Recent years have seen the advent of novel treatment options for hepatocellular carcinoma (HCC). Given a strong biological rationale supporting this strategy, multiple studies have explored the role of combination treatments including locoregional plus systemic therapies to produce a synergistic effect and enhance antitumor activity. Among locoregional therapies, several clinical trials assessing trans-arterial chemoembolization (TACE) have been recently presented and published. In the current paper, we discuss available evidence and current and future research on combined TACE and systemic treatments, including antiangiogenic agents, immune checkpoint inhibitors, and immune-based combinations for HCC patients.

Immune checkpoint inhibitors (ICIs), such as durvalumab, tremelimumab, and atezolizumab, have emerged as a significant therapeutic option for the treatment of hepatocellular carcinoma (HCC). In fact, the efficacy of ICIs as single agents or as part of combination therapies has been demonstrated in practice-changing phase III clinical trials. However, ICIs confront several difficulties, including the lack of predictive biomarkers, primary and secondary drug resistance, and treatment-related side effects. Herein, we provide an overview of current issues and future challenges in this setting.

Treatment options for intrahepatic cholangiocarcinoma (iCCA), a highly malignant tumor with poor prognosis, are limited. Recent developments in immunotherapy and immune checkpoint inhibitors (ICIs) have offered new hope for treating iCCA. However, several issues remain, including the identification of reliable biomarkers of response to ICIs and immune-based combinations. Tumor immune microenvironment (TIME) of these hepatobiliary tumors has been evaluated and is under assessment in this setting in order to boost the efficacy of ICIs and to convert these immunologically “cold” tumors to “hot” tumors. Herein, the review TIME of ICCA and its critical function in immunotherapy. Moreover, this paper also discusses potential avenues for future research, including novel targets for immunotherapy and emerging treatment plans aimed to increase the effectiveness of immunotherapy and survival rates for iCCA patients.

Background. Recent years have witnessed the advent of molecular profiling for intrahepatic cholangiocarcinoma (iCCA), and new techniques have led to the identification of several molecular alterations. Precision oncology approaches have been widely evaluated and are currently under assessment, as shown by the recent development of a wide range of agents targeting Fibroblast Growth Factor Receptor (FGFR) 2, Isocitrate Dehydrogenase 1 (IDH-1), and BRAF. However, several knowledge gaps persist in the understanding of the genomic landscape of this hepatobiliary malignancy. Methods. In the current study, we aimed to comprehensively analyze clinicopathological features of BAP1-mutated iCCA patients in public datasets to increase the current knowledge on the molecular and biological profile of iCCA. Results. The current database study, including 772 iCCAs, identified BAP1 mutations in 120 cases (15.7%). According to our analysis, no differences in terms of overall survival and relapse-free survival were observed between BAP1-mutated and BAP1 wild-type patients receiving radical surgery. In addition, IDH1, PBRM1, and ARID1A mutations were the most commonly co-altered genes in BAP1-mutated iCCAs. Conclusions. The genomic characterization of iCCA is destined to become increasingly important, and more efforts aimed to implement iCCA genomics analysis are warranted.

Recent years have observed the emergence of novel therapeutic opportunities for advanced hepatocellular carcinoma (HCC), such as combination therapies including immune checkpoint inhibitors. We performed a meta-analysis with the aim to compare median overall survival (OS), median progression-free survival (PFS), complete response (CR) rate, and partial response (PR) rate in advanced HCC patients receiving immune-based combinations versus sorafenib. A total of 2176 HCC patients were available for the meta-analysis (immune-based combinations = 1334; sorafenib = 842) and four trials were included. Immune-based combinations decreased the risk of death by 27% (HR, 0.73; 95% CI, 0.65–0.83; p < 0.001); similarly, a PFS benefit was observed (HR, 0.64; 95% CI, 0.5–0.84; p < 0.001). In addition, immune-based combinations showed better CR rate and PR rate, with ORs of 12.4 (95% CI, 3.02–50.85; p < 0.001) and 3.48 (95% CI, 2.52–4.8; p < 0.03), respectively. The current study further confirms that first-line immune-based combinations have a place in the management of HCC. The CR rate observed in HCC patients receiving immune-based combinations appears more than twelve times higher compared with sorafenib monotherapy, supporting the long-term benefit of these combinatorial strategies, with even the possibility to cure advanced disease.