Eosinophil is a predictor of severe immune-related adverse events induced by ipilimumab plus nivolumab therapy in patients with renal cell carcinoma: a retrospective multicenter cohort study

Abstract

Introduction: Immune-related adverse events (irAEs) induced by immune checkpoint inhibitors are difficult to predict and can lead to severe events. Although it is important to develop strategies for the early detection of severe irAEs, there is a lack of evidence on irAEs associated with ipilimumab plus nivolumab therapy for metastatic renal cell carcinoma (RCC). Therefore, this study aimed to investigate the association between eosinophil and severe irAEs in patients receiving ipilimumab plus nivolumab therapy for RCC.

Methods: In this retrospective study, 161 patients receiving ipilimumab plus nivolumab therapy for RCC were divided into three groups based on whether they experienced <grade 2 irAEs (non-severe irAE group), ≥grade 3 irAEs (severe irAE group), or not (non-irAE group). We examined the proportion of eosinophils before and 2 weeks after treatment (baseline and 2-week samples, respectively).

Results: Although the eosinophil in the baseline samples did not differ between the severe irAE and non-irAE groups (2.8% vs. 2.5%, P = 0.75), regarding the 2-week samples, the eosinophil was significantly higher in the severe irAE group (mean, 6.6% vs. 3.3%; P < 0.05). Multivariate analysis showed that an eosinophil of ≥3.0% was a risk factor for severe irAEs (odds ratio, 6.01). Median progression-free survival (mPFS), mPFS from the start of ipilimumab plus nivolumab therapy to second-line therapy (mPFS2), and median overall survival (mOS) were the shortest in the non-irAE group. Although the mPFS did not differ between the severe and non-severe irAE groups (9.2 vs 14.2 months, P = 0.45), notably, mPFS2 and mOS in the former group tended to be shorter than those in the latter group (mPFS2: 29.2 vs not reached, P = 0.10; mOS: 36.9 vs 52.3 months, P = 0.06).

Discussion: An increased eosinophil 2 weeks after ipilimumab plus nivolumab therapy may be a predictor of severe irAEs, which are associated with poor prognoses, compared with non-severe irAEs among patients with RCC. We provide a novel rationale for the importance of monitoring eosinophil counts for the early detection of severe irAEs.

Keywords: eosinophil; immune-related adverse event; ipilimumab; nivolumab; renal cell carcinoma.

Figure 1

Schema of patient enrollment.

Figure 2

Changes in eosinophils over time. (A), Bar graph showing eosinophils in the baseline samples: non-irAEs (n = 54), non-severe irAEs (n = 48), and severe irAEs (n = 59). (B), Bar graph showing eosinophils in 2-week samples from the non-irAE (n = 28), non-severe irAE (n = 20), and severe irAE (n = 35) groups. (C), Receiver operating characteristic curve analysis of eosinophil count for the occurrence of severe irAEs. Results are presented as the mean ± SD. (A) One-way analysis of variance followed by Tukey’s test. (B) Welch t-test followed by Bonferroni test. irAEs, immune-related adverse events.

Figure 3

Survival outcomes by grades of irAEs. (A–C), Kaplan–Meier survival curves for (A) overall survival rate (non-irAE group, n = 54; non-severe irAE group, n = 48; and severe irAE group, n = 59), (B) progression-free survival (non-irAE group, n = 54; non-severe irAE group, n = 48; and severe irAE group, n = 59), and (C) progression-free survival 2 (non-irAE group, n = 54; non-severe irAE group, n = 48; and severe irAE group, n = 59) in patients. (A–C) Log-rank test. irAE, immune-related adverse events; mOS, median overall survival; mPFS, median progression-free survival.