with nivolumab or atezolizumab. CI, confidence interval; IIPs, idiopathic interstitial pneumonias; ILD, interstitial lung disease; NR, not reached; NSIP, nonspecific interstitial pneumonia; PE, pulmonary emphysema; UIP, usual interstitial pneumonia.

Figure 3

Radiographic pattern of immune checkpoint inhibitor (ICI)‐related pneumonitis (ICI pneumonitis. (a) COP pattern; (b) NSIP pattern; (c) HP pattern; and (d) AIP/ARDS pattern. COP, cryptogenic organizing pneumonia; NSIP, nonspecific interstitial pneumonia; HP, hypersensitivity pneumonitis; AIP/ARDS, acute interstitial pneumonia/acute respiratory distress syndrome.

Figure 4

Radiographic pattern, grade, treatment, and outcome of immune checkpoint inhibitor (ICI)‐related pneumonitis (ICI pneumonitis). Data are presented as number of patients or range of time in days to onset of ICI pneumonitis. AIP/ARDS, acute interstitial pneumonia/acute respiratory distress syndrome; COP, cryptogenic organizing pneumonia; HP, hypersensitivity pneumonitis; mPSL, methylprednisolone; NSIP, nonspecific interstitial pneumonia; PSL, prednisolone.