Novel approaches for molecular targeted therapy against hepatocellular carcinoma

Eso, Yuji; Marusawa, Hiroyuki

doi:10.1111/hepr.13181

Cited by 66 publications

(71 citation statements)

References 82 publications

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“…13,14 Thus, compared with sorafenib, lenvatinib could inhibit several additional cell signalings, including fibroblast growth factor (FGF) signaling. 13,14 Thus, compared with sorafenib, lenvatinib could inhibit several additional cell signalings, including fibroblast growth factor (FGF) signaling.…”

Section: Discussionmentioning

confidence: 99%

Early response and safety of lenvatinib for patients with advanced hepatocellular carcinoma in a real‐world setting

et al. 2019

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Background and Aim Lenvatinib has been recently approved as a first‐line systematic therapy for patients with advanced hepatocellular carcinoma (HCC) based on the results of the phase 3 clinical trial REFLECT. This trial excluded patients with a history of systemic chemotherapy, bile duct invasion, and Child‐Pugh grade B. We aimed to investigate the efficacy and safety of lenvatinib for these patients and in the real‐world setting. Methods Among patients who were administered lenvatinib for advanced HCC between April and October 2018 in Hokkaido University Hospital and related hospitals, we evaluated those who were followed for more than 2 months and whose treatment response was evaluated via dynamic computed tomography at baseline and 2 months after treatment initiation. Meanwhile, patients were excluded if they had decompensated liver cirrhosis, were followed up less than 2 months, or were not evaluated at 2 months. Patients were also stratified according to compliance with the REFLECT inclusion criteria for further analysis. Results A total of 41 patients were included; more than 50% did not meet the REFLECT inclusion criteria. In total, 5 (12.2%), 20 (48.8%), 12 (29.3%), and 4 (9.3%) showed complete response, partial response, stable disease, and progressive disease, respectively. The objective response rate was 61.2%. The objective response rate and disease control rate were similar between patients who did and did not meet the REFLECT inclusion criteria. Moreover, the safety profile was also similar between the two patient groups. Conclusion Lenvatinib showed high early response rate and tolerability in patients with advanced HCC. Favorable outcomes were similarly observed in patients who did not meet the REFLECT inclusion criteria.

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Section: Discussionmentioning

confidence: 99%

Early response and safety of lenvatinib for patients with advanced hepatocellular carcinoma in a real‐world setting

et al. 2019

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“…Lenvatinib is an oral multikinase inhibitor that inhibits vascular endothelial growth factor receptors 1–3, fibroblast growth factor receptors, platelet‐derived growth factor receptor‐α, KIT, and RET . Based on the results of the phase III clinical trial, REFLECT, lenvatinib has been clinically available as an effective first‐line therapy, along with sorafenib, for advanced unresectable hepatocellular carcinoma (HCC) since 2018 . In the REFLECT trial, the objective response rate (ORR) of lenvatinib, according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST), was significantly higher than that of sorafenib (40.6% and 12.4%, P < 0.0001) …”

Section: Introductionmentioning

confidence: 99%

“…[1][2][3] Based on the results of the phase III clinical trial, REFLECT, lenvatinib has been clinically available as an effective first-line therapy, along with sorafenib, for advanced unresectable hepatocellular carcinoma (HCC) since 2018. [4][5][6][7][8][9][10] In the REFLECT trial, the objective response rate (ORR) of lenvatinib, according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST), 11 was significantly higher than that of sorafenib (40.6% and 12.4%, P < 0.0001). 4 In our previous study, we reported that early clinical responses after 2 weeks of sorafenib therapy, such as changes in tumor staining on contrasted-enhanced computed tomography (CE-CT) and alpha-fetoprotein (AFP) levels might be useful for predicting the outcomes and antitumor response to sorafenib in patients with advanced HCC.…”

Section: Introductionmentioning

confidence: 99%

Favorable radiological antitumor response at 2 weeks after starting lenvatinib for patients with advanced hepatocellular carcinoma

