Article

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

ABSTRACT

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; ClinicalTrials.gov number, NCT00428597.).

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    • "different malignancies (Chow and Eckhardt, 2007; Raymond et al., 2011). As it was introduced into clinical development around 2000 and tested against numerous malignancies, sunitinib provided an opportunity to study a large sample of preclinical studies across a broad range of malignancies—including several supporting successful translation trajectories. "
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    ABSTRACT: Poor study methodology leads to biased measurement of treatment effects in preclinical research. We used available sunitinib preclinical studies to evaluate relationships between study design and experimental tumor volume effect sizes. We identified published animal efficacy experiments where sunitinib monotherapy was tested for effects on tumor volume. Effect sizes were extracted alongside experimental design elements addressing threats to valid clinical inference. Reported use of practices to address internal validity threats was limited, with no experiments using blinded outcome assessment. Most malignancies were tested in one model only, raising concerns about external validity. We calculate a 45% overestimate of effect size across all malignancies due to potential publication bias. Pooled effect sizes for specific malignancies did not show apparent relationships with effect sizes in clinical trials, and we were unable to detect dose–response relationships. Design and reporting standards represent an opportunity for improving clinical inference.
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    • "Nevertheless, two of the included studies showed an increased 5-year survival rate for patients who underwent resection[27,28], while one study showed no difference[18].There has been substantial progress in the treatment of advanced P-NET, both systemic and locally ablative, in recent years. Everolimus has been shown to increase progression-free survival[29], and sunitinib prolonged both progression-free and overall survival in a multicenter randomized controlled trial[30]. Equally, peptide receptor radionuclide therapy has shown promising results in several studies[31,32]. Furthermore, there are multiple promising options for locally ablative treatments of liver metastases, comprising radiofrequency or microwave ablation, transarterial chemoembolization, and selective internal radiother- apy[33], and even liver transplantation has been proposed for metastatic NET[34]. "
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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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