Sunitinib Malate for the Treatment of Pancreatic Neuroendocrine Tumors

Service Inter-Hospitalier de Cancérologie et Service de Gastroenteropancréatologie, Hôpital Beaujon, Clichy, France.
New England Journal of Medicine (Impact Factor: 55.87). 02/2011; 364(6):501-13. DOI: 10.1056/NEJMoa1003825
Source: PubMed


The multitargeted tyrosine kinase inhibitor sunitinib has shown activity against pancreatic neuroendocrine tumors in preclinical models and phase 1 and 2 trials.
We conducted a multinational, randomized, double-blind, placebo-controlled phase 3 trial of sunitinib in patients with advanced, well-differentiated pancreatic neuroendocrine tumors. All patients had Response Evaluation Criteria in Solid Tumors-defined disease progression documented within 12 months before baseline. A total of 171 patients were randomly assigned (in a 1:1 ratio) to receive best supportive care with either sunitinib at a dose of 37.5 mg per day or placebo. The primary end point was progression-free survival; secondary end points included the objective response rate, overall survival, and safety.
The study was discontinued early, after the independent data and safety monitoring committee observed more serious adverse events and deaths in the placebo group as well as a difference in progression-free survival favoring sunitinib. Median progression-free survival was 11.4 months in the sunitinib group as compared with 5.5 months in the placebo group (hazard ratio for progression or death, 0.42; 95% confidence interval [CI], 0.26 to 0.66; P<0.001). A Cox proportional-hazards analysis of progression-free survival according to baseline characteristics favored sunitinib in all subgroups studied. The objective response rate was 9.3% in the sunitinib group versus 0% in the placebo group. At the data cutoff point, 9 deaths were reported in the sunitinib group (10%) versus 21 deaths in the placebo group (25%) (hazard ratio for death, 0.41; 95% CI, 0.19 to 0.89; P=0.02). The most frequent adverse events in the sunitinib group were diarrhea, nausea, vomiting, asthenia, and fatigue.
Continuous daily administration of sunitinib at a dose of 37.5 mg improved progression-free survival, overall survival, and the objective response rate as compared with placebo among patients with advanced pancreatic neuroendocrine tumors. (Funded by Pfizer; number, NCT00428597.).

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    • "Approval was based on results of a placebo-controlled phase III trial in patients with advanced, well-differentiated pancreatic neuroendocrine tumors. The study was discontinued early owing to a higher incidence of adverse events and deaths in the placebo group compared with the sunitinib group (progression-free survival 11.4 months in the sunitinib group compared with 5.5 months in the placebo group) (Raymond et al., 2011). Only 2 patients in the treatment group had a VHL mutation. "
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    ABSTRACT: Von Hippel-Lindau disease, Cowden syndrome, and Proteus syndrome are cancer syndromes which affect multiple organs and lead to significant decline in quality of life in affected patients. These syndromes are rare and typically affect the adolescent and young adult population, resulting in greater cumulative years of life lost. Improved understanding of the underpinnings of the genetic pathways underlying these syndromes and the rapid evolution of targeted therapies in general have made it possible to develop therapeutic options for these patients and other genetic cancer syndromes. Targeted therapies especially antiangiogenics and inhibitors of the PIK3CA/AKT/mTOR signaling pathway have shown activity in selected group of patients affected by these syndromes or in patients harboring specific sporadic mutations which are otherwise characteristic of these syndromes. Unfortunately due to the rare nature, patients with these syndromes are not the focus of clinical trials and unique results seen in these patients can easily go unnoticed. Most of the data suggesting benefits of targeted therapies are either case reports or small case series. Thus, a literature review was indicated. In this review we explore the use of molecularly targeted therapy options in Von Hippel-Lindau disease, Cowden syndrome, and Proteus syndrome.
    Discovery medicine 02/2015; 19(103):109-116. · 3.63 Impact Factor
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    • "Sunitinib is an oral multi-tyrosine kinase inhibitor with its main affinity to the vEgf receptor. in a multicentre phase iii CrT including 173 patients with p-NETs, sunitinib treatment resulted in a significant improvement in pfS of 11.4 versus 5.5 months for placebo [47]. Major side effects include rash, diarrhoea, nausea , vomiting, asthenia and fatigue. "
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    ABSTRACT: Background: The diagnostic work-up and treatment of patients with neuroendocrine neoplasms (NENs) has undergone major recent advances and new methods are currently introduced into the clinic. An update of the WHO classification has resulted in a new nomenclature dividing NENs into neuroendocrine tumours (NETs) including G1 (Ki67 index ≤ 2%) and G2 (Ki67 index 3-20%) tumours and neuroendocrine carcinomas (NECs) with Ki67 index > 20%, G3. Aim. These Nordic guidelines summarise the Nordic Neuroendocrine Tumour Group's current view on how to diagnose and treat NEN-patients and are meant to be useful in the daily practice for clinicians handling these patients.
    Acta Oncologica 09/2014; 53(10). DOI:10.3109/0284186X.2014.941999 · 3.00 Impact Factor
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    • "Sunitinib malate, an oral tyrosine kinase inhibitor, has activity against VEGFRs, PDGFRs, stem-cell factor (KIT) receptor, glial cell line-derived neurotrophic factor, and FMS-like tyrosine kinase-3 15. Recently, several phase II and phase III trials have demonstrated that the administration of sunitinib can significantly improve the progression-free survival and overall survival, and that it shows an acceptable safety profile in patients with advanced pNETs 16-18. "
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    ABSTRACT: Background and Aim: Pancreatic neuroendocrine tumor (pNET) is a clinically rare and heterogeneous group of tumors; its pharmacogenetic characteristics are not fully understood. This study was designed to examine the relationship between key gene variations and disease development and prognosis among Chinese patients with pNET. Methods: Various pNET associated genes such as DAXX/ATRX, KRAS, MEN1, PTEN, TSC2, SMAD4/DPC, TP53 and VHL were analyzed in high-throughput sequencing. The links between the gene mutations and the clinicopathological features and prognosis of the patients were determined. Results: The somatic mutation frequencies of the DAXX/ATRX, KRAS, MEN1, mTOR pathway genes (PTEN and TSC2), SMAD4/DPC, TP53, and VHL in Chinese pNET patients were 54.05%, 10.81%, 35.14%, 54.05%, 2.70%, 13.51%, and 40.54%, respectively, while the same figures in Caucasians pNET patients were 43%, 0%, 44%, 15%, 0%, 3%, and 0%, respectively. The numbers of mutated genes were from 0 to 6; 4 patients with more than 3 mutated genes had higher proliferation (Ki-67) index or nerve vascular invasion or organ involvement, but only 9 of 27 patients with 3 or few mutated genes had such features. Mutations in KRAS and DAXX/ATRX, but not other genes analyzed, were associated with a shortened survival. Conclusion: The mutation rates of these genes in Chinese pNET patients are different from those in Caucasians. A higher number of gene mutations and the DAXX/ATRX and KRAS gene mutations are correlated with a poor prognosis of patients with pNET.
    International journal of biological sciences 08/2014; 10(9):957-65. DOI:10.7150/ijbs.9773 · 4.51 Impact Factor
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