Metabolic disease and adverse events from immune checkpoint inhibitors

Objective: Obese and overweight body mass index (BMI) categories have bee n associated with increased immune-related adverse events (irAEs) in patients with cancer receivin g immune checkpoint inhibitors (ICIs); however, the impact of being overweight in conjunction with related metaboli c syndrome-associated factors on irAEs have not been investigated. We aimed to evaluate the impact of overweight and obese BMI according to metabolic disease burden on the development of irAEs. Design and methods: We conducted a retrospective observational study of patients r eceiving ICIs at a cancer center. Our main study outcome was development of ≥grade 2 (moderate) irAEs. Our main predictor was weight/metabol ic disease risk category: (1) normal weight (BMI 18.5-24.9 kg/m 2)/low metabolic risk (<2 metabolic diseases (diabetes, dyslipidemia, hypertension)), (2) normal weight/high metabolic risk (≥2 metabolic diseases), (3) overweight (BMI ≥ 25 kg/m2)/low metabolic risk, and (4) overweight/high metabolic risk. Results: Of 411 patients in our cohort, 374 were eligible for analysis. Overall, 111 (30%) patients developed ≥grade 2 irAEs. In Cox analysis, overweight/low metabolic risk was signi ficantly associated with ≥grade 2 irAEs (hazard ratio (HR): 2.0, 95% confidence interval (95% CI): 1.2-3.4) when compared to normal weight/low metabolic risk, while overweight/ high metabolic risk (HR: 1.3, 95% CI: 0.7-2.2) and normal weigh t/high metabolic risk (HR: 1.5, 95% CI: 0.7-3.0) were not. Conclusions: Overweight patients with fewer metabolic comorbidities were at increased risk for irAEs. This study provides an important insight that BMI should be evaluated in t he context of associated metabolic comorbidities in assessing risk of irAE development and ICI immune response.