Response Prediction in Immune Checkpoint Inhibitor Immunotherapy for Advanced Hepatocellular Carcinoma

Abstract

Immune checkpoint inhibitors (ICI) have been applied to treat advanced stage hepatocellular carcinoma (HCC) and obtain promising effects. However, tumor response to treatment was unpredictable. A predicting biomarker of objective response or disease-control is an unmet need for patient selection. In this study, 45 advanced HCC patients who failed to sorafenib treatment and received nivolumab, 3 mg/kg bi-weekly, were included. Tumor responses to nivolumab treatment were assessed by the modified response evaluation criteria in solid tumors (mRECIST) criteria. Tumor responses were correlated to clinical characteristics to find out response predictors. In this small series, the prevalence of extrahepatic nodal metastasis, distant metastasis, and portal vein thrombus among the patients were 22.2% (n = 10), 48.9% (n = 22), and 42.2% (n = 19), respectively. The pre-treatment tumor size was 7.2 ± 4.2 cm in maximal diameter, and the calculated total tumor volume was 619.0 ± 831.1 cm3. Among 45 patients, 3 patients had partial response (PR), 11 had stable disease (SD), and the other 31 had progression of disease. By correlating clinical data to the patients with PR and SD, serum neutrophil-to-lymphocyte ratio (NLR) (hazard ratio (HR) = 2.04) and patient-generated subjective global assessment (PG-SGA) score (HR = 2.30) were the independent factors in multivariate analysis. By receiver operating characteristic curve analysis, pre-treatment NLR ≤ 2.5 and PG-SGA score < 4 were the cutoff points to predict tumor response to ICI treatment. In conclusion, biomarkers to predict tumor response for HCC are still lacking in this costly ICI therapy. In this study, NLR ≤ 2.5 and PG-SGA score < 4 indicated disease-control, and can be applied as biomarkers to select the right patients to receive this costly therapy.

Pretreatment Neutrophil-to-Lymphocyte Ratio as a Predictive Marker of Response to Atezolizumab Plus Bevacizumab for Hepatocellular Carcinoma

“…Bagley et al analyzed 175 patients with advanced non-small cell lung cancer treated with nivolumab and found that pretreatment NLR > 5 was significantly associated with inferior OS and PFS [10]. With regard to ICI therapy for HCC, Hung et al reported that NLR ≤ 2.5 was a useful predictor of response to SD or better in 45 patients treated with nivolumab monotherapy, which is similar to our report [19]. On the other hand, Dharmapuri et al reported that NLR after three cycles of nivolumab treatment was more strongly associated with the response and OS prolongation compared with NLR before treatment in 103 patients with HCC treated with nivolumab.…”

Safety and efficacy of atezolizumab plus bevacizumab in patients with unresectable hepatocellular carcinoma in early clinical practice: A multicenter analysis

“…prior to ICI treatment had a better chance of disease-control. 21 In the present study, NLR ≤ 2.74 was associated with an OR to ATZ + BV treatment with both RECIST and mRECIST. These results…”

“…[17][18][19] NLR has also been recognized as a predictor of immune checkpoint inhibitor (ICI) therapy in several cancers. 20,21 The aim of this study was to assess the safety and efficacy of ATZ + BV therapy in patients with u-HCC from the viewpoint of their clinical features, including hepatic function, history of MTA therapy, and NLR.…”

The CRAFITY score: A new guidepost for prognosis prediction in patients with hepatocellular carcinoma undergoing immunotherapy

“…On the other hand, the additional inflammatory indices that are easily acquired should be integrated into the survival prediction model, such as neutrophil-to-lymphocyte ratio. 8,9 Moreover, some indices reflecting liver function are important predictors of prognosis for patients with HCC, which help to build a more comprehensive and accurate prediction model.Last, but not least, since the characteristics of patients with HCC are heterogeneous in terms of liver function, treatment line and type of immunotherapy, subgroup analysis should be generally conducted to evaluate the effectiveness of using the CRAFITY score. The results of subgroup analysis will adequately reflect the predictive performance in different subgroups.In conclusion, the flaws do not detract from the jade's essential beauty.…”

“…On the other hand, the additional inflammatory indices that are easily acquired should be integrated into the survival prediction model, such as neutrophil-to-lymphocyte ratio. 8,9 Moreover, some indices reflecting liver function are important predictors of prognosis for patients with HCC, which help to build a more comprehensive and accurate prediction model.…”