Vandetanib in patients with inoperable hepatocellular carcinoma: A phase II, randomized, double-blind, placebo-controlled study

doi:10.1016/j.jhep.2011.12.013

Journal of Hepatology

Volume 56, Issue 5, May 2012, Pages 1097-1103

https://doi.org/10.1016/j.jhep.2011.12.013 Get rights and content

Background & Aims

Inhibitors of vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR) have shown anti-tumor activities in advanced hepatocellular carcinoma (HCC). The present study evaluated the efficacy and safety of vandetanib, an oral inhibitor of both VEGFR and EGFR, in patients with unresectable advanced HCC.

Methods

Eligible patients were randomized 1:1:1 to receive vandetanib 300 mg/day, vandetanib 100 mg/day, or placebo. Upon disease progression, all patients had the option to receive open-label vandetanib 300 mg/day. The primary objective was to evaluate tumor stabilization rate (complete response + partial response + stable disease ⩾4 months). Secondary assessments included progression-free survival (PFS), overall survival (OS) and safety. Biomarker studies included circulating pro-angiogenic factors and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI).

Results

Sixty-seven patients were randomized to vandetanib 300 mg (n = 19), vandetanib 100 mg (n = 25) or placebo (n = 23) groups. Twenty-nine patients entered open-label treatment. Vandetanib induced a significant increase in circulating VEGF and decrease in circulating VEGFR levels. In both vandetanib arms, tumor stabilization rate was not significantly different from placebo: 5.3% (vandetanib 300 mg), 16.0% (vandetanib 100 mg) and 8.7% (placebo). DCE-MRI did not detect significant vascular change after vandetanib treatment. Although trends of improved PFS and OS after vandetanib treatment were found, they were statistically insignificant. The most common adverse events were diarrhea and rash, whose incidence did not differ significantly between treatment groups.

Conclusions

Vandetanib has limited clinical activity in HCC. The safety profile was consistent with previous studies.

Introduction

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, with approximately 80% of cases arising in Asia and Africa [1]. HCC is typically a hypervascular tumor. The extensive tumor vasculature forms the basis of HCC imaging diagnosis [2], [3]. The inhibition of tumor angiogenesis is a promising approach for systemic therapy of patients with advanced HCC. Sorafenib, a multi-target kinase inhibitor that targets both RAF and vascular endothelial growth factor receptor (VEGFR) kinases, improves overall survival of advanced HCC patients in both Western and Asian populations [4], [5]. Most of the other agents under development for HCC treatment, such as sunitinib, brivanib, and linifanib, also target tumor angiogenesis as their major anti-tumor mechanism [6].

The epidermal growth factor receptor (EGFR) is involved in liver regeneration and hepatocarcinogenesis [7], [8]. The EGFR inhibitor erlotinib has modest anti-tumor effects in patients with advanced HCC [9]. Additionally, EGFR inhibitors may indirectly inhibit tumor angiogenesis [10]. Combination of erlotinib and the anti-VEGF antibody bevacizumab produced an objective response rate of 25% in 40 patients with advanced HCC [11]. Therefore, simultaneous inhibition of both pathways may provide greater benefits than targeting either pathway alone.

Vandetanib targets both VEGFR and EGFR signaling pathways [12]. Vandetanib can also inhibit the REarranged during Transfection (RET) receptor tyrosine kinase. RET is associated with the development of certain types of thyroid cancer; however, the significance of RET signalling in HCC is not clear [13], [14], [15]. Phase I dose-escalation studies performed in Western and Japanese patients showed that vandetanib was generally well tolerated at daily doses up to 300 mg [16], [17]. Vandetanib can significantly prolong progression-free survival (PFS) of patients with advanced medullary thyroid cancer [18] and is not inferior to erlotinib as a second-line therapy for patients with advanced non-small-cell lung cancer (NSCLC) [19]. Vandetanib plus docetaxel can significantly prolong PFS, compared with docetaxel alone, in patients with advanced NSCLC after progression following first-line chemotherapy [20].

