Dynamic Changes of Neutrophil-to-Lymphocyte Ratio on Predicting Response of Immune Checkpoint Inhibitors Plus Targeted Therapies for Unresectable Hepatocellular Carcinoma

Jianming Yang,1,&ast; Yu Zhang,2,&ast; Yewu Chen,1,&ast; Yang Yang,1,3 Yinan Deng1 1Department of Hepatic Surgery and Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People’s Republic of China; 2Department of Breast Surgery, Sun Yat-sen Memorial Hospital, Guangzhou, People’s Republic of China; 3Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yang Yang; Yinan Deng, Department of Hepatic Surgery and Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, People’s Republic of China, Tel +86 20 85253106, Fax +86 20 85252276, Email yysysu@163.com; dengyinan2010@163.comBackgrounds and Aims: Multiple regimens of immune checkpoint inhibitors (ICIs) plus targeted therapies are commonly prescribed as first-line treatments for unresectable hepatocellular carcinoma (uHCC). Here, we aimed to investigate the correlation between dynamic changes of neutrophil-to-lymphocyte ratio (NLR) and tumor response to the combination of ICIs and targeted therapies for uHCC.Methods: Sixty-one patients who received ICIs plus targeted therapies for uHCC were enrolled in this retrospective study. The NLR before and at 3– 6 weeks after treatments were assessed to calculate the dynamic NLR changes (ΔNLR). Multivariate logistic regression and Cox regression models were used to explore the relationship between dynamic NLR changes and tumor response or progression-free survival (PFS), respectively. Furthermore, we assessed the predictive effect of alpha-fetoprotein (AFP) changes in combination with dynamic NLR changes compared to AFP changes alone.Results: The NLR at 3– 6 weeks and ΔNLR after treatments significantly increased in patients who underwent progressive disease (PD), while the baseline NLR showed no significant difference between different tumor responses. Increased NLR and AFP after treatments were both independent predictors of PD (For NLR increase: OR, 2.28; 95% CI, 1.47– 3.88, P < 0.001; For AFP increase: OR, 1.46; 95% CI, 1.03– 2.17, P = 0.043), and correlated with worse PFS (for NLR increase: HR, 4.08; 95% CI, 1.99– 8.36, P < 0.001; for AFP increase: HR, 2.10; 95% CI, 1.04– 4.24, P = 0.039). The receiver operating characteristic (ROC) curve and net reclassification index (NRI) showed that the combination of dynamic NLR and AFP changes was better than AFP changes alone on predicting PD (AUC: 0.83 vs 0.68, P = 0.034; NRI: 0.340, P = 0.048) and PFS (AUC: 0.80 vs 0.70, P = 0.166; NRI: 0.431, P = 0.042).Conclusion: Dynamic changes of NLR might be an effective predictor of the therapeutic response to ICIs plus targeted therapies for uHCC.Keywords: hepatocellular carcinoma, neutrophil-to-lymphocyte ratio, immune checkpoint inhibitors, targeted therapies