Nivolumab for the treatment of hepatocellular carcinoma

Introduction: T-cell checkpoint inhibition as a cancer treatment approach has been the main breakthrough in cancer treatment during the last years. Since the approval of the first commercial CTLA-4 antibody ipilimumab in 2011 for the treatment of melanoma, research and drug development in this field has accelerated massively. In 2014, the US Food and Drug Administration (FDA) approved the first PD-1 targeting agent, namely pembrolizumab, shortly followed by nivolumab.

Areas covered: Nivolumab is a fully human immunoglobulin G4 anti-PD-1 monoclonal antibody which is approved for multiple advanced malignancies, including melanoma, non-small cell lung cancer, renal cell cancer, Hodgkin’s lymphoma, squamous head and neck cancer, and urothelial carcinoma. In September 2017, nivolumab was approved by the FDA for liver cancer as a second line treatment after failure of sorafenib based on the data of the multi-cohort phase 1/2 trial CheckMate-040. This article reviews the concept of immunotherapy in liver cancer with focus on nivolumab.

Expert commentary: Immunotherapy in hepatocellular carcinoma is safe and is a new treatment option for patients with advanced stage disease besides sorafenib and regorafenib in the US. Randomized phase III trials of nivolumab, pembrolizumab, atezolizumab, durvalumab and tislelizumab as mono- or combination-therapy are ongoing.     

Transarterial chemoembolization and sorafenib in hepatocellular carcinoma

Transarterial chemoembolization (TACE) is considered as the standard therapy for patients with intermediate-stage hepatocellular carcinoma. However, given the high heterogeneity of this population, no common strategy or protocol standardization has been defined yet. In the last few years TACE treatment has been combined with sorafenib systemic therapy, reporting overall positive results both in terms of safety and efficacy. This systematic review presents and critically discusses the evidence available on the use of TACE in combination (concomitant or sequential) with sorafenib, focusing also on clinical trials currently ongoing to better define an optimal therapeutic strategy for this group of patients.     

Clinical trials of antiangiogenic therapy for hepatocellular carcinoma

Angiogenesis is a promising therapeutic target to inhibit tumor growth. This review summarizes data from clinical trials of antiangiogenic agents in hepatocellular carcinoma. A systematic search of PubMed was performed to identify clinical trials of specific antiangiogenic agents in hepatocellular carcinoma treatment, particularly phase III trials involving treatment guidelines for advanced hepatocellular carcinoma. Sorafenib is the only systemic drug approved for the treatment of advanced hepatocellular carcinoma. Two large-scale, randomized phase III trials using sorafenib involving patients with unresectable HCC showed a significant survival benefit compared with placebo control groups. However, subsequent phase III trials of antiangiogenic agents in hepatocellular carcinoma have failed to improve survival compared with standard treatment protocols using sorafenib. The efficacy of antiangiogenic agents in combination with other drugs, transarterial chemoembolization, and surgical resection is currently being investigated. Future research is expected to optimize antiangiogenic therapies in combination with standard treatment with sorafenib.     

Sorafenib: key lessons from over 10 years of experience

Introduction: In 2005, sorafenib was the first targeted therapy approved for advanced renal cell carcinoma (RCC), transforming treatment. In hepatocellular carcinoma (HCC), for more than a decade, sorafenib remained the only approved systemic therapy to have demonstrated a survival benefit in first-line unresectable HCC. In 2013, sorafenib was the first targeted agent approved for patients with differentiated thyroid cancer (DTC) refractory to radioactive iodine treatment.

Areas covered: This review discusses the development, advances, and challenges associated with sorafenib use in RCC, HCC, and DTC over the past decade. A search was performed on PubMed and key congresses as required, with no time limits.

Expert commentary: Sorafenib has had a lasting impact on the therapeutic landscape of RCC, HCC, and DTC, and remains an important treatment option despite a rapidly evolving treatment landscape. Extensive clinical and real-world experience has been invaluable in improving patient management and maximizing benefit from treatment. Ongoing clinical trials continue to evaluate sorafenib in different settings, and in combination with other therapies in HCC and DTC. We have no doubt that sorafenib will continue to be an important treatment option in the coming years.     

