FDA Approval Summary: Sunitinib for the Treatment of Progressive Well-Differentiated Locally Advanced or Metastatic Pancreatic Neuroendocrine Tumors

Abstract

On May 20, 2011, the U.S. Food and Drug Administration (FDA) approved sunitinib malate capsules (Sutent; Pfizer, Inc., New York) for the treatment of progressive, well-differentiated pancreatic neuroendocrine tumors (pNETs) in patients with unresectable locally advanced or metastatic disease. In a phase III randomized trial, 171 patients received either sunitinib (37.5 mg) or placebo once daily. The progression-free survival (PFS) interval was the primary efficacy endpoint. Secondary endpoints included the overall survival (OS) time, objective response rate (ORR), patient-reported outcomes, and safety.Based on early results favoring sunitinib, the independent data monitoring committee recommended trial termination prior to the prespecified interim analysis. This premature analysis may have led to an overestimate of the treatment effect. In the FDA analysis of investigator-assessed PFS times, the median values for the sunitinib and placebo arms were 10.2 months and 5.4 months, respectively. The ORRs were 9.3% and 0% in the sunitinib and placebo arms, respectively. The OS data were not mature at the time of approval and were confounded by 69% crossover.Common adverse reactions in patients receiving sunitinib included diarrhea, nausea, asthenia, fatigue, neutropenia, hypertension, and palmar-plantar erythrodysesthesia syndrome. Two patients on sunitinib died as a result of cardiac failure.The Oncologic Drugs Advisory Committee voted eight to two that, despite residual uncertainty about the magnitude of the PFS effect because of early trial termination, sunitinib demonstrated a favorable benefit-risk profile in pNET patients. The FDA concurred with the committee's assessment and granted sunitinib regular approval for this rare malignancy with few available therapies. The Oncologist 2012;17:1108 -1113

Efficacy and Safety of Sunitinib in Patients with Well-Differentiated Pancreatic Neuroendocrine Tumours

“…Sunitinib was approved by the EMA in 2010 and the FDA in 2011 for the treatment of patients with progressive, unresectable, or recurrent/metastatic, well-differentiated panNETs [7,8]. Due to the early termination of the phase III study, the phase IV study reported here was conducted to provide additional information in this population, and to meet regulatory post-approval commitments to confirm the efficacy and safety of sunitinib in advanced/metastatic, well-differentiated, unresectable panNETs.…”

Large artery stiffness and hypertension after antiangiogenic drugs

“…Tyrosine kinase inhibitors (TKIs) such as sunitinib (Sutent; Pfizer, New York, New York, USA) and sorafenib (Nexavar; Bayer, Leverkusen, Germany) directly inhibit the vascular endothelium growth factor (VEGF) receptors and other receptors involved in angiogenesis. Sunitinib is proposed as a first-line treatment in metastatic renal cell carcinoma and as a second-line treatment in gastrointestinal stromal tumors (GISTs) and pancreatic neuroendocrine tumor; sorafenib, is proposed as a first-line treatment in hepatocellular carcinoma and as a second-line treatment in metastatic clear carcinoma of the kidney and metastatic thyroid cancer [2,3].…”

Clinical trial end points relevant to patients and society for rare cancers

“…The initial OS analysis, based on 18% of events, suggested an OS benefit for the sunitinib group (HR for death was 0.41 [95% CI: 0.19-0.89; p = 0.02]). However, further analysis based on 43% of the events did not show a statistically significant difference between the two groups (HR: 0.74 [0.47-1.17]) [60]. It has been suggested that the early unplanned efficacy assessment may have resulted in an overestimation of the PFS magnitude.…”

“…It has been suggested that the early unplanned efficacy assessment may have resulted in an overestimation of the PFS magnitude. The FDA recommended that such practice should be discouraged as unplanned early analyses, with subjective end points such as PFS, can increase the risk of identifying an erroneous false positive result, thereby leading to a type I error and overestimating the treatment effect of the experimental agent [60].…”