Sunitinib in advanced pancreatic neuroendocrine tumors: latest evidence and clinical potential

Based on preclinical data available in the RIP1-Tag2 transgenic mouse model, sunitinib is an inhibitor of angiogenesis in pancreatic neuroendocrine tumors blocking vascular endothelial growth factor receptors and platelet-derived growth factor receptors in endothelial cells and pericytes, respectively. Evidence of objective response in phase I trials justified the initiation of a large phase II/III program using sunitinib in patients with advanced/metastatic well-differentiated pancreatic neuroendocrine tumors. In the phase II study, sunitinib showed potent antitumor activity and a safe toxicity profile. In a recent double-blind placebo-controlled randomized phase III trial, sunitinib doubled the progression-free survival of patients, induced objective responses, and reduced the risk of death of patients with advanced/metastatic well-differentiated tumors. These data allowed the approval of sunitinib in several countries including Europe and the United States of America. These recent data provide hope for patients with well-differentiated pancreatic neuroendocrine tumors and will change standards of care in this disease.

[1]  E. D. de Vries,et al.  Everolimus for advanced pancreatic neuroendocrine tumors. , 2011, The New England journal of medicine.

[2]  Y. Bang,et al.  Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. , 2011, The New England journal of medicine.

[3]  E. Raymond,et al.  Sunitinib paves the way for targeted therapies in neuroendocrine tumors , 2009, Targeted Oncology.

[4]  C. Schade-Brittinger,et al.  Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[5]  N. Ballian,et al.  A simplified prognostic system for resected pancreatic neuroendocrine neoplasms. , 2009, HPB : the official journal of the International Hepato Pancreato Biliary Association.

[6]  M. Pavel,et al.  ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Chemotherapy in Patients with Neuroendocrine Tumors , 2009, Neuroendocrinology.

[7]  Masahiro Inoue,et al.  Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. , 2009, Cancer cell.

[8]  G. Baron,et al.  Heterogeneity of tumor prognostic markers: a reproducibility study applied to liver metastases of pancreatic endocrine tumors , 2009, Modern Pathology.

[9]  G. Procopio,et al.  Activity of sunitinib in patients with advanced neuroendocrine tumors. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[10]  E. Raymond,et al.  Benefit-Risk Assessment of Sunitinib in Gastrointestinal Stromal Tumours and Renal Cancer , 2009, Drug safety.

[11]  U. Knigge,et al.  Interventional treatment of neuroendocrine liver metastases. , 2008, The surgeon : journal of the Royal Colleges of Surgeons of Edinburgh and Ireland.

[12]  F. Kabbinavar,et al.  A phase I and pharmacokinetic study of sunitinib administered daily for 2 weeks, followed by a 1-week off period , 2008, Cancer Chemotherapy and Pharmacology.

[13]  G. Demetri,et al.  Molecular basis for sunitinib efficacy and future clinical development , 2007, Nature Reviews Drug Discovery.

[14]  J. Tabernero,et al.  Chemotherapy and role of the proliferation marker Ki-67 in digestive neuroendocrine tumors. , 2007, Endocrine-related cancer.

[15]  Douglas B. Evans,et al.  Elevated expression of vascular endothelial growth factor correlates with increased angiogenesis and decreased progression‐free survival among patients with low‐grade neuroendocrine tumors , 2007, Cancer.

[16]  R. Figlin,et al.  Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. , 2007, The New England journal of medicine.

[17]  J. Christensen,et al.  78 POSTER Combined anti-VEGFR and anti-PDGFR actions of sunitinib on blood vessels in preclinical tumor models , 2006 .

[18]  Xin Huang,et al.  Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial , 2006, The Lancet.

[19]  E. Raymond,et al.  Safety, pharmacokinetic, and antitumor activity of SU11248, a novel oral multitarget tyrosine kinase inhibitor, in patients with cancer. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[20]  Oriol Casanovas,et al.  Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. , 2005, Cancer cell.

[21]  E. Raymond,et al.  Subungual splinter hemorrhages: a clinical window to inhibition of vascular endothelial growth factor receptors? , 2005, Annals of internal medicine.

[22]  R. Arnold.  Introduction: Definition, historical aspects, classification, staging, prognosis and therapeutic options , 2005 .

[23]  G. Klöppel,et al.  Epidemiology, tumour biology and histopathological classification of neuroendocrine tumours of the gastrointestinal tract. , 2005, Best practice & research. Clinical gastroenterology.

[24]  Kristian Pietras,et al.  A multitargeted, metronomic, and maximum-tolerated dose "chemo-switch" regimen is antiangiogenic, producing objective responses and survival benefit in a mouse model of cancer. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[25]  A. Harris,et al.  Microvascular density and hypoxia-inducible factor pathway in pancreatic endocrine tumours: negative correlation of microvascular density and VEGF expression with tumour progression , 2004, British Journal of Cancer.

[26]  R. Arnold.  Endocrine tumours of the gastrointestinal tract. Introduction: definition, historical aspects, classification, staging, prognosis and therapeutic options. , 2005, Best practice & research. Clinical gastroenterology.

[27]  M. Heinrich,et al.  Synergistic effect of SU11248 with cytarabine or daunorubicin on FLT3 ITD-positive leukemic cells. , 2004, Blood.

