Immune Checkpoint Inhibitor-Related Adverse Cardiovascular Events in Patients With Lung Cancer

Abstract

Objectives: The purpose of this study was to evaluate whether immune checkpoint inhibitors (ICIs) are associated with an increased risk of major adverse cardiovascular events (MACE) compared with non-ICI therapies in patients with lung cancer.

Background: ICIs activate the host immune system to target cancer cells. Though uncommon, cardiovascular immune-related adverse events can be life-threatening.

Methods: A retrospective single-institution cohort study of 252 patients with pathologically confirmed lung cancer who received ICI or non-ICI therapy was analyzed. The primary endpoint was MACE, defined as a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and hospitalization for heart failure.

Results: During a median follow-up of 6 months, MACE occurred in 13.3% of ICI-treated patients, with a median time to event of 51 days, compared with 10.3% and 64 days in non-ICI patients. ICIs were not associated with MACE (hazard ratio [HR]: 1.18; 95% confidence interval [CI]: 0.57 to 2.43; p = 0.66) in a univariable Fine-Gray regression analysis incorporating noncardiovascular death as a competing risk. Multivariable regression analyses determined that patients treated with ICIs with elevated serum troponin I >0.01 ng/ml (HR: 7.27; 95% CI: 2.72 to 19.43; p < 0.001) and B-type natriuretic peptide (BNP) >100 pg/ml (HR: 2.65; 95% CI: 1.01 to 6.92; p = 0.047) had an increased risk of MACE. Patients pre-treated or receiving combined immunotherapy with ICIs and vascular endothelial growth factor inhibitors (VEGFIs) or tyrosine kinase inhibitors (TKIs) had an increased risk of MACE (HR: 2.15; 95% CI: 1.05 to 4.37; p = 0.04).

Conclusions: ICIs were not independently associated with an increased risk of MACE in patients with lung cancer, although power is an important limitation in these analyses. ICI-associated cardiotoxicity was associated with elevations in serum troponin and BNP, and combined immunotherapy with VEGFIs or TKIs. Future studies are needed to further define the role of cardiac biomarkers as a monitoring strategy with ICI therapy.

Keywords: BNP; BNP, B-type natriuretic peptide; CI, confidence interval; HR, hazard ratio; ICI, immune checkpoint inhibitor; IQR, interquartile range; LVEF, left ventricular ejection fraction; MACE; MACE, major adverse cardiovascular events; PD, programmed cell death protein; PD-L1, programmed cell death-ligand 1; TKI, tyrosine kinase inhibitor; TnI, troponin I; VEGFI, vascular endothelial growth factor inhibitor; cardiotoxicity; immune checkpoint inhibitors; lung cancer; troponin.

Graphical abstract

Figure 1

Patient Cohort Selection

Figure 2

Time From Initiation of Anti-Cancer Treatment for Lung Cancer to MACE Horizontal histogram depicting total elapsed days from initial dose of ICI or non-ICI therapy for treatment of lung cancer and MACE: X-axis: Time elapsed (in days) from initial dose of ICI or non-ICI therapy for lung cancer and MACE. Y-axis: Treatment type (ICI or non-ICI) and individual subject number for 30 of 252 total cohort patients who sustained MACE in the study. ICI = immune checkpoint inhibitor; MACE = major adverse cardiac events.

Figure 3

Cumulative Incidence of MACE After Initiation of Anti-Cancer Treatment Analyses adjusted for the competing risk of death. The hazard ratio for the association between ICI and MACE is 1.18, 95% confidence interval: 0.57 to 2.43; p = 0.66. Abbreviations as in Figure 2.

Central Illustration

Burden of Immune Checkpoint Inhibitor–Associated Cardiovascular Adverse Events According to the Common Terminology Criteria of Adverse Events (CTCAE) version 5.0, 37.8% of patients receiving immune checkpoint inhibitors (ICIs) developed cardiovascular adverse events. This bar graph depicts the distribution of cardiovascular adverse events, identified by CTCAE, that were adjudicated as major adverse cardiac events. For example, 25 patients on ICI had chest pain by CTCAE, and in 11 patients (44%), these were adjudicated as a major adverse cardiac event. Some patients developed multiple major adverse cardiac events, and each event is counted in this figure. Of note, myopericardial disease includes both pericardial disease and myocarditis.