Immune Checkpoint Inhibitor-Related Pneumonitis in Lung Cancer: Real-World Incidence, Risk Factors, and Management Practices Across Six Health Care Centers in North Carolina

Abstract

Background: Immune checkpoint inhibitors (ICIs) are standard treatments for advanced non-small cell lung cancer and have expanded use in small cell lung cancer. Although generally better tolerated than traditional chemotherapy, immune-related adverse events, such as immune checkpoint inhibitor-related pneumonitis (ICI-P), remain poorly understood toxicities that limit ICI treatment and can result in considerable morbidity. In this retrospective case-control study, we assessed a lung cancer cohort to identify ICI-P risk factors.

Research question: What are the risk factors, clinical presentations, radiographic findings, and outcomes for ICI-P in a real-world lung cancer cohort? Do chronic pulmonary diseases confer increased risk for ICI-P?

Study design and methods: Medical records from lung cancer patients receiving nivolumab, pembrolizumab, or combination ipilimumab and nivolumab at six centers in North Carolina were reviewed (January 2004-July 2017). Patients with ICI-P and control participants were characterized, and logistic regression was used to assess for ICI-P risk factors.

Results: Three hundred fifteen lung cancer patients who predominantly received nivolumab (76.5%) or pembrolizumab (22%) were included. The incidence of ICI-P was 9.5%, with a median time to diagnosis of 52.5 days. Most patients with ICI-P had cases of high severity, and eight patients (27%) died with ongoing ICI-P treatment. Development of ICI-P was independently associated with the presence of baseline fibrosis on chest CT scan (adjusted OR [aOR], 6.61; 95% CI, 2.48-17.7), a composite measure of obstructive lung disease (aOR, 2.79; 95% CI, 1.07-7.29), and treatment with pembrolizumab (aOR, 2.57; 95% CI, 1.08-6.11).

Interpretation: In this cohort, ICI-P was more common and severe than previously reported and carried an unexpectedly high mortality rate. Risk for ICI-P was shown to be independently associated with several chronic pulmonary diseases, which may account for the higher incidence of ICI-P in patients with lung cancer.

Keywords: immune checkpoint inhibitor; lung cancer; pneumonitis.

Figure 1

Flow chart showing cohort selection. ^ai2b2 is a cohort identification tool developed by the Informatics for Integrating Biology and the Bedside Center, a National Institutes of Health-funded National Center for Biomedical Computing. ^bEMERSE allows users to search free text (unstructured) clinical notes from the electronic health record. EMERSE = Electronic Medical Record Search Engine; ICI-P = immune checkpoint inhibitor-related pneumonitis; NSCLC = non-small cell lung cancer; pts = patients; SCLC = small cell lung cancer; UNC = University of North Carolina.

Figure 2

A-D, Bar graphs showing ICI-P clinical and radiographic features. A, Relative frequency of ICI-P radiographic patterns as classified by Naidoo et al. B, Relative frequency of cardiopulmonary signs and symptoms at the time of ICI-P diagnosis. C, Relative frequency of confirmed or clinically suspected comorbid and confounding cardiopulmonary diseases treated at the time of ICI-P diagnosis. D, Relative frequency of ASCO pneumonitis severity grade. ASCO = American Society of Clinical Oncology; ICI-P = immune checkpoint inhibitor-related pneumonitis; NOS = not otherwise specified; PNA = pneumonia.

Figure 3

Kaplan-Meier estimates for time to death after ICI initiation stratified by ICI-P status. The P value for the log-rank test for differences between ICI-P status is shown (middle right), along with median survival (days) for patients with ICI-P and control participants without ICI-P (bottom table). Of 285 patients, 30 were excluded because of unknown vital status (resulting from loss to follow-up). Censoring occurred on the day of chart extraction if patient was living. Median survival is reported in days. Event = death; ICI = immune checkpoint inhibitor; ICI-P = immune checkpoint inhibitor-related pneumonitis.