The Impact of Immune-Related Adverse Events on the Survival of Patients Treated with Immune Checkpoint Inhibitors: The Distinct Role of Cardiac Toxicities

Abstract

Background: Immunotherapy with immune checkpoint inhibitors (ICIs) has fundamentally transformed cancer treatments. Unfortunately, its benefits are accompanied by the occurrence of immune-related adverse events (irAEs). While non-cardiac irAEs have been consistently associated with a favorable prognosis, the impact of cardiac toxicities remains insufficiently explored. Methods: We conducted a retrospective, observational study at the Oncology Department of Colțea Clinical Hospital, Bucharest. All the patients treated with ICIs between 1 May 2019 and 1 February 2024 were selected in the initial cohort. Of 512 eligible patients, 435 were included in the final analysis, with comprehensive recordings of clinical, oncological, and cardiac monitoring parameters, and at least one complete cycle of ICI treatment. Adverse events were classified according to CTCAE v5.0, and overall survival (OS) and progression-free survival (PFS) were assessed using Kaplan-Meier estimates and Cox regression models. Results: Our results showed that patients who developed non-cardiac irAEs experienced a significant survival benefit: median OS 26.0 months (95% CI, 15.5-NA) vs. 13.9 months (95% CI, 12.4-16.5), 0.66 (95% CI, 0.49-0.9) hazard ratio (HR); median PFS 12.3 months (95% CI, 8.1-26.0) vs. 8.7 months (95% CI, 7.3-10.3), 0.74 (95% CI, 0.56-0.97) HR. Conversely, patients with cardiac toxicities did not derive the same advantage, with similar OS and PFS values that did not reach statistical significance: median OS 15.0 months (95% CI, 13.3-19.3) vs. 15.8 months (95% CI, 12.0-30.3), 1.11 (95% CI, 0.78-1.57) HR; median PFS 9.1 months (95% CI, 7.6-10.4) vs. 8.1 months (95% CI, 5.3-19.3), 1.003 (95% CI, 0.72-1.39) HR. Conclusions: These findings support the role of non-cardiac irAEs as markers of favorable therapeutic response, while cardiac irAEs do not confer the same prognostic benefit. The results underscore the importance of active cardiovascular monitoring and close multidisciplinary collaboration in the management of patients receiving ICIs.

Keywords: cardiotoxicity; immune checkpoint inhibitors; immune-related adverse events; progression-free survival; real-world data; survival analysis.

Figure 1

Overall study design.

Figure 2

Kaplan-Meyer curves showing the following variables: (a) OS comparison of no non-cardiac irAEs (0) vs. non-cardiac irAEs (1) patients, p-value of 0.008. The curves showed a clear and consistent separation throughout the follow-up period, indicating a favorable prognostic effect of these events. (b) OS comparison of no cardiac irAEs (0) vs. cardiac irAEs patients (1), p-value of 0.56. Although the curves suggest a trend toward poorer prognosis in the presence of cardiac toxicities, the lack of statistical significance likely reflects both the low incidence of these events and the limitations of statistical power. These findings highlight the contrast between non-cardiac irAEs, which correlate with survival benefits, and cardiac irAEs, which remain rare but carry distinct prognostic implications.