[28]  Douglas B. Evans,et al.  Fluorouracil, doxorubicin, and streptozocin in the treatment of patients with locally advanced and metastatic pancreatic endocrine carcinomas. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[29]  Jeffrey W. Clark,et al.  Lack of Efficacy of Streptozocin and Doxorubicin in Patients With Advanced Pancreatic Endocrine Tumors , 2004, American journal of clinical oncology.

[30]  Tim Eisen,et al.  Kinase Inhibition with BAY 43–9006 in Renal Cell Carcinoma , 2004, Clinical Cancer Research.

[31]  A. Goh,et al.  Imatinib mesylate causes hypopigmentation in the skin , 2004, Cancer.

[32]  Nathalie Lassau,et al.  Validation of a New Method for Quantifying In Vivo Murine Tumor Necrosis by Sonography , 2004, Investigative radiology.

[33]  G. Imokawa,et al.  Mechanisms underlying the dysfunction of melanocytes in vitiligo epidermis: role of SCF/KIT protein interactions and the downstream effector, MITF‐M , 2004, The Journal of pathology.

[34]  J. Cherrington,et al.  Gene expression profiling of human colon xenograft tumors following treatment with SU11248, a multitargeted tyrosine kinase inhibitor , 2004, Oncogene.

[35]  Ricky T. Tong,et al.  Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer , 2004, Nature Medicine.

[36]  C. James,et al.  Quantitation of SU11248, an oral multi-target tyrosine kinase inhibitor, and its metabolite in monkey tissues by liquid chromatograph with tandem mass spectrometry following semi-automated liquid–liquid extraction , 2004 .

[37]  N. Pryer,et al.  SU11248 inhibits tumor growth and CSF-1R-dependent osteolysis in an experimental breast cancer bone metastasis model , 2004, Clinical & Experimental Metastasis.

[38]  D. Hallahan,et al.  The receptor tyrosine kinase inhibitor SU11248 impedes endothelial cell migration, tubule formation, and blood vessel formation in vivo, but has little effect on existing tumor vessels , 2004, Angiogenesis.

[39]  M. Heinrich,et al.  An innovative phase I clinical study demonstrates inhibition of FLT3 phosphorylation by SU11248 in acute myeloid leukemia patients. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[40]  J. Cherrington,et al.  Hair Depigmentation Is a Biological Readout for Pharmacological Inhibition of KIT in Mice and Humans , 2003, Journal of Pharmacology and Experimental Therapeutics.

[41]  N. Pryer,et al.  Preclinical evaluation of the tyrosine kinase inhibitor SU11248 as a single agent and in combination with "standard of care" therapeutic agents for the treatment of breast cancer. , 2003, Molecular cancer therapeutics.

[42]  Seth M Steinberg,et al.  A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. , 2003, The New England journal of medicine.

[43]  J. Berkhof,et al.  Potential role of platelets in endothelial damage observed during treatment with cisplatin, gemcitabine, and the angiogenesis inhibitor SU5416. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[44]  D. Kwiatkowski.  Rhebbing up mTOR: New Insights on TSC1 and TSC2, and the Pathogenesis of Tuberous Sclerosis , 2003, Cancer biology & therapy.

[45]  N. Pryer,et al.  SU11248 inhibits KIT and platelet-derived growth factor receptor beta in preclinical models of human small cell lung cancer. , 2003, Molecular cancer therapeutics.

[46]  E. Raymond,et al.  Tyrosine kinase inhibition and grey hair , 2003, The Lancet.

[47]  Juthamas Sukbuntherng,et al.  In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[48]  P. Cony-Makhoul,et al.  Imatinib mesylate and gray hair. , 2002, The New England journal of medicine.

[49]  N. Pavlakis,et al.  Unexpected serious toxicity with chemotherapy and antiangiogenic combinations: time to take stock! , 2002, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[50]  D. Hanahan,et al.  VEGF-A has a critical, nonredundant role in angiogenic switching and pancreatic beta cell carcinogenesis. , 2002, Cancer cell.

[51]  A. Benson,et al.  Indications and results of liver resection and hepatic chemoembolization for metastatic gastrointestinal neuroendocrine tumors. , 2001, Surgery.

[52]  B. Gilchrest,et al.  SCF/c‐kit signaling is required for cyclic regeneration of the hair pigmentation unit , 2001, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[53]  L. Saltz,et al.  Failure to confirm major objective antitumor activity for streptozocin and doxorubicin in the treatment of patients with advanced islet cell carcinoma , 1999, Cancer.

[54]  E. Price,et al.  MAP kinase links the transcription factor Microphthalmia to c-Kit signalling in melanocytes , 1998, Nature.

[55]  S. Lipsitz,et al.  Streptozocin-doxorubicin, streptozocin-fluorouracil or chlorozotocin in the treatment of advanced islet-cell carcinoma. , 1992, The New England journal of medicine.

[56]  L. Kvols,et al.  Treatment of neuroendocrine carcinomas with combined etoposide and cisplatin. Evidence of major therapeutic activity in the anaplastic variants of these neoplasms , 1991, Cancer.

[57]  J. Hanley,et al.  Streptozocin alone compared with streptozocin plus fluorouracil in the treatment of advanced islet-cell carcinoma. , 1980, The New England journal of medicine.

[58]  H. Dull,et al.  Benefit-Risk Assessment , 1979 .

[59]  Randomized Study on the Effect of Octreotide LAR in the Control of Tumor Growth in Patients with Metastatic , 2022 .