Effect of the Hypoxia Inducible Factor on Sorafenib Resistance of Hepatocellular Carcinoma

Sorafenib a multi-target tyrosine kinase inhibitor, is the first-line drug for treating advanced hepatocellular carcinoma (HCC). Mechanistically, it suppresses tumor angiogenesis, cell proliferation and promotes apoptosis. Although sorafenib effectively prolongs median survival rates of patients with advanced HCC, its efficacy is limited by drug resistance in some patients. In HCC, this resistance is attributed to multiple complex mechanisms. Previous clinical data has shown that HIFs expression is a predictor of poor prognosis, with further evidence demonstrating that a combination of sorafenib and HIFs-targeted therapy or HIFs inhibitors can overcome HCC sorafenib resistance. Here, we describe the molecular mechanism underlying sorafenib resistance in HCC patients, and highlight the impact of hypoxia microenvironment on sorafenib resistance.

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Predictive and Prognostic Factors in HCC Patients Treated with Sorafenib

Medicina ◽

10.3390/medicina55100707 ◽

2019 ◽

Vol 55 (10) ◽

pp. 707 ◽

Cited By ~ 12

Author(s):

Oronzo Brunetti ◽

Antonio Gnoni ◽

Antonella Licchetta ◽

Vito Longo ◽

Angela Calabrese ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Prognostic Factors ◽

Prognostic Markers ◽

Kinase Inhibitor ◽

Quality Standard ◽

Advanced Hepatocellular Carcinoma ◽

Line Treatment ◽

First Line ◽

Advanced Hcc ◽

First Line Treatment

Sorafenib is an oral kinase inhibitor that enhances survival in patients affected by advanced hepatocellular carcinoma (HCC). According to the results of two registrative trials, this drug represents a gold quality standard in the first line treatment of advanced HCC. Recently, lenvatinib showed similar results in terms of survival in a non-inferiority randomized trial study considering the same subset of patients. Unlike other targeted therapies, predictive and prognostic markers in HCC patients treated with sorafenib are lacking. Their identification could help clinicians in the daily management of these patients, mostly in light of the new therapeutic options available in the first.

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Evolution of Survival Impact of Molecular Target Agents in Patients with Advanced Hepatocellular Carcinoma

Liver Cancer ◽

10.1159/000519868 ◽

2021 ◽

pp. 1-13

Author(s):

Kazufumi Kobayashi ◽

Sadahisa Ogasawara ◽

Aya Takahashi ◽

Yuya Seko ◽

Hidemi Unozawa ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Treatment Duration ◽

Molecular Target ◽

Advanced Hepatocellular Carcinoma ◽

Advanced Stage ◽

First Line ◽

Advanced Hcc ◽

Period 2 ◽

Study Population ◽

The Impact

Background and Aims: The prognosis of patients with advanced hepatocellular carcinoma (HCC) is expected to improve as multiple molecular target agents (MTAs) are now available. However, the impact of the availability of sequential MTAs has not been fully verified yet. Approach and Results: We retrospectively collected the data on the whole clinical course of 877 patients who received any MTAs as first-line systemic therapy for advanced HCC between June 2009 and March 2019. The study population was divided into 3 groups according to the date of first-line MTA administration (period 1: 2009–2012, n = 267; period 2: 2013–2016, n = 352; period 3: 2017–2019, n = 258). Then, we compared the number of MTAs used, overall survival (OS), and MTA treatment duration among the 3 groups. Analysis was also performed separately for advanced-stage and nonadvanced-stage HCC. The proportion of patients who received multiple MTAs was remarkably increased over time (1.1%, 10.2%, and 42.6% in periods 1, 2, and 3, respectively, p < 0.001). The median OS times were prolonged to 10.4, 11.3, and 15.2 months in periods 1, 2, and 3, respectively (p = 0.016). Similarly, the MTA treatment durations were extended (2.7, 3.2, and 6.6 months in periods 1, 2, and 3, respectively; p < 0.001). We confirmed that the correlation between OS and MTA treatment duration was strengthened (period 1: 0.395, period 2: 0.505, and period 3: 0.667). All these trends were pronounced in the patients with advanced-stage HCC but limited in the patients with nonadvanced-stage HCC. Conclusions: The availability of multiple MTAs had steadily improved the prognosis of patients with advanced HCC patients, particularly advanced-stage HCC patients.

