BackgroundImmune checkpoint inhibitors (ICIs) have improved survival and are increasingly used for non-small cell lung cancer. However, use may be limited by immune-related adverse events such as checkpoint-inhibitor pneumonitis (CIP). Literature estimates for CIP incidence are inconsistent. Real-world adherence to guidelines, clinical course, and healthcare utilization in the treatment of CIP has not been described in large cohorts.MethodsA combined claims and electronic health record database (TriNetX) was used to identify 13,113 patients with lung cancer treated with programmed cell death receptor/ligand 1 (PD-1/PD-L1) inhibitors, and a propensity score-matched control cohort treated with chemotherapy or targeted therapies. The attributable risk of CIP was calculated in the first 12 months after therapy by comparing the incidence of diagnosis codes for pneumonitis/pneumonia between cohorts. Cases of CIP, identified by the most specific code for drug-induced respiratory conditions, were further analyzed for medication usage, rates of diagnostic bronchoscopy, ICI discontinuation rates, and usage of hospital services compared with patients receiving PD-1/PD-L1 inhibitors who did not develop CIP.ResultsThe attributable risk of pneumonitis to PD-1/PD-L1 inhibitors was 2.49% (95% CI, 1.50% to 3.47%). Median time to onset in the CIP subcohort was 3.9 months (IQR, 2.1–7.3 months). Steroid and antibiotic use increased dramatically after a pneumonitis diagnosis, and 70.2% of patients permanently discontinued ICI therapy. Compared with controls, patients with CIP had more than a threefold increased risk of needing critical care (relative risk 3.59, 95% CI, 2.31 to 5.57) and an increased risk of mortality (HR 2.34, 95% CI, 1.47 to 3.71).ConclusionsIn a large claims-based analysis, PD-1/PD-L1 inhibitors increase the risk of pneumonitis in patients with lung cancer by 2.49%. Cases of CIP are associated with high healthcare utilization, discontinuation of ICIs, and mortality.

BackgroundImmune checkpoint inhibitors (ICI) generate T-cell mediated anti-tumor responses that are effective across numerous malignancies, but their use is frequently complicated by immune-related adverse events (irAEs). irAEs may lead to treatment delays, need for immunosuppression, morbidity, and even mortality.1–3Checkpoint inhibitor pneumonitis (CIP) is the most common cause of fatality related to anti-programmed cell death receptor/ligand 1 (PD-1/PD-L1) agents, and can be difficult to diagnose.3 We aimed to characterize the real-world incidence and management of CIP, as well as its impact on clinical course and healthcare utilization, in a large cohort of ICI patients using a multi-institutional database.MethodsPropensity score-matched cohorts of 14,461 lung cancer patients who did or did not receive PD-1/PD-L1 inhibitors between 2014 to 2021 were identified from TriNetX Dataworks, a database of health records and claims data from over 40 institutions. Incidence of pneumonia/pneumonitis was estimated using billing codes. A subgroup of 158 patients was selected by the most specific code group and confirmed to have features consistent with suspected CIP, permitting analysis of management practices and outcomes. To describe differences in healthcare utilization and survival, a second propensity score-matched cohort was generated for the subgroup.ResultsThe attributable risk of pneumonitis to PD-1/PD-L1 inhibitors in lung cancer at 1 year after ICI initiation was 6.88% (95% CI 6.01–7.75%). Median time to onset of drug-induced pneumonitis in the subgroup was 4.4 months (IQR 2.1–7.8 months). Of 158 patients, 21 (13.3%) underwent bronchoscopy within 30 days after diagnosis. Prednisone (130/158, 82.3%), methylprednisolone (80/158, 50.6%), and antibiotics (135/158, 85.4%) were frequently prescribed. ICI was discontinued in 69.5% of patients within 90 days of drug-induced pneumonitis. Within the first year of PD-1/PD-L1 therapy, patients with pneumonitis had more hospitalizations (83.5% vs 49.4%, RR 1.69, p<0.0001) and ICU requirements than controls (28.5% vs 8.9%, RR 3.21, p<0.0001). Landmark analysis at 6 months demonstrated that CIP associated with reduced overall survival, with a mortality HR of 1.43 (95% CI 1.03–1.97, p=0.03).ConclusionsTo our knowledge, this is the largest study of CIP to date. Importantly, the study found that the incidence of PD-1/PD-L1-induced pneumonitis, 6.88%, is higher than clinical trial estimates (2–5%), but lower than reported in uncontrolled real-world studies (17–19%).4–8 CIP had significant negative impacts on therapy continuation, healthcare utilization, and overall survival in lung cancer. This work demonstrates proof of concept that studies of irAE incidences and patient outcomes are feasible using large claims and electronic health record databases.ReferencesBrahmer JR, Lacchetti C, Schneider BJ, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American society of clinical oncology clinical practice guideline. Journal of Clinical Oncology 2018;36(17):1714–1768. doi:10.1200/JCO.2017.77.6385.Puzanov I, Diab A, Abdallah K, et al. Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group. Journal for ImmunoTherapy of Cancer 2017;5(1):95. doi:10.1186/s40425-017-0300-z.Wang DY, Salem JE, Cohen JV, et al. Fatal toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis. JAMA Oncology 2018;4(12):1721–1728. doi:10.1001/jamaoncol.2018.3923.Nishino M, Giobbie-Hurder A, Hatabu H, Ramaiya NH, Hodi FS. Incidence of programmed cell death 1 inhibitor-related pneumonitis in patients with advanced cancer a systematic review and meta-analysis. JAMA Oncology 2016;2(12):1607–1616. doi:10.1001/jamaoncol.2016.2453.Naidoo J, Wang X, Woo KM, et al. Pneumonitis in patients treated with anti-programmed death-1/programmed death ligand 1 therapy. Journal of Clinical Oncology 2017;35(7):709–717. doi:10.1200/JCO.2016.68.2005.Delaunay M, Cadranel J, Lusque A, et al. Immune-checkpoint inhibitors associated with interstitial lung disease in cancer patients. European Respiratory Journal 2017;50(2). doi:10.1183/13993003.00050-2017.Suresh K, Voong KR, Shankar B, et al. Pneumonitis in non–small cell lung cancer patients receiving immune checkpoint immunotherapy: incidence and risk factors. Journal of Thoracic Oncology 2018;13(12):1930–1939. doi:10.1016/j.jtho.2018.08.2035.Cathcart-Rake EJ, Sangaralingham LR, Henk HJ, Shah ND, Riaz I bin, Mansfield AS. A population-based study of immunotherapy-related toxicities in lung cancer. Clinical Lung Cancer 2020;21(5):421–427.e2. doi:10.1016/j.cllc.2020.04.003Ethics ApprovalAs described on TriNetX's website (https://trinetx.com/trinetx-publication-guidelines/), all data available on the network is de-identified and in-line with HIPAA Privacy Rule standards.

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