索拉菲尼治疗肝癌常见不良反应及处理的研究进展

索拉菲尼是一种口服多激酶抑制剂。通过作用于Raf激酶直接抑制肿瘤细胞增殖,还可作用于血管内皮生长因子受体1,2,3（VEGFR-1, -2, -3）,以及血小板源生长因子受体-β（PDGFR-β）、受体酪氨酸激酶、抑制肿瘤新生血管生成。索拉菲尼通过抑制肿瘤细胞增殖和抗血管生成的双重作用,从而达到抗肿瘤的目的。已被多个国家批准作为首个系统治疗肝细胞肝癌的分子靶向药物。其常见不良反应包括皮肤反应、恶心、腹泻、体质量减轻、高血压等,影响了患者的长期使用依从性,进而影响治疗效果。正确地认识和管理索拉非尼的不良反应则有助于发挥索拉非尼的治疗作用,提高临床效果。本文从索拉菲尼靶向治疗的常见不良反应、发生机制及处理方法等方面进行综述。      

The Impact of Sorafenib in Combination with Transarterial Chemoembolization on the Outcomes of Intermediate-Stage Hepatocellular Carcinoma

Background: We investigated the treatment outcomes and hepatic reserve of transarterial chemoembolization (TACE)-refractory patients with recurrent advanced hepatocellular carcinoma (HCC) treated with TACE plus sorafenib. Methods: Forty-one patients with intermediate-stage HCC defined as being TACE refractory on imaging were treated with sorafenib and TACE between 2009 and 2012 and comprised the combination treatment group. Twenty-nine patients who received repeated TACE after becoming refractory to TACE between 2005 and 2008 comprised the TACE continuation group. Results: Although the interval between successive rounds of TACE was significantly shorter before the patients developed TACE refractoriness, it was significantly longer after the development of TACE refractoriness, in the combination treatment group compared with the TACE continuation group. The appearance of extrahepatic spread and/or vascular invasion differed significantly between the two groups. The median overall survival was significantly longer in the combination treatment group than in the TACE continuation group (20.5 vs. 15.4 months, respectively; hazard ratio = 2.04; 95% confidence interval = 1.20–3.48). The 3-year overall survival rate was 33.4% in the combination treatment group and 3.5% in the TACE continuation group. Downstaging of the Child–Pugh class was significantly less frequent in the combination treatment group than in the TACE continuation group. In COX proportional hazards analyses, sorafenib plus TACE resulted in a better prognosis compared with repeated TACE. Conclusions: Treatment with sorafenib plus TACE in TACE-refractory patients with intermediate-stage HCC resulted in longer intervals between TACE rounds, better maintenance of hepatic reserve, and significantly longer OS compared with repeated TACE.     

Metastatic melanoma: scientific rationale for sorafenib treatment and clinical results

In advanced metastatic melanoma (AJCC stage IV), the prognosis is still poor, and views differ on the appropriate systemic treatment for these patients. Therefore, new approaches in therapeutic regimens are mandatory. Sorafenib is an oral multikinase inhibitor that targets 2 classes of kinases which are known to be involved in both tumor proliferation and angiogenesis. These kinases include Raf kinases and the vascular endothelial growth factor (VEGF) receptor. Sorafenib has been evaluated as a single therapy agent as well as in combination with various chemotherapeutical drugs in a number of clinical trials. The vast majority of clinical data exists for patients with advanced renal cell cancer for which sorafenib has been approved by the FDA and EMEA. Very recently, sorafenib was approved for advanced hepatocellular cancers due to its overall survival improvement. Since B-raf gene mutations have been found in 69% of melanoma cell lines, sorafenib was brought into various phase I/II and phase III trials in metastatic melanoma. However, as a single-agent therapy, sorafenib seems to be of limited use. Also, the combination of sorafenib with the chemotherapeutic agents carboplatin and paclitaxel has failed to show superiority in progression-free and overall survival compared to the same chemoregimen plus an oral placebo in a phase III trial (PRISM study). More promising data were observed in large-sized phase II studies on dacarbazine (DTIC) plus sorafenib and temozolomide plus sorafenib. However, these data need to be confirmed in prospective randomized phase III trials. Till then, sorafenib remains an interesting but still experimental new agent for melanoma.     

Transarterial chemoembolization plus sorafenib: a sequential therapeutic scheme for HCV-related intermediate-stage hepatocellular carcinoma: a randomized clinical trial

Background.

Recurrence of hepatocellular carcinoma (HCC) is a major problem after surgical or ablative treatments. The aim of this prospective, single-center, placebo-controlled, randomized, double-blind clinical study was to evaluate the effectiveness of transarterial chemoembolization (TACE) combined with sorafenib as a sequential treatment regimen in delaying time to progression (TTP) of intermediate-stage HCC in patients with chronic hepatitis C virus (HCV) infection.

Material and Methods.

Between October, 2007 and January, 2011, 80 HCV-infected patients with Barcelona Clinic Liver Cancer stage B HCC underwent the TACE procedure. All had Child-Pugh class A disease. They were randomized 1:1 to receive sorafenib at a dose of 400 mg twice daily or placebo. Endpoints were the TTP and the rates of adverse events and toxicity.

