Use of ramucirumab for various treatment lines in real-world practice of patients with advanced hepatocellular carcinoma.

PURPOSE: Ramucirumab was shown to be effective as a second-line treatment after sorafenib in patients with advanced hepatocellular carcinoma (HCC) with alpha-fetoprotein levels > 400 ng/mL in a worldwide phase 3 trial. Ramucirumab is used in patients pretreated with various systemic therapies in clinical practice. We retrospectively examined the treatment outcomes of ramucirumab administered to advanced HCC patients after diverse systemic therapies. METHODS: Data were collected from patients with advanced HCC who received ramucirumab at three institutions in Japan. Radiological assessments were determined according to both Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 and modified RECIST and the Common Terminology Criteria for Adverse Events version 5.0 was used to assess adverse events. RESULTS: A total of 37 patients treated with ramucirumab between June 2019 and March 2021 were included in the study. Ramucirumab was administered as second, third, fourth, and fifth-line treatment in 13 (35.1%), 14 (37.8%), eight (21.6%), and two (5.4%) patients, respectively. Most patients (29.7%) who received ramucirumab as a second-line therapy were pretreated with lenvatinib. We found grade 3 or higher adverse events only in seven patients and no significant changes in the albumin-bilirubin score during ramucirumab treatment in the present cohort. The median progression-free survival of patients treated with ramucirumab was 2.7 months (95% confidence interval, 1.6-7.3). CONCLUSION: Although ramucirumab is used for various lines of treatment other than second-line immediately after sorafenib, its safety and effectiveness were not significantly different from the findings of the REACH-2 trial.

Changes in therapeutic options for hepatocellular carcinoma in Asia.

The incidence rate of hepatocellular carcinoma (HCC) is expected to increase, with most cases occurring in Asia. In some parts of Asia, the occurrence of HCC developing from metabolic-related liver disease has markedly increased in recent years, whereas the occurrence of HCC developing from viral-hepatitis-related liver disease has decreased. Advancements in the treatment of HCC over the past few decades has been remarkable, with most treatment strategies to remove or control liver tumours (hepatic resection, local ablation, radiation therapy, transarterial chemoembolisation, hepatic arterial infusion chemotherapy) primarily developing in Asia. In addition, recent progress in systemic therapies has prolonged the prognosis of advanced HCC. Nowadays, six regimens of systemic therapies have become available in most countries, according to phase III trials (atezolizumab plus bevacizumab, sorafenib, lenvatinib, regorafenib, cabozantinib and ramucirumab). In a global randomised phase III trial (IMbrave 150 trial), the most effective of the latest drug designs was newly emerged combination immunotherapy (atezolizumab plus bevacizumab), which has shown significantly prolonged overall survival compared with sorafenib, which was the first-line systemic therapy for more than a decade. Now, the treatment dynamics for HCC are undergoing a major transition as a result of two important changes: the replacement of viral-related HCC by metabolic-related HCC and the emergence of combination immune therapy.

EZH1/2 inhibition augments the anti-tumor effects of sorafenib in hepatocellular carcinoma.

Both EZH2 and its homolog EZH1 function as histone H3 Lysine 27 (H3K27) methyltransferases and repress the transcription of target genes. Dysregulation of H3K27 trimethylation (H3K27me3) plays an important role in the development and progression of cancers such as hepatocellular carcinoma (HCC). This study investigated the relationship between the expression of EZH1/2 and the level of H3K27me3 in HCC. Additionally, the role of EZH1/2 in cell growth, tumorigenicity, and resistance to sorafenib were also analyzed. Both the lentiviral knockdown and the pharmacological inhibition of EZH1/2 (UNC1999) diminished the level of H3K27me3 and suppressed cell growth in liver cancer cells, compared with EZH1 or EZH2 single knockdown. Although a significant association was observed between EZH2 expression and H3K27me3 levels in HCC samples, overexpression of EZH1 appeared to contribute to enhanced H3K27me3 levels in some EZH2lowH3K27me3high cases. Akt suppression following sorafenib treatment resulted in an increase of the H3K27me3 levels through a decrease in EZH2 phosphorylation at serine 21. The combined use of sorafenib and UNC1999 exhibited synergistic antitumor effects in vitro and in vivo. Combination treatment canceled the sorafenib-induced enhancement in H3K27me3 levels, indicating that activation of EZH2 function is one of the mechanisms of sorafenib-resistance in HCC. In conclusion, sorafenib plus EZH1/2 inhibitors may comprise a novel therapeutic approach in HCC.

Switching to systemic therapy after locoregional treatment failure: Definition and best timing.

In patients with unresectable hepatocellular carcinoma (HCC) without both macrovascular invasion and extrahepatic metastasis, the initial treatment choice recommended is transarterial chemoembolization (TACE). Before sorafenib came into wide use, TACE had been pointlessly carried out repeatedly. It was in the early 2010s that the concept of TACE refractory was advocated. Two retrospective studies from Japan indicated that conversion from TACE to sorafenib the day after patients were deemed as TACE refractory improved overall survival compared with continued TACE, according to the definition by the Japan Society of Hepatology. Nowadays, phase 3 trials have shown clinical benefits of several novel molecular target agents. Compared with the era of sorafenib, sequential treatments with these molecular target agents have gradually prolonged patients' survival and have become major strategies in patients with HCC. Taking these together, conversion from TACE to systemic therapies at the time of TACE refractory, compared with before, may have a greater impact on survival and may be considered deeper in the decisions-making process in patients with unresectable HCC who are candidate for TACE. Up-to-date information on the concept of TACE refractory is summarized in this review. We believe that the survival of patients with unresectable HCC without both macrovascular invasion and extrahepatic metastasis may be dramatically improved by optimal timing of TACE refractory and switching to systemic therapies.

Sequential therapy with sorafenib and regorafenib for advanced hepatocellular carcinoma: a multicenter retrospective study in Japan.

Background Conversion from sorafenib to regorafenib is primarily an evidence-based treatment strategy in patients with advanced hepatocellular carcinoma (HCC). This study aimed to assess the safety and efficacy of sequential therapy with sorafenib and regorafenib in patients with advanced HCC by analysis of outcomes in clinical practice with the aim to complement phase III findings. Methods The medical records of patients with advanced HCC receiving regorafenib were retrieved to collect data on sorafenib administration at seven Japanese institutions. Radiological responses and adverse events were evaluated using the Response Evaluation Criteria in Solid Tumors version 1.1 and the Common Terminology Criteria for Adverse Events version 4.0, respectively. Results Before March 2018, 44 patients were administered regorafenib for advanced HCC. The median sorafenib treatment duration was 8.4 months. The most common adverse events were similar to those reported by the RESORCE trial. The median overall survival (OS) was 17.3 months (95% confidence interval [CI] 11.4-22.9), and 17 of 37 patients (45.9%) discontinued regorafenib and received sequential systemic therapy after regorafenib. These patients had significantly longer OS than those who were treated by the best supportive care or sub-optimal therapy (not reached versus 8.7 months [95% CI 5.8-11.7]; P < 0.001). Conclusion The results based on Japanese clinical practices verified the tolerability of regorafenib in advanced HCC. Major regorafenib-associated adverse events were similar to those related to sorafenib. OS was significantly longer than expected, which might be associated with the sequential systemic therapies after regorafenib, mainly lenvatinib.