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Predictive and Prognostic Factors in HCC Patients Treated with Sorafenib

10.20944/preprints201909.0071.v1 ◽

2019 ◽

Cited By ~ 1

Author(s):

Oronzo Brunetti ◽

Antonio Gnoni ◽

Antonella Licchetta ◽

Vito Longo ◽

Angela Calabrese ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Prognostic Factors ◽

Prognostic Markers ◽

Kinase Inhibitor ◽

Quality Standard ◽

Advanced Hepatocellular Carcinoma ◽

Line Treatment ◽

First Line ◽

Advanced Hcc ◽

First Line Treatment

Sorafenib is an oral kinase inhibitor that enhances survival in patients affected by advanced hepatocellular carcinoma (HCC). According to the results of two registrative trials, this drug represents a gold quality standard in the first line treatment of advanced HCC. Recently, lenvatinib showed similar results in terms of survival in a non-inferiority randomized trial study considering the same subset of patients. Unlike other targeted therapies, currently predictive and prognostic markers in HCC patients treated with sorafenib are lacking. Their identification could help clinicians in the daily management of these patients, mostly in light of the new therapeutic options available in the first.

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Ipilimumab and nivolumab/pembrolizumab in advanced hepatocellular carcinoma refractory to prior immune checkpoint inhibitors

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-001945 ◽

2021 ◽

Vol 9 (2) ◽

pp. e001945 ◽

Cited By ~ 1

Author(s):

Jeffrey Sum Lung Wong ◽

Gerry Gin Wai Kwok ◽

Vikki Tang ◽

Bryan Cho Wing Li ◽

Roland Leung ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Objective Response ◽

Acquired Resistance ◽

Survival Rates ◽

Advanced Hepatocellular Carcinoma ◽

Primary Resistance ◽

Advanced Hcc

BackgroundProgrammed cell death protein 1 (PD-1) pathway blockade with immune checkpoint inhibitors (ICIs) is a standard therapy in advanced hepatocellular carcinoma (HCC) nowadays. No strategies to overcome ICI resistance have been described. We aimed to evaluate the use of ipilimumab and anti-PD-1 ICIs (nivolumab or pembrolizumab) combinations in patients with advanced HCC with progression on prior ICIs.MethodsPatients with advanced HCC with documented tumor progression on prior ICIs and subsequently received ipilimumab with nivolumab/pembrolizumab were analyzed. Objective response rate (ORR), median duration of response (DOR), time-to-progression (TTP), overall survival (OS), and treatment-related adverse events (TRAEs) were assessed.ResultsTwenty-five patients were included. The median age was 62 (range: 51–83). About 68% were of Child-Pugh (CP) Grade A and 48% had primary resistance to prior ICI. At median follow-up of 37.7 months, the ORR was 16% with a median DOR of 11.5 months (range: 2.76–30.3). Three patients achieved complete response. The median TTP was 2.96 months (95% CI: 1.61 to 4.31). Median OS was 10.9 months (95% CI: 3.99 to 17.8) and the 1 year, 2 year and 3 year survival rates were 42.4%, 32.3% and 21.6%, respectively. The ORR was 16.7% in primary resistance group and 15.4% in acquired resistance group (p=1.00). All responders were of CP A and Albumin-Bilirubin (ALBI) Grade 1 or 2. CP and ALBI Grades were significantly associated with OS (p=0.006 and p<0.001, respectively). Overall, 52% of patients experienced TRAEs and 12% experienced Grade 3 or above TRAEs.ConclusionsIpilimumab and nivolumab/pembrolizumab can achieve durable antitumor activity and encouraging survival outcomes with acceptable toxicity in patients with advanced HCC who had prior treatment with ICIs.

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Impact of Individual Components of the Metabolic Syndrome on the Outcome of Patients with Advanced Hepatocellular Carcinoma Treated with Sorafenib

Digestive Diseases ◽

10.1159/000477578 ◽

2017 ◽

Vol 36 (1) ◽

pp. 78-88 ◽

Cited By ~ 4

Author(s):

Christian Labenz ◽

Vera Prenosil ◽

Sandra Koch ◽

Yvonne Huber ◽

Jens U. Marquardt ◽

...