In this randomized, placebo-controlled phase II study, the efficacy and safety of vandetanib in patients with advanced HCC was examined. The primary objective was to evaluate the tumor stabilization rate of vandetanib. Secondary objectives were to evaluate the safety of vandetanib in patients with advanced HCC and to explore the correlation between treatment responses and biomarkers, including circulating angiogenic factors and vascular response measured by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI).

Section snippets

Patients

Eligible patients had locally advanced or metastatic inoperable HCC with at least one measurable lesion by Response Evaluation Criteria In Solid Tumors (RECIST), version 1.0, and no treatment with curative intent was available. The diagnosis of HCC could be histological or clinical. Clinical diagnosis required chronic viral hepatitis and/or cirrhosis, presence of hepatic tumor(s) with typical vascular patterns of HCC, and persistent elevation of serum α-fetoprotein (AFP) level ⩾400 ng/ml. The

Patients

Between July 2007 and November 2008, 67 patients were randomized (Fig. 1). Twenty-nine patients entered the secondary phase to receive treatment with open-label V300 (13 initially randomized to V100 and 16 initially randomized to placebo). At data cut-off (30 June 2009), 63 patients had progressed and 54 had died. Two patients (one from each of the V100 and placebo groups) were continuing to receive treatment in the randomized phase and no patient was receiving treatment in the open-label

Discussion

Anti-angiogenic agents usually exert cytostatic rather than cytotoxic effects in established tumors. Therefore, a randomized phase II trial design with time-to-event end points is recommended to better detect treatment efficacy [22]. This study was designed before the proof of efficacy of sorafenib for advanced HCC, therefore a placebo was used as control. A non-significant positive trend was observed for both PFS and OS after vandetanib treatment; however, it is possible that due to dose

Conflict of interest

Dr. Ann-Lii Cheng is a consultant for Sanofi-Aventis Inc.; Pfizer, Bayer Schering Pharma; Bristol-Myers Squibb (Taiwan) Ltd.; Boehringer Ingelheim Taiwan Limited; Novartis Inc. Dr. Chiun Hsu is a member of the speaker’s bureau of Bayer-Schering Pharma. Dr. Robin Meng is an employee of AstraZeneca. Other authors have nothing relevant to this manuscript to disclose.

Financial support

This study, including medical writing support provided by Zoë van Helmond of Mudskipper Bioscience, was sponsored by AstraZeneca.

Authors’ contributions

Chiun Hsu: design of the clinical trial, conduct of the clinical trial, data analysis and interpretation, writing of the manuscript, approval of the manuscript.

Tsai-Sheng Yang, Teh-Ia Huo, Ruey-Kuen Hsieh, Wei-Shou Hwang, Tsai-Yuan Hsieh, Wen-Tsung Huang, Yee Chao: design of the clinical trial, conduct of the clinical trial, approval of the manuscript.

Chih-Wei Yu: analysis and interpretation of the dynamic contrast-enhanced magnetic resonance imaging data.

Robin Meng: support for design and

Acknowledgements

The authors thank the following co-investigators for their help in trial conduct and patient care:

Zhong-Zhe Lin, Chih-Hung Hsu, Chih-Hsin Yang, Yen-Shen Lu, Ruey-Long Hong, Kun-Huei Yeh, Ying-Chun Shen, Yu-Lin Lin, Sung-Hsin Kuo, Jo-Pai Chen, Ta-Chen Huang: Department of Oncology, National Taiwan University Hospital, Taipei; Jen-Shi Chen: Division of Hematology and Oncology, Chang-Gung Memorial Hospital Linkou, Linkou; Tsu-Yi Chao: Division of Hematology and Oncology, Tri-Service General

References (32)