Kuzuya

Ishigami

Ito

et al. 2019

Hepatology Research

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Aim We aimed to investigate the radiological antitumor response at 2 weeks after starting lenvatinib for patients with advanced hepatocellular carcinoma in real‐world practice. Methods This retrospective study enrolled 40 patients who received lenvatinib. Radiological antitumor response was evaluated according to the modified Response Evaluation Criteria in Solid Tumors. Results The objective response rate at 2 weeks and best overall response on confirmation of complete response, partial response (PR), and stable disease required (confirmed response) were 57.5% and 32.5%, respectively. Based on confirmed response, the overall survival rate was significantly longer in patients with an objective response rate than in those with stable disease or progressive disease after 12 months (73.2% and 54.2%, P = 0.0358). All 13 patients with an objective response rate on confirmed response were evaluated as PR at 2 weeks. The alpha‐fetoprotein ratio at 2 weeks was a significant factor associated with PR of response rate at 2 weeks. The median relative dose intensity from 2 to 6 weeks was significantly lower than that from 0 to 2 weeks (69.6% vs. 100%, P < 0.0001). Stratified by the antitumor response at 6 weeks considering the image evaluation at 2 weeks, the median relative dose intensity from 2 to 6 weeks was significantly lower in patients with progressive disease than in those with PR or stable disease (45.2% vs. 72.6%, P = 0.0482). Conclusions The radiological antitumor response at 2 weeks was favorable. Information on a favorable visible therapeutic response very early after lenvatinib initiation can help patients maintain their motivation for treatment, and allow physicians to continue treatment effectively and safely.

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“…However, clinically, sorafenib has either not significantly increased survival or only increased survival by 2.8 months in advanced HCC patients . More recently, some new TKI drugs have been reported to be effective for advanced stage HCC in phase III studies: lenvatinib as the first line of therapy, and regorafenib as second‐line therapy . As a current research hotspot, blockade of cytotoxic T lymphocyte‐associated protein 4 and programmed cell death protein 1 (PD‐1)/programmed cell death ligand 1(PD‐L1) are the two most studied for HCC.…”

Section: Introductionmentioning

confidence: 99%

Role of cyclin‐dependent kinases (CDKs) in hepatocellular carcinoma: Therapeutic potential of targeting the CDK signaling pathway

Shen

Dean²,

et al. 2019

Hepatology Research

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Liver cancer is the fourth leading cause of cancer related mortality in the world, with hepatocellular carcinoma (HCC) representing the most common primary subtype. Two‐thirds of HCC patients have advanced disease when diagnosed, and for these patients, treatment strategies remain limited. In addition, there is a high incidence of tumor recurrence after surgical resection with the current treatment regimens. The development of novel and more effective agents is required. Cyclin‐dependent kinases (CDKs) constitute a family of 21 different protein kinases involved in regulating cell proliferation, apoptosis, and drug resistance, and are evaluated in preclinical and clinical trials as chemotherapeutics. To summarize and discuss the therapeutic potential of targeting CDKs in HCC, recent published articles identified from PubMed were comprehensively reviewed. The key words included hepatocellular carcinoma, cyclin‐dependent kinases, and CDK inhibitors. This review focuses on the emerging evidence from studies describing the genetic and functional aspects of CDKs in HCC. We also present an overview of CDK inhibitors that have shown efficacy in laboratory studies of HCC. Although many of the studies assessing CDK‐targeting therapies in HCC are at the preclinical stage, there is significant evidence that CDK inhibitors used alone or in combination with established chemotherapy drugs could have significant applications in HCC.

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Novel approaches for molecular targeted therapy against hepatocellular carcinoma

Cited by 66 publications

References 82 publications

Early response and safety of lenvatinib for patients with advanced hepatocellular carcinoma in a real‐world setting

Early response and safety of lenvatinib for patients with advanced hepatocellular carcinoma in a real‐world setting

Favorable radiological antitumor response at 2 weeks after starting lenvatinib for patients with advanced hepatocellular carcinoma

Role of cyclin‐dependent kinases (CDKs) in hepatocellular carcinoma: Therapeutic potential of targeting the CDK signaling pathway

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