Keyword(s):

Diabetes Mellitus ◽

Hepatocellular Carcinoma ◽

Metabolic Syndrome ◽

Group Performance ◽

Performance Status ◽

Eastern Cooperative Oncology Group ◽

Advanced Hepatocellular Carcinoma ◽

Advanced Hcc ◽

The Metabolic Syndrome ◽

The Impact

Background/Aim: Individual components of the metabolic syndrome (MS) such as obesity or diabetes mellitus impair the prognosis of patients with hepatocellular carcinoma (HCC) following curative treatment approaches or transarterial therapies. The aim of this retrospective study was to assess the impact of these factors on the overall survival (OS) of patients with advanced HCC treated with sorafenib. Methods: Univariate and multivariate analyses were performed to assess the impact of individual components of the MS on the OS of 152 consecutive patients with advanced HCC treated with sorafenib. Results: The presence of overweight/obesity, type 2 diabetes mellitus, hypertension, dyslipidemia, and of the MS itself did not impair the median OS. Multivariate analysis showed that Eastern Cooperative Oncology Group Performance Status ≥1 (hazards ratio [HR] 2.03), presence of macrovascular invasion (HR 1.71), Child-Pugh score B/C (HR 2.19), tumor grading G3 (HR 2.17), no prior HCC treatment (HR 2.34), and the presence of 2 or more out of 5 individual components of the MS (HR 0.65) were independent prognostic factors regarding the median OS. Conclusions: Our investigations do not confirm a negative prognostic role of individual components of the MS or the MS itself for patients with advanced HCC treated with sorafenib.

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Combination therapy of intra-arterial 5-fluorouracil and systemic pegylated interferon alpha-2b for advanced hepatocellular carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.4_suppl.216 ◽

2013 ◽

Vol 31 (4_suppl) ◽

pp. 216-216

Author(s):

Kazuhiro Kasai ◽

Kei Sawara ◽

Kazuyuki Suzuki

Keyword(s):

Hepatocellular Carcinoma ◽

Survival Rates ◽

Pegylated Interferon ◽

Early Response ◽

The Other ◽

Advanced Hepatocellular Carcinoma ◽

Arterial Infusion ◽

Cumulative Survival ◽

Advanced Hcc ◽

Sorafenib Group

216 Background: Two recent phase III clinical trials have shown that sorafenib improves the survival in patients with advanced hepatocellular carcinoma (HCC). However, patients with HCC and portal vein tumor thrombosis (PVTT) usually have very short survival even when treated with sorafenib. On the other hand, recent advances in implantable drug delivery systems have made it possible to administer repeated hepatic arterial infusion chemotherapy (HAIC) agent. Since 2006, we have treated the patients displaying advanced HCC with PVTT by combined HAIC of 5-fluorouracil (5-FU) and systemic pegylated interferon (PEG-IFN)α-2b, and reported favorable results. In this article, we evaluated the efficacy of combined 5-FU and PEG-IFN α-2b, and compared outcomes between advanced HCC patients with PVTT treated using sorafenib. Methods: Forty patients with HCC and PVTT were enrolled. Of these, 21 patients were treated using subcutaneous administration of PEG-IFNα-2b and intra-arterial infusion of 5-FU [5-FU / PEG-IFN group], 19 patients were treated using continuous oral treatment with 400-800 mg of sorafenib [Sorafenib group]. We compared the early response to the therapy and the cumulative survival rate between these two groups. Results: The objective early response rate in the 5-FU / PEG-IFN group was significantly higher than that in the Sorafenib group (71.4 vs. 10.5%, P<0.01). The cumulative survival rates at 6, 12, 18, and 24 months, respectively, were 83.8, 77.8, 55.6, and 55.6% in the 5FU / PEG-IFN group, and 68.4, 37.7, 16.2, and 16.2% in the Sorafenib group. The cumulative survival rates was significantly higher in the 5FU / PEG-IFN group than in the Sorafenib group (P=0.03). Serious complications and treatment-related deaths were not observed in the 5FU / PEG-IFN group. On the other hand, the rate of discontinuation of treatment due to adverse events was 36.8% of the patients who were treated sorafenib. Conclusions: Based on our findings, this newly developed combination therapy may be useful for patients with advanced HCC, although a large-scale randomized controlled study by comparison with sorafenib is needed.