Results.

Sixty-two of 80 patients (77%), 31 in the sorafenib group and 31 in the control group, completed the study. The median TTP was 9.2 months in the sorafenib group and 4.9 months in the placebo group (hazard ratio, 2.5; 95% confidence interval, 1.66–7.56; p < .001). Metachronous, multicentric HCC progression occurred less frequently in sorafenib-treated patients (p < .05). Adverse reactions to sorafenib caused withdrawal from the study of 9 (22%) patients.

Conclusion.

A conventional TACE procedure followed by sorafenib treatment resulted in a significantly longer TTP in patients with intermediate-stage HCV-related HCC, with no unexpected side effects.     

Sorafenib and DE605, a novel c-Met inhibitor,synergistically suppress hepatocellular carcinoma

Sorafenib, an oral multikinase inhibitor of Raf, VEGF and PDGF receptor signaling is approved for advanced hepatocellular carcinoma (HCC). One strategy to improve HCC therapy is to combine agents that target key signaling pathways. Aberrant mesenchymal-epithelial transition factor (c-Met) activation is associated with a variety of human malignancies and therefore represents a target for therapy. In this study, we investigated a novel c-Met inhibitor, DE605, together with sorafenib in hepatocellular carcinoma cells in vitro and in vivo. DE605 and sorafenib synergistically induced apoptosis in hepatocellular carcinoma cells. Mechanistically, DE605 activated the FGFR3/Erk pathway, which in turn was inhibited by sorafenib, resulting in synergism. Finally, DE605 and sorafenib significantly inhibited growth of PLC/PRF/5 hepatocellular carcinoma tumor xenografts in athymic nude mice. Importantly, no obvious weight loss (toxicity) was detected. Thus in combination, DE605 and sorafenib target complementary anti-apoptotic pathways and synergistically suppress HCC, providing the rationale for clinical studies with this novel combination.     

Impressive efficacy of sorafenib in a patient with an hepatocellular carcinoma and a portal vein thrombosis associated with a metastatic ENT cancer

Sorafenib, a new antiangiogenic and antiproliferative agent, is currently used for hepatocellular and renal cell carcinoma. We report here the case of a patient with two cancers, a locally advanced cancer of the piriform sinus and a hepatocellular carcinoma, who was given sorafenib. Tumor response of both cancers might suggest that sorafenib could be effective against head and neck cancer.

     

Systemic Treatment of Patients with Advanced,Unresectable Hepatocellular Carcinoma: Emergence of Therapies

To date, sorafenib, a multiple tyrosine kinase inhibitor, is the only systemic agent approved by the FDA in the first-line treatment of patients with unresectable hepatocellular carcinoma (HCC). Several other tyrosine kinase-inhibiting agents have been investigated in the first-line setting, either alone (sunitinib, brivanib, linifanib, and lenvatinib) or in combination with sorafenib (erlotinib and doxorubicin) in phase 3 trials. However, none of these studies demonstrated an improvement in survival over sorafenib. Many agents have also been tested in patients with HCC whose disease has progressed on sorafenib, but regorafenib is the only one to have demonstrated efficacy in this setting in a randomized, phase 3 trial. There were no clear survival benefits shown with everolimus, brivanib, or ramucirumab as second-line therapy. Nivolumab has also shown promising efficacy in patients with HCC who progressed on sorafenib, which was recently granted approval by the FDA, although larger confirmative trials may be considered. The treatment landscape for patients with advanced unresectable hepatocellular tumors has remained fairly static for the past 10 years, with multiple failed trials yield little change in the way these patients might be treated. However, recent findings for regorafenib, lenvatinib, and nivolumab have led to the most significant changes in the treatment paradigm in years.     

Chimioembolisation et hépatocarcinome: pour quel type de patient ?

Transarterial chemoembolization (TACE) is widely used in the treatment of Hepatocellular carcinoma. Recent technical advances (drug-eluting beads) have led to the standardization of injection techniques. Recognized indications for TACE are patients with an intermediate stage of cancer (BCLC classification). However the best indications are patients with well compensated liver cirrhosis (Child-Pugh A or B7), one or a few nodules of median size which can receive a selective embolization, without portal thrombosis, extra-hepatic metastases or severe comorbidities. For other intermediate-stage patients, systemic treatment with sorafenib would be the treatment of choice.     