A.L. Cheng et al.
Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial
Lancet Oncol
(2009)
N. Fausto
Growth factors in liver development, regeneration and carcinogenesis
Prog Growth Factor Res
(1991)
S.N. Holden et al.
Clinical evaluation of ZD6474, an orally active inhibitor of VEGF and EGF receptor signaling, in patients with solid, malignant tumours
Ann Oncol
(2005)
T. Tamura et al.
A Phase I dose-escalation study of ZD6474 in Japanese patients with solid, malignant tumours
J Thorac Oncol
(2006)
R.S. Herbst et al.
Vandetanib plus docetaxel versus docetaxel as second-line treatment for patients with advanced non-small-cell lung cancer (ZODIAC): a double-blind, randomised, phase 3 trial
Lancet Oncol
(2010)
M.C. Su et al.
Absence of epidermal growth factor receptor exon 18–21 mutation in hepatocellular carcinoma
Cancer Lett
(2005)
R. Pang et al.
Angiogenesis and antiangiogenic therapy in hepatocellular carcinoma
Cancer Lett
(2006)
K.A. McGlynn et al.
International trends and patterns of primary liver cancer
Int J Cancer
(2001)
J. Bruix et al.
Management of hepatocellular carcinoma: an update
Hepatology
(2011)
M. Omata et al.
Asian pacific association for the study of the liver consensus recommendations on hepatocellular carcinoma
Hepatol Int
(2010)

J.M. Llovet et al.

Sorafenib in advanced hepatocellular carcinoma

N Engl J Med

(2008)

Y.C. Shen et al.

Molecular targeted therapy for advanced hepatocellular carcinoma: current status and future perspectives

J Gastroenterol

(2010)

K. Harada et al.

Transforming growth factor-alpha and epidermal growth factor receptor in chronic liver disease and hepatocellular carcinoma

Liver

(1999)

P.A. Philip et al.

Phase II study of erlotinib (OSI-774) in patients with advanced hepatocellular cancer

J Clin Oncol

(2005)

A. De Luca et al.

The role of the EGFR signaling in tumour microenvironment

J Cell Physiol

(2008)

M.B. Thomas et al.

Phase II trial of the combination of bevacizumab and erlotinib in patients who have advanced hepatocellular carcinoma

J Clin Oncol

(2009)

Cited by (81)

