Factors associated with myocarditis in patients with cancer treated with immune checkpoint inhibitors.

person Zara Izadi Bristol Myers Squibb, Princeton, NJ info_outline Zara Izadi, Yan Zhang, Youbei Lou, Brian Dreyfus, Greg Plautz, Robert Wolf, Leslie Cooper

Authors person Zara Izadi Bristol Myers Squibb, Princeton, NJ info_outline Zara Izadi, Yan Zhang, Youbei Lou, Brian Dreyfus, Greg Plautz, Robert Wolf, Leslie Cooper Organizations Bristol Myers Squibb, Princeton, NJ, Mayo Clinic, Jacksonville, FL Abstract Disclosures Research Funding Pharmaceutical/Biotech Company Bristol Myers Squibb Background: Myocarditis is an uncommon but serious adverse event (AE) of immune checkpoint inhibitor (ICI) therapy. We aimed to identify factors associated with ICI-related myocarditis in cancer patients using pooled data from multiple clinical trials. Methods: Data on 25,965 adults receiving at least one dose of an ICI (nivolumab [NIVO] or ipilimumab [IPI])-containing regimen were extracted from corporate safety and clinical trial databases. Patients missing documentation of AEs, indication, or trial ID were excluded. Myocarditis events were identified using MedDRA preferred terms. A nested case-control study design with controls who had no myocarditis selected at random from the risk sets and matched 1:5 on ICI regimen, duration of exposure to ICI regimen, and trial ID was used. Descriptive statistics were used to derive time to onset of myocarditis and to investigate patterns of myositis and rhabdomyolysis relative to myocarditis. A multivariable conditional logistic regression model was used to identify factors associated with myocarditis. Covariates included age, sex, race/ethnicity, medical history (cardiovascular disease, diabetes, sleep apnea), smoking, cancer type, medication use (within the prior 6 months), and co-occurrences of other AEs (pneumonitis, colitis, and hepatitis). Results: Myocarditis was documented in 122/24,106 (0.5%) patients meeting study eligibility criteria. A total of 732 patients (122 cases and 610 matched controls) from 46 trials were included in the analyses. Mean (SD) age was 63 (12) years; 65% of patients were male, 76% Caucasian, and 52% had a history of cardiovascular disease. NIVO + IPI was the most commonly used regimen (36%), followed by NIVO + relatlimab (25%) and NIVO + chemotherapy (14%). Median (Q1-Q3) time to onset of myocarditis was 38 (26-77) days from first dose of ICI. Myositis was reported in 18/122 (15%) cases and in 2/610 (0.3%) controls (p<0.001). Among the 18 cases, a majority (83%) developed myositis within 3 days before the onset of myocarditis. Rhabdomyolysis was reported in 4/122 (3%) cases, all within a month before myocarditis, and in none of the controls (p=0.001). In adjusted analyses, older age (odds ratio 1.38 per 10-year increase, 95% CI 1.12-1.70) and hepatitis (5.69, 2.24-14.44) were significantly associated with the development of myocarditis. Conclusions: In this large cohort of ICI-treated cancer patients, myocarditis had an early onset and was associated with older age and co-occurrences of hepatitis. Due to a low incidence among controls, rhabdomyolysis and myositis could not be included as covariates in adjusted analyses; however bivariate results showed strong associations between myocarditis and rhabdomyolysis or myositis. These findings suggest that co-occurrences of myositis, rhabdomyolysis, or hepatitis are associated with myocarditis and may originate from a more generalized ICI myopathy.