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Organ Specific Responses to First-line Lenvatinib Plus Anti-PD-1 Antibodies in Patients With Unresectable Hepatocellular Carcinoma: a Retrospective Analysis

10.21203/rs.3.rs-143399/v1 ◽

2021 ◽

Author(s):

Cheng Huang ◽

Xiao-Dong Zhu ◽

Ying-Hao Shen ◽

Dong Wu ◽

Yuan Ji ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Retrospective Analysis ◽

Surgical Resection ◽

Chinese Patients ◽

Specific Response ◽

Advanced Hepatocellular Carcinoma ◽

First Line ◽

Advanced Hcc ◽

Overall Response ◽

Organ Specific

Abstract BackgroundWe evaluated organ-specific response rates (OSRRs) to first-line lenvatinib plus anti-PD-1 antibodies in patients with advanced hepatocellular carcinoma (HCC).MethodsThis retrospective analysis included Chinese patients with unresectable/advanced HCC who received first-line lenvatinib (8 mg/day) plus ≥3 infusions of anti-PD-1 antibodies between October 2018 and May 2020. Tumor and macrovascular tumor thrombi (MVTT) treatment responses were evaluated every 2 months using RECIST v1.1. The overall response rate (ORR)/OSRR was defined as the percentage of patients with a best overall response of complete or partial response (CR or PR).ResultsIn total, 60 patients were included in the analysis; 96.7% had measurable intrahepatic lesions, 55% had MVTT and 26.7% had extrahepatic disease. In all 60 patients, the ORR was 33.3%, median progression-free survival was 7.0 months (95% CI, 1.7-12.3) and median overall survival was not reached. The OSRR for MVTT (54.5%) was higher versus intrahepatic tumors (32.8%), extrahepatic lung metastases (37.5%) and lymph node metastases (33.3%). Among 33 patients with intrahepatic tumors and MVTT, 18 had differential responses in each site, including 13 with a better response in MVTT versus intrahepatic lesions. Among 18 patients whose MVTT achieved a radiographic CR or PR, six underwent surgical resection: 4/6 achieved a pathological CR in MVTT and 2/6 in the intrahepatic tumor.ConclusionsFirst-line lenvatinib plus anti-PD-1 antibodies resulted in better tumor responses in MVTT versus intrahepatic lesions. Complete MVTT necrosis may allow downstaging and subsequent eligibility for surgical resection in a proportion of patients with advanced HCC.

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Role and strategies of radiofrequency ablation in treating advanced hepatocellular carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.e14701 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. e14701-e14701

Author(s):

Min Hua Chen ◽

Wei Yang ◽

Jie Wu ◽

Wei Wu ◽

Kun Yan

Keyword(s):

Hepatocellular Carcinoma ◽

Overall Survival ◽

Radiofrequency Ablation ◽

Survival Rates ◽

Treatment Strategies ◽

Percutaneous Ablation ◽

Advanced Hepatocellular Carcinoma ◽

Advanced Hcc ◽

Tnm System ◽

Liver Protection

e14701 Background: To investigate the application value and strategies of ultrasound-guided percutaneous radiofrequency ablation (RFA) in treating advanced hepatocellular carcinoma (HCC) which is common in china. Methods: A total of 655 patients with unresectablely advanced HCC underwent percuatenous RFA therapy and 92 patients with 136 tumors among them were enrolled into the study. According to the 6th UICC/AJCC-TNM system, 82 and 10 patients were in stage III and IV, respectively. The tumor size ranged from 1.5 to 8.0 cm (mean±SD, 4.5±1.6 cm). 59 patients had solitary tumor and the remaining 33 patients had multiple tumors. The Child-Pugh classification of A, B and C were 58,32 and 2 patients, respectively. Established strategies included: (1) select RFA indications based on the contrast-enhanced ultrasound (CEUS) results; (2) design radical protocols based on invasive range showed by CEUS; (3) multiple overlapping ablations based on mathematical protocol; (4) two or three bipolar RFA electrodes with three dimensional localization; (5) color US guided percutaneous ablation of tumor feeding artery (including TACE) + RFA for HCC with rich supply. The patients underwent follow-up using enhanced CT at one month, and then every three months after RFA. The ablation was considered a success if no abnormal enhancement or wash-out was detected in the treated area on the CT scan at one month. All patients after RFA received liver protection treatments. Overall survival was estimated by Kaplan-Meier analysis. Results: Early complete tumor necrosis rate after initial RFA was 90.4% (123/136 tumors). Serious complications were developed in two patients (2.2%) and no treatment-related death occurred. 3~129 months were followed up. Local recurrence rate was 15.4 %(21/136 tumors). The 1-, 3-, 5-year overall survival rates were 83.3 %, 48.3 %, 21.9%, respectively, and the median survival time was 35 months. Conclusions: RFA treatment of advanced HCC proved to be feasible. Paying attention to apply treatment strategies and liver protection therapies in RFA can effectively improve the survival.