Management of cirrhotic patients with hepatocellular carcinoma treated with sorafenib

Sorafenib (Nexavar?, Bayer), a multi-targeted tyrosine kinase inhibitor, was the first systemic agent that demonstrated a significant improvement in the overall survival in patients with advanced hepatocellular carcinoma and well-preserved liver function. This drug is now recommended in patients with advanced hepatocellular carcinoma as first-line therapy and for patients not suitable for locoregional treatment. This brief article, produced by a multidisciplinary panel including specialists in gastroenterology and oncology, provides an overview of the major issues related to systemic treatment of hepatocellular carcinoma with sorafenib, including staging and prognostic strategies, assessment of liver disease and its complications, and efficacy and safety of this molecule. Particular emphasis is given on how to improve tolerability of sorafenib in difficult-to-treat patients.     

A novel small molecule hydroxamate preferentially inhibits HDAC6 activity and tumour growth

Background:

Sorafenib is a potent inhibitor against Raf kinase and several receptor tyrosine kinases that has been approved for the clinical treatment of advanced renal and liver cancer. Combining sorafenib with other agents has been shown to improve its antitumour efficacy by not only reducing the toxic side effects but also preventing primary and acquired resistance to sorafenib. We have previously observed that tetrandrine exhibits potent antitumour effects in human hepatocellular carcinoma. In this study, we investigated the synergistic antitumour activity of sorafenib in combination with tetrandrine.

Methods:

This was a two-part investigation that included the in vitro effects of sorafenib in combination with tetrandrine on cancer cells and the in vivo antitumour efficacy of this drug combination on tumour xenografts in nude mice.

Results:

Combined treatment showed a good synergistic antitumour effect yet spared nontumourigenic cells. The potential molecular mechanism may be mainly that it activated mitochondrial death pathway and induced caspase-dependent apoptosis in the cancer cells. Accumulation of intracellular reactive oxygen species (ROS) and subsequent activation of Akt may also be involved in apoptosis induction.

Conclusion:

The antitumour activity of sorafenib plus tetrandrine may be attributed to the induction of the intrinsic apoptosis pathway through ROS/Akt signaling. This finding provides a novel approach that may broaden the clinical application of sorafenib.     

Three cases of hepatocellular carcinoma without distant metastasis effectively treated by sorafenib

Sorafenib is a novel, orally administered multi-kinase inhibitor that has recently been approved for the treatment of advanced hepatocellular carcinoma. We report three cases of hepatocellular carcinoma without distant metastasis effectively treated by sorafenib. Case 1 was a 71-year-old male with multiple hepatocellular carcinomas, Child-Pugh status A, and asthma. He received sorafenib 400 mg twice daily. The efficacy evaluated by the RECIST was partial response. Case 2 was a 75-year-old male with multiple hepatocellular carcinomas and Child-Pugh status A. He previously received surgical resection and transarterial chemoembolization. He received sorafenib 400 mg twice daily. The efficacy evaluated by the RECIST and modified RECIST was partial response and complete response, respectively. Case 3 was a 62-year-old male with multiple hepatocellular carcinomas and Child-Pugh status A. He previously received surgical resection, percutaneous radiofrequency ablation therapy and transarterial chemoembolization. He received sorafenib 400 mg twice daily. The efficacy evaluated by the RECIST was stable disease. The majority of adverse events were grade 1-2 stomatitis and hand-foot skin reaction. No patients discontinued the treatment because of adverse events. Sorafenib might be promising as an effective therapy for advanced hepatocellular carcinoma without distant metastasis.     

Systemic therapy for hepatocellular carcinoma (HCC): from bench to bedside

Primary liver cancer is the fifth most common cancer worldwide and the third most common cause of cancer mortality. For patients with early resectable disease, surgical resection or transplantation is considered a potentially curative modality for hepatocellular carcinoma (HCC); on the other hand, for patients with unresectable or metastatic disease, treatment is essentially palliative and prior to the approval of sorafenib, there was no globally approved systemic treatment for patients presenting with unresectable or metastatic HCC. Sorafenib is the only systemic treatment to demonstrate a statistically significant but modest overall survival benefit in a large phase III trial. Thus, novel systemic approaches represent a high unmet medical need in advanced HCC. In this review article, we will try to take a journey through the history of systemic therapeutic options for HCC passing through the current standard options and exploring the potential new systemic options for this disease.     

Radiologic Complete Response with Sirolimus and Sorafenib in a Hepatocellular Carcinoma Patient who Relapsed After Orthotopic Liver Transplantation

Background

No standard therapies have been established for the treatment of recurrent hepatocellular carcinoma (HCC) after liver transplantation.