Structure and activity relationship analysis of xanthones from mangosteen: Identifying garcinone E as a potent dual EGFR and VEGFR2 inhibitor
2024, Phytomedicine
Xanthones are among the most fundamental phytochemicals in nature. The anti-cancer activities of xanthones and their derivatives have been extensively studied. Recently, we found that garcinone E (GE), an effective anti-cancer phytochemical isolated from mangosteen (Garcinia mangostanal.), showed promising anti-cancer effects in vitro and in vivo. However, little is known about its effects on epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor 2 (VEGFR2) activity.
This study aimed to identify potent dual EGFR and VEGFR2 inhibitors from mangosteen-derived xanthones using structure-activity relationship analyses.
The interaction of xanthones with EGFR and VEGFR2 was analyzed using molecular docking experiments. The kinase activities of EGFR and VEGFR2 were determined using bioluminescence assays. The rat aortic ring and Matrigel plug angiogenesis assays were used to evaluate blood vessel formation ex vivo and in vivo. A breast tumor-bearing nude mouse model was established to examine the anti-tumor effects of different xanthones.
Molecular docking analysis showed that GE bound tightly to EGFR and VEGFR2, with binding energies of -9.73 and -9.56 kcal/mol, respectively. Kinase activity assessment showed that GE strongly inhibited both EGFR and VEGFR2 kinase activity, with IC₅₀ values of 315.4 and 158.2 nM, respectively. Moreover, GE significantly abolished the EGF- and VEGF-induced phosphorylation of EGFR and VEGFR2, respectively. GE also showed strong inhibitory effects on cancer cell growth, endothelial cell migration, invasion, and tube formation. Ex vivo and in vivo angiogenesis assays showed that GE dose-dependently suppressed blood vessel formation in the rat aorta, Matrigel plugs, and transgenic zebrafish embryos, with the lowest effective concentration of 0.25 μM. Furthermore, GE (2 mg/kg) strongly inhibited tumor growth and reduced tumor weight in MDA-MB-231 breast tumor-xenografted mice. GE significantly reduced microvessel density and downregulated the expression of VEGFR2, EGFR, and Ki67 in tumor tissues.
The present study demonstrated that GE was the most potent dual inhibitor of EGFR and VEGFR2 among all xanthones tested. These findings may provide valuable information for the future development of novel and effective dual inhibitors of EGFR and VEGFR2.
Phase 0 Study of Vandetanib-Eluting Radiopaque Embolics as a Preoperative Embolization Treatment in Patients with Resectable Liver Malignancies
2022, Journal of Vascular and Interventional Radiology
Citation Excerpt :
Following BTG-002814 TACE, there was no marked change in any perfusion CT parameter assessed. Previous perfusion studies (7,20–22) have also shown mixed results in response to TACE and oral vandetanib, suggesting that the antiangiogenic effects of vandetanib are not detectable using currently available perfusion imaging or within the time period evaluated in these trials. This study evaluated potential biomarkers of response to BTG-002814 for patient selection in subsequent larger studies.
To assess the safety and tolerability of a vandetanib-eluting radiopaque embolic (BTG-002814) for transarterial chemoembolization (TACE) in patients with resectable liver malignancies.
The VEROnA clinical trial was a first-in-human, phase 0, single-arm, window-of-opportunity study. Eligible patients were aged ≥18 years and had resectable hepatocellular carcinoma (HCC) (Child-Pugh A) or metastatic colorectal cancer (mCRC). Patients received 1 mL of BTG-002814 transarterially (containing 100 mg of vandetanib) 7–21 days prior to surgery. The primary objectives were to establish the safety and tolerability of BTG-002814 and determine the concentrations of vandetanib and the N-desmethyl vandetanib metabolite in the plasma and resected liver after treatment. Biomarker studies included circulating proangiogenic factors, perfusion computed tomography, and dynamic contrast-enhanced magnetic resonance imaging.
Eight patients were enrolled: 2 with HCC and 6 with mCRC. There was 1 grade 3 adverse event (AE) before surgery and 18 after surgery; 6 AEs were deemed to be related to BTG-002814. Surgical resection was not delayed. Vandetanib was present in the plasma of all patients 12 days after treatment, with a mean maximum concentration of 24.3 ng/mL (standard deviation ± 13.94 ng/mL), and in resected liver tissue up to 32 days after treatment (441–404,000 ng/g). The median percentage of tumor necrosis was 92.5% (range, 5%–100%). There were no significant changes in perfusion imaging parameters after TACE.
BTG-002814 has an acceptable safety profile in patients before surgery. The presence of vandetanib in the tumor specimens up to 32 days after treatment suggests sustained anticancer activity, while the low vandetanib levels in the plasma suggest minimal release into the systemic circulation. Further evaluation of this TACE combination is warranted in dose-finding and efficacy studies.
Chemotherapy for hepatocellular carcinoma—an updated review
2022, Theranostics and Precision Medicine for the Management of Hepatocellular Carcinoma: Volume 3: Translational and Clinical Outcomes
Hepatocellular carcinoma (HCC) is the leading liver cancer with high morbidity and mortality globally. The etiological factors involved in HCC comprises of hepatitis B and C virus infection, genetic factors, smoking, obesity, alcohol abuse, environmental carcinogens, and microbial toxins. Despite its widespread incidence, the treatment is still a hard challenge due to lack of therapeutic choices at disease advanced stage. HCC can be cured if it is diagnosed at an early stage. Drug development in past few years against HCC is getting increased due to overall survival in HCC treatment. So far no approved first-line and second-line systemic treatments are available for advanced liver cancer treatment, and only sorafenib, regorafenib, and nivolumab are used. There is a paucity of information available on treatment of HCC. Several chemotherapeutic drugs have been developed particularly against HCC-related therapeutic targets. In the present chapter, a brief overview is provided on the HCC and its prevention through chemotherapeutic drugs.