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Final phase Ib data for the oral c-Met inhibitor tepotinib in patients with previously treated advanced hepatocellular carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e15676 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e15676-e15676 ◽

Cited By ~ 1

Author(s):

Sandrine J. Faivre ◽

Jean-Frédéric Blanc ◽

Philippe Merle ◽

Angelica Fasolo ◽

Angelo Iacobellis ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Phase Ii ◽

Tumor Size ◽

Advanced Hepatocellular Carcinoma ◽

First Line ◽

Phase Ib ◽

Advanced Hcc ◽

Peripheral Edema ◽

Met Inhibitor ◽

Grade 3

e15676 Background: The prognosis for patients (pts) with advanced hepatocellular carcinoma (HCC) after failure of sorafenib is poor, with few systemic therapy options. c-Met is a receptor tyrosine kinase implicated in the progression of HCC. Tepotinib, a highly selective c-Met inhibitor, has shown activity first-line in patients with c-Met+ HCC. We report final results of a phase Ib study of tepotinib in pts with advanced HCC after failure of first-line sorafenib. Methods: Eligible pts were ≥18 years with advanced HCC, Child-Pugh Class A, ECOG PS 0-1, and progression after ≥4 weeks of sorafenib. Tepotinib doses of 300 and 500 mg/day on a 21-day cycle were explored to establish the recommended phase II dose (RP2D) of tepotinib. Secondary objectives included antitumor activity by RECIST v1.1, biochemical response, and safety. Results: Seventeen pts were enrolled: 4 pts received tepotinib 300 mg/day and 13 pts 500 mg/day, confirmed as the RP2D. Fourteen pts experienced treatment-related adverse events (TRAEs), the most frequent being peripheral edema (n = 5, 2 grade 3), lipase increase (2, 1 grade 3), acute kidney injury (2, 1 grade 3), renal impairment (2, 1 grade 3), fatigue (2), nausea (2), asthenia (2). One pt with peripheral edema permanently discontinued treatment. No grade ≥4 TRAEs and no dose-limiting toxicities (DLTs) were reported. The best overall response was partial response (PR) in 2 pts and stable disease (SD) in 4 pts. The duration of the PRs was 57 and 91 weeks. In the first of these pts, tumor size decreased by 55% and serum alfa-fetoprotein (AFP) levels had decreased from 15,923 μg/L at baseline to < 3,000 μg/L by day 15 of cycle 2 and remained at this level until progression. In the second pt, tumor size decreased by > 60% from baseline. No consistent change in AFP was seen in pts with SD. Median overall survival was 7.2 months (range 0.7–22.9 months). Conclusions: The RP2D of tepotinib as second-line therapy for pts with advanced HCC who progress after sorafenib treatment is 500 mg/day. Tepotinib was well tolerated at this dose and showed signs of activity. The ongoing phase II part of this trial is investigating the efficacy and safety of tepotinib 500 mg/day in pts with c-Met+ HCC. Clinical trial information: NCT02115373.

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Non-immunotherapy options for the first-line management of hepatocellular carcinoma: exploring the evolving role of sorafenib and lenvatinib in advanced disease

Current Oncology ◽

10.3747/co.27.7159 ◽

2020 ◽

Vol 27 (S3) ◽

Author(s):

S. Perera ◽

D. Kelly ◽

G. M. O'Kane

Keyword(s):

Hepatocellular Carcinoma ◽

Kinase Inhibitor ◽

Treatment Options ◽

Optimal Timing ◽

Advanced Hepatocellular Carcinoma ◽

Line Treatment ◽

First Line ◽

First Line Treatment ◽

Line Management

The results of the sharp trial established sorafenib, a tyrosine kinase inhibitor (TKI), as the sole first-line treatment option in advanced hepatocellular carcinoma (HCC) for more than a decade. In 2020, there has been a surge in new therapies for hcc, including immunotherapeutic strategies and the approval of a number of novel tkis. In addition to sorafenib, lenvatinib and combination atezolizumab–bevacizumab now represent standard first-line treatment options. As those systemic options begin to be better utilized, assurance of adequate liver function and optimal timing are required to improve patient outcomes. Furthermore, sequencing of the agents will have to be carefully tailored, given the increasing armamentarium of choices. Here, we discuss the role of lenvatinib and sorafenib in the first-line management of HCC.

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