Incidence and risk factors of immune checkpoint inhibitor myocardial and muscle toxicity: a French nationwide study

Immune checkpoint inhibitor (ICI)-induced (cardio)-myotoxicities, including myocarditis and myositis, are uncommon but frequently severe adverse drug reactions seen in cancer patients. Real-life ICI myotoxicity incidence estimates span from limited-size cohorts, with risk factors and prognosticators poorly established, as well as their impact on survival.

This retrospective French National Health Data System cohort study included all adult patients starting ICI between 1 January 2012 and 30 September 2022. A ‘narrow’ and a ‘broad’ code combination (based on International Classification of Diseases-10 codes) were used for studied outcomes. The primary outcome was the occurrence of myotoxicities and secondary outcomes of myocarditis and myositis. Risk factors of these outcomes at 6 months were identified with Fine and Gray multivariable models, considering demographics, comorbidities, co-treatments, and cancer. Immune checkpoint inhibitor myotoxicity (as a time-dependent variable) association with overall survival was tested using Cox models. Risk factors of 1- and 3-month letality in ICI myotoxicity cases were assessed by multivariable logistic regression.

In 172 363 ICI-treated adult patients, incidence of ICI myotoxicities at 6 months ranged between 0.7% and 0.9% (narrow or broad definitions, respectively), with up to 7.1% in patients with thymic cancer. Immune checkpoint inhibitor myocarditis and ICI myositis incidence ranged between 0.3% and 0.6%, co-occurring in ∼13%–23% of cases. The main risk factors for developing ICI myotoxicities (broad, n = 1520) were thymic tumour (sub-distribution hazard ratio [sHR] 12.94, 95% confidence interval [CI] 5.22–32.03), melanoma (2.41 [2.06–2.83]) and other skin cancers (2.07 [1.55–2.76]), history of thymic disorders (5.61 [2.66–11.86]), history of myasthenia gravis (2.50 [1.45–4.32]), combination of ICI (2.44 [1.99–2.98]), and age > 85 [1.79 [1.24–2.59] vs <45 years. Immune checkpoint inhibitor myotoxicity occurrence was the factor impacting most mortality after ICI start (HR 3.51 [95% CI 3.17–3.89] at 1 month), over metastatic status (1.55 [1.52–1.58]). In ICI myotoxicity patients, 1-month fatality was 20.3% and increased if severe arrhythmia (risk ratio 1.64 [95% CI 1.03–2.61]), heart failure (1.49 [1.06–2.07]), and respiratory failure (1.50 [1.05–2.15]) were reported. Additionally, results were consistent with secondary outcomes, using narrow and broad definitions.

This pharmaco-epidemiological study assessed >170 000 French patients treated by ICI in real life, establishing the incidence and identifying risk factors of developing ICI myotoxicities, with severity surrogates associated with fatality.