Fever following Treatment with Atezolizumab plus Bevacizumab Predicts Liver Injury in Patients with Unresectable Hepatocellular Carcinoma: A Prospective Observational Analysis

Introduction: Liver injury is a treatment-related adverse event (liver-TRAE), one of the most common complications of atezolizumab plus bevacizumab (Atez/Bev) therapy, when treating unresectable hepatocellular carcinoma (uHCC). Fever following immune checkpoint inhibitor (ICI) therapy may predict ICI-induced liver injury in various malignancy types. However, the association between fever and liver-TRAEs in patients with uHCC treated with Atez/Bev has not been investigated. We prospectively evaluated the relationship between the onset of liver-TRAEs and preceding fever and sought to identify circulating biomarkers that predict liver injury in patients with Atez/Bev-treated uHCC. Methods: The primary outcome of this prospective, multicenter study was the association between liver-TRAEs (grade ≥2) and the presence of ICI-induced fever before the onset of liver injury. We used a multiplex bead-based immunoassay to evaluate 40 circulating proteins in the serum before and at 1, 3, and 6 weeks after initial Atez/Bev treatment. Results: Among 99 patients receiving Atez/Bev, grade ≥2 liverTRAEs occurred in 10 (10.1%) during the follow-up period (median, 14.7 months). The incidences of liver-TRAEs associated with fever before liver injury were 27.8% (n = 5/ 18) and 6.2% (n = 5/81) in the fever and non-fever groups, respectively. Multivariable analysis showed that the presence of fever was a significant risk factor for liver-TRAEs (odds ratio 7.57; 95% confidence interval, 1.83 33.89; p = 0.006). Furthermore, the prognosis was worse in the liver-TRAE (grade ≥2) group (p = 0.065 for progression-free survival and p = 0.074 for overall survival). Among patients with preceding fever, the liver-TRAE group had significantly lower CXCL-5 levels before treatment, higher IL-6 levels at 1 and 3 weeks, and lower CXCL-5, IFN-γ, and IL-10 levels at 6 weeks (p < 0.05). Conclusion: Fever during Atez/Bev treatment may predict liver-TRAEs, which leads to poor prognosis in patients with uHCC. Altered inflammatory cytokine and chemokine levels may help predict liverTRAEs in patients with fever after Atez/Bev therapy.