Design, molecular docking, in vitro, and in vivo studies of new quinazolin-4(3H)-ones as VEGFR-2 inhibitors with potential activity against hepatocellular carcinoma
2021, Bioorganic Chemistry
A series of new VEGFR-2 inhibitors were designed, synthesized and evaluated for their anti-proliferative activities against hepatocellular carcinoma (HepG-2 cell line). Compound 29_b (IC₅₀ = 4.33 ± 0.2 µg/ml) was found to be the most potent derivative as it has showed to be more active than doxorubicin (IC₅₀ = 4.50 ± 0.2 µg/ml) and 78% of sorafenib activity (IC₅₀ = 3.40 ± 0.25 µg/ml). The inhibitory profiles against VEGFR-2 were also assessed for the most promising candidates (16_b, 20_c, 22_b, 24_a, 24_b, 28_c, 28_e, 29_a, 29_b and 29_c). Compounds 29_b, 29_c and 29_a exhibited potent inhibitory activities towards VEGFR-2 at IC₅₀ values of 3.1 ± 0.04, 3.4 ± 0.05 and 3.7 ± 0.06 µM, respectively, comparing sorafenib (IC₅₀ = 2.4 ± 0.05 µM). Furthermorer, compound 29_b induced apoptosis and arrested the cell cycle growth at G2/M phase. Additionally, in vivo antitumor experiments revealed that compounds 29_b and 29_c have significant tumor growth inhibition. The test of immuno-histochemical expression of activated caspase-3 revealed that there is a time-dependent increase in cleaved caspase-3 protein expression upon exposure of HepG-2 cells to compound 29_b. Moreover, the fibroblastic proliferative index test revealed that compound 29_b could attenuate liver fibrosis. Docking studies also supported the results concluded from the biological screening via prediction of the possible binding interactions of the target compounds with VEGFR-2 active sites using the crystal structure of VEGFR-2 downloaded from the Protein Data Bank, (PDB ID: 2OH4) using Discovery Studio 2.5 software. Further structural optimization of the most active candidates may serve as a useful strategy for getting new lead compounds in search for powerful and selective antineoplastic agents.
MERTK in cancer therapy: Targeting the receptor tyrosine kinase in tumor cells and the immune system
2020, Pharmacology and Therapeutics
The receptor tyrosine kinase MERTK is aberrantly expressed in numerous human malignancies, and is a novel target in cancer therapeutics. Physiologic roles of MERTK include regulation of tissue homeostasis and repair, innate immune control, and platelet aggregation. However, aberrant expression in a wide range of liquid and solid malignancies promotes neoplasia via growth factor independence, cell cycle progression, proliferation and tumor growth, resistance to apoptosis, and promotion of tumor metastases. Additionally, MERTK signaling contributes to an immunosuppressive tumor microenvironment via induction of an anti-inflammatory cytokine profile and regulation of the PD-1 axis, as well as regulation of macrophage, myeloid-derived suppressor cell, natural killer cell and T cell functions. Various MERTK-directed therapies are in preclinical development, and clinical trials are underway. In this review we discuss MERTK inhibition as an emerging strategy for cancer therapy, focusing on MERTK expression and function in neoplasia and its role in mediating resistance to cytotoxic and targeted therapies as well as in suppressing anti-tumor immunity. Additionally, we review preclinical and clinical pharmacological strategies to target MERTK.
Diarrhea with epidermal growth factor receptor tyrosine kinase inhibitors in cancer patients: A meta-analysis of randomized controlled trials
2019, Critical Reviews in Oncology/Hematology
Citation Excerpt :
When examining by agent, vandetanib was investigated in 6 trials (Arnold et al., 2007; Lee et al., 2012a; Ahn et al., 2013; Hsu et al., 2012; Wells et al., 2012; Leboulleux et al., 2012), gefitinib in 6 trials (Thatcher et al., 2005; Zhang et al., 2012; Goss et al., 2009; Dutton et al., 2014; Gaafar et al., 2011; Goss et al., 2013a), erlotinib in 4 trials (Cappuzzo et al., 2010; Kelly et al., 2015; Lee et al., 2012b; Shepherd and Rodrigues Pereira, 2005), afatinib in 1 trial (Miller et al., 2012), dacomitinib in 1 trial (Ellis et al., 2014), lapatinib in 6 trials (Harrington et al., 2015; Powles et al., 2017; Decensi et al., 2011; Del Campo et al., 2011; Harrington et al., 2013; Goss et al., 2013b). The most common underlying malignancies represented were small-cell lung cancer (SCLC) (Arnold et al., 2007), NSCLC (Lee et al., 2012a; Ahn et al., 2013; Thatcher et al., 2005; Zhang et al., 2012; Goss et al., 2009; Gaafar et al., 2011; Ellis et al., 2014), hepatocellular carcinoma (HCC) (Hsu et al., 2012), thyroid cancer (Wells et al., 2012; Leboulleux et al., 2012), oesophageal cancer (Dutton et al., 2014), squamous cell carcinoma (SCC) (Harrington et al., 2015; Del Campo et al., 2011; Harrington et al., 2013), bladder cancer (Powles et al., 2017), and breast cancer (Decensi et al., 2011; Goss et al., 2013b). The methods of randomization were reported in 19 studies.
We performed an meta-analysis to fully investigate the diarrhea of EGFR-TKIs in cancer patients. The relevant studies of the randomized controlled trials (RCTs) in cancer patients treated with EGFR-TKIs were retrieved and the systematic evaluation was conducted. EMBASE, MEDLINE, and PubMed were searched for articles published till August 2017. The relevant RCTs in cancer patients treated with EGFR-TKIs were retrieved and the systematic evaluation was conducted. Twenty-four RCTs and 13,748 patients were included. The current analysis suggested that the use of EGFR-TKIs increased the risk of all-grade diarrhea (RR 3.45; 95%CI, 2.94–4.06; p＜0.00001) and high-grade (≥grade 3) diarrhea (RR 8.22；95%CI, 6.02–11.23; p＜0.00001). On subgroup analysis, the risk of all-grade and high-grade diarrhea varied significantly within drug type. The risk of all-grade diarrhea varied significantly according to cancer type, whereas the risk of high-grade diarrhea did not. The risk of all-grade and high-grade diarrhea did not varied significantly based on treatment line, treatment duration and median age. The available data suggested that the use of EGFR-TKIs is associated with a significantly increased risk of diarrhea in cancer patients.

