Immune checkpoint inhibitors and myocarditis in advanced non-small cell lung cancer: a nationwide cohort study

<h2>Abstract</h2><h3>Background</h3> Emerging evidence suggests immune checkpoint inhibitor (ICI) therapies can increase the risk of myocarditis —a life-threatening rare adverse event. High quality population-level evidence on the association remains lacking. We investigated this association in a large national cohort in China. <h3>Methods</h3> We conducted a retrospective cohort study of patients with stage IIIB-IV non-small cell lung cancer (NSCLC) using data from China's National Anti-Tumor Drug Surveillance System between January 2013 and December 2021. Those with a prior history of myocarditis before cancer diagnosis or ICI initiation were excluded. Exposure density sampling with replacements was applied to match each ICI user with up to 10 ICI non-users on major risk factors, so as to control the immortal time bias which typically exists in such pharmacoepidemiological studies. Multivariate Cox regression with time-dependent exposures was used to examine the association between ICI therapy and the incidence of myocarditis while controlling for confounders. Potential effect modifications of gender and other covariates at baseline (age, calendar year, bone metastasis, contralateral lung metastasis, chemotherapy, and glucocorticoid use) were examined. Several sensitivity analyses were performed: excluding ICI users initiated before 2019 because most ICI drugs were approved in China since June 2018; competing risk regression treating death as a competing event; restricting the length of follow-up to 3 or 6 months to investigate hazard ratios within a shorter observation window; using ICI non-users who received target therapy as an active comparator to further mitigate channeling bias since patients receiving these two drugs shared more similarities in the course of the disease. The Institutional Review Board of Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences (Shenzhen, China) approved the study (SIAT-IRB-220315-H0590). The study is based on existing de-identified electronic medical record data, and the informed consent was waived by ethics review. <h3>Findings</h3> A total of 55,219 eligible patients were included and used for matching. The median age was 61 years, and 62% were males. At one-year follow-up (median 335 days), the matched cohort analyses show that 26 ICI users and 28 ICI non-users developed myocarditis, resulting in a cumulative incidence of 4.8 and 0.6 per 1000 person-years respectively. The adjusted hazard ratio (HR) of myocarditis for ICI use was 7.41 (95% confidence interval [CI]: 3.29-16.67). For programmed cell death receptor-1 users only, the HR was 8.39 (95% CI: 3.56-19.77). The hazard ratio increased to 10.93 and 11.63 when follow-up is restricted to 6 months. The findings remained stable in sensitivity analyses. No significant effect modifications were observed. <h3>Interpretation</h3> ICI therapies in advanced NSCLC patients are associated with a 7-fold increased risk of myocarditis within one year following initiation, which suggests close monitoring for myocarditis especially within 6 months for susceptible patients, acknowledging that the background risk is small. Further studies are needed to clarify whether the association of ICI therapy with myocarditis is seen in other cancer sites, and whether type and dose of ICIs matter. Laboratory indicators or molecular markers could be developed to help diagnose myocarditis early in susceptible people.