PD-1 checkpoint inhibitors are associated with a specific spectrum of immune-related adverse events (irAEs). Body composition has been proven to influence the pharmacokinetics of many anti-neoplastic drugs. We evaluated the effect of decreased muscle mass (sarcopenia) on PD-1 inhibitors toxicity.
Pre-therapeutic biological and clinical assessments were prospectively performed for patients (pts) treated with anti-PD1. Muscle mass was estimated using Creatinine/Cystatine C (Cr/CysC) clearance ratio (Kim SW, 2016). Univariate and multivariate analysis tested the association between anti-PD1 induced severe toxicity and age, sex, Performans Status (PS), (Cr/CysC) clearance ratio, body mass index (BMI), lymphocytes, C-Reactive Protein (CRP) and albuminemia. The severity of AEs was graded according to the NCI CTC for AE V4.
From July 2015 to April 2016, 74 pts, median age 65 years (41-84), 58.1% men, received at least one infusion of nivolumab (85%) or pembrolizumab (15%), for lung cancer (n = 44), melanoma (n = 13), renal carcinoma (n = 9) and others (n = 8). A total of 418 cycles (median per pt: 4, range 1-20) were analyzed. Median Cr/CysC clearance ratio was 1.17. Twenty pts (27%) had both Cr/CysC clearance ratio >1.17, reflecting low lean body mass and a BMI > 25 kg.m−2. Fifteen pts (20.2%) developed grade 3-5 AEs, some rare, such as insipid diabetes with hypophysitis (n = 1) after 1st cycle (C1), pulmonary arterial hypertension (n = 3, C1, C1, C5), polymyositis (n = 2, C2, C2) and thrombocytopenia (n = 1, C6). In univariate analysis, gr 3-5 AE was associated with Cr/CysC clearance ratio >1.17 (p = 0.006), high CRP (p = 0.036) and the combination of Cr/Cyst clearance ratio >1.17 with BMI > 25 kg/m2 (p= 0.024). In multivariate analysis, Cr/CysC clearance ratio >1.17 (p = 0.03) and the combination of Cr/CysC clearance ratio >1.17 with BMI >25 kg/m2 (p = 0.014) remained significant.
The Creatinine/Cystatine C clearance ratio associated with BMI helps to identify sarcopenic overweight pts who are at high risk of severe PD-1 inhibitors induced toxicity. To date, it is unknown if the development of irAEs is an inherent component of checkpoint blockade with anti–PD-1 or if modifying the dosage can decrease the rates of these events.
Clinical trial identification
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D. Damotte: research contract (MSD) All other authors have declared no conflicts of interest.