View all citing articles on Scopus

View full text

Research ArticleVandetanib in patients with inoperable hepatocellular carcinoma: A phase II, randomized, double-blind, placebo-controlled study

Background & Aims

Methods

Results

Conclusions

Introduction

Section snippets

Patients

Patients

Discussion

Conflict of interest

Financial support

Authors’ contributions

Acknowledgements

Lancet Oncol

Prog Growth Factor Res

Ann Oncol

J Thorac Oncol

Lancet Oncol

Cancer Lett

Cancer Lett

International trends and patterns of primary liver cancer

Int J Cancer

Management of hepatocellular carcinoma: an update

Hepatology

Asian pacific association for the study of the liver consensus recommendations on hepatocellular carcinoma

Hepatol Int

Sorafenib in advanced hepatocellular carcinoma

N Engl J Med

Molecular targeted therapy for advanced hepatocellular carcinoma: current status and future perspectives

J Gastroenterol

Transforming growth factor-alpha and epidermal growth factor receptor in chronic liver disease and hepatocellular carcinoma

Liver

Phase II study of erlotinib (OSI-774) in patients with advanced hepatocellular cancer

J Clin Oncol

The role of the EGFR signaling in tumour microenvironment

J Cell Physiol

Phase II trial of the combination of bevacizumab and erlotinib in patients who have advanced hepatocellular carcinoma

J Clin Oncol

Research Article
Vandetanib in patients with inoperable hepatocellular carcinoma: A phase II, randomized, double-blind, placebo-controlled study