Discussion

Sirolimus is a mTOR inhibitor which has been used as an immunosuppressive medication in patients who are at high risk of tumor reoccurrence after liver transplantation. Sorafenib is a multikinase inhibitor approved for the treatment of advanced HCC. However the role of sorafenib in patients with HCC reoccurrence after liver transplantation is unclear.

Results

Combination of sirolimus and sorafenib appears to have synergistic effect when treating HCC in preclinical settings. We report a case of a post-liver transplant patient treated with sorafenib and sirolimus for hepatic HCC recurrence who exhibited complete radiologic response after 5 months of therapy.     

A Phase I Trial of Trametinib in Combination with Sorafenib in Patients with Advanced Hepatocellular Cancer

Lessons Learned

• The combination of trametinib and sorafenib has an acceptable safety profile, albeit at doses lower than approved for monotherapy.
• Maximum tolerated dose is trametinib 1.5 mg daily and sorafenib 200 mg twice daily.
• The limited anticancer activity observed in this unselected patient population does not support further exploration of trametinib plus sorafenib in patients with hepatocellular carcinoma.

BackgroundThe RAS/RAF/MEK/ERK signaling pathway is associated with proliferation and progression of hepatocellular carcinoma (HCC). Preclinical data suggest that paradoxical activation of the MAPK pathway may be one of the resistance mechanisms of sorafenib; therefore, we evaluated trametinib plus sorafenib in HCC.MethodsThis was a phase I study with a 3+3 design in patients with treatment‐naïve advanced HCC. The primary objective was safety and tolerability. The secondary objective was clinical efficacy.ResultsA total of 17 patients were treated with three different doses of trametinib and sorafenib. Two patients experienced dose‐limiting toxicity, including grade 4 hypertension and grade 3 elevation of aspartate aminotransferase (AST)/alanine aminotransferase (ALT)/bilirubin over 7 days. Maximum tolerated dose was trametinib 1.5 mg daily and sorafenib 200 mg twice a day. The most common grade 3/4 treatment‐related adverse events were elevated AST (37%) and hypertension (24%). Among 11 evaluable patients, 7 (63.6%) had stable disease with no objective response. The median progression‐free survival (PFS) and overall survival (OS) were 3.7 and 7.8 months, respectively. Phosphorylated‐ERK was evaluated as a pharmacodynamic marker, and sorafenib plus trametinib inhibited phosphorylated‐ERK up to 98.1% (median: 81.2%) in peripheral blood mononuclear cells.ConclusionTrametinib and sorafenib can be safely administered up to trametinib 1.5 mg daily and sorafenib 200 mg twice a day with limited anticancer activity in advanced HCC.     

Current status of molecularly targeted therapy for hepatocellular carcinoma: clinical practice

In recent years, molecular-targeted agents have been used clinically to treat various malignant tumors. In May 2009, sorafenib (Nexavar^®) was approved in Japan for “unresectable hepatocellular carcinoma (HCC)”, and was the first molecular-targeted agent for use in liver cancer. To date, sorafenib is the only molecular-targeted agent whose survival benefit has been demonstrated in two global phase III randomized controlled trials, and it has now been approved worldwide. Phase III clinical trials are now underway to compare other molecular-targeted agents with sorafenib as first-line treatment agents, and to evaluate other multi-kinase inhibitors of the vascular endothelial growth factor and platelet-derived growth factor receptors, as well as drugs targeting the epidermal growth factor receptor, insulin-like growth factor receptor, and mammalian target of rapamycin, in addition to other molecules targeting other components of the signal transduction pathways. This review outlines the main pathways involved in the development and progression of HCC and the agents that target these pathways.     

Tolerable sorafenib therapy for a renal cell carcinoma patient with hemodialysis: a case study

Sorafenib (Nexavar^®) has been approved for the treatment of advanced renal cell carcinoma (RCC) and hepatocellular carcinoma. There is little information on the dosage adjustment of sorafenib for patients with end-stage renal failure. Herein, we have examined the effect of hemodialysis on the pharmacokinetics of sorafenib and its major active metabolite, M-2, and assessed sorafenib-related toxicity throughout the therapy. The patient was a 54-year-old man who was diagnosed with advanced RCC. Pharmacokinetic analysis was carried out on days 9 and 183. The patient had stable disease on day 77 and showed progression on day 181. He has received about 6 months of continuous treatment with sorafenib 800 mg/day without any clinically relevant toxicity. The pharmacokinetic parameters of sorafenib such as C _max and AUC_0–12 on day 183 were in the range of the reference values reported in patients with normal renal function. Our results suggest that sorafenib administered at a dose of 400 mg twice per day was well tolerated, at least for 6 months, for a patient undergoing hemodialysis.