Summary : Sunitinib for the Treatment of Progressive Well-Differentiated Locally Advanced or Metastatic Pancreatic Neuroendocrine Tumors
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 INTRODUCTION Pancreatic neuroendocrine tumors (pNETs), also known as well-differentiated pancreatic islet cell tumors, are rare, with an estimated incidence in the U.S. of 0.32 per 100,000 adults [1]. Although typically slow growing with low mitotic activity, locally advanced or metastatic pNETs can be aggressive, with an estimated 10-year overall survival rate of 11% for patients with distant disease [1]. Aside from sunitinib, there are three systemic treatments approved by the U.S. Food and Drug Administration (FDA) for patients with pNETs. Streptozocin (Zanosar ; Teva Pharmaceuticals USA, Philadelphia, PA) was approved in 1982 based on response rates in patients with functional and nonfunctional pancreatic islet cell tumors [2]. Studies combining streptozocin with 5-fluorouracil and with doxorubicin have shown response rates in the range of 39%– 69% [3, 4]. OcCorrespondence: Gideon M. Blumenthal, M.D., Food and Drug Administration, White Oak Campus, 10903 New Hampshire Avenue, Building 22, Room 1243, Silver Spring, Maryland 20993-0002, USA. Telephone: 301-796-5369; Fax: 301-796-9845; e-mail: gideon.blumenthal@fda.hhs.gov Received January 27, 2012; accepted for publication June 15, 2012; first published online in The Oncologist Express on July 26, 2012. ©AlphaMed Press 1083-7159/2012/$20.00/0 http://dx.doi.org/10.1634/theoncologist.2012-0044 The Oncologist Regulatory Issues: FDA The Oncologist 2012;17:1108–1113 www.TheOncologist.com by gest on July 1, 2017 http://thologist.alpham edpss.org/ D ow nladed from treotide acetate (Sandostatin ; Novartis Pharmaceuticals Corporation, East Hanover, NJ) was approved in 1998 for the symptomatic treatment of diarrhea and flushing episodes associated with carcinoid syndrome and vasoactive intestinal peptide tumors. Recently, everolimus (Afinitor ; Novartis Pharmaceuticals Corporation, East Hanover, NJ) was approved for the treatment of progressive NETs of pancreatic origin in patients with unresectable, locally advanced or metastatic disease based on a progression-free survival (PFS) advantage over placebo. Sunitinib is a small molecule receptor tyrosine kinase (RTK) inhibitor that blocks signaling of multiple RTKs, including vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), Kit, and Flt-3. Sunitinib is approved by the FDA for the treatment of patients with gastrointestinal stromal tumors after disease progression on or intolerance to imatinib and for the treatment of patients with advanced renal cell carcinoma. The approved dose for these indications is 50 mg orally daily for 4 weeks, followed by 2 weeks off. Preclinical data suggest that pNETs overexpress VEGF, PDGF, and their cognate receptors. Studies of sunitinib in a RIP-TAG mouse model of pNETs suggested activity [5, 6], and a single-arm, phase II study of sunitinib revealed a 16.7% response rate in a cohort of patients with pNETs [7]. This provided justification for a phase III study comparing sunitinib with placebo in patients with progressive pNETs. PATIENTS AND METHODS A single international, multicenter, double-blinded, randomized, phase III study was submitted to the FDA in support of a new efficacy claim for sunitinib for patients with locally advanced or metastatic well-differentiated pancreatic islet cell tumors. Patients had to have disease that was not amenable to local therapy with curative intent, that was measurable by the Response Evaluation Criteria in Solid Tumors (RECIST), and that had progressed on a scan in the year prior to screening. In addition, patients had to have adequate organ function and an Eastern Cooperative Oncology Group performance status score of 0 or 1. Patients could be treatment naive or could have received any number of prior treatments, including systemic or liver-directed therapy. Concomitant somatostatin analog use was permitted. Patients were randomized 1:1 to either sunitinib (37.5 mg oral continuous daily dosing) or placebo. Randomization was balanced by region with no additional stratification factors. Patients were treated until investigator-determined RECIST progression or unacceptable toxicity. At the time of progression, placebo-treated patients were unblinded and offered crossover to sunitinib in an open-label continuation study. Tumor imaging was performed at screening, week 5, week 9, and every 8 weeks thereafter. The primary endpoint, the PFS interval, was defined as the time from randomization to investigator-determined progression of disease, death for any reason, or radiation therapy. Censoring definitions were standard. Secondary endpoints included the overall survival (OS) time, objective response rate (ORR), and patient-reported outcomes (PRO) using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30. The study was designed to have 90% power to detect a 50% longer (hazard ratio [HR] of 0.67) median PFS time, 7.6 months versus 5.1 months, in patients randomized to sunitinib. The corresponding planned sample size was 340 patients. The final PFS analysis, planned at 260 events, was to compare PFS outcomes between the two treatments with a two-sided value of 0.049 after an adjustment for one planned interim analysis at 130 events. The major change in study conduct occurred with the third protocol amendment, 8 months after accrual began, which installed an independent data monitoring committee (IDMC). The IDMC had access to unblinded subject treatment assignment. In addition to monitoring the safety of subjects, the IDMC was to be involved in the conduct and interpretation of the prespecified interim analysis of efficacy at 130 PFS events. RESULTS In February 2009, at its third meeting, the IDMC recommended closure of the study based on its review of the preliminary safety and efficacy data after 73 PFS events (28.1% of the planned events) had been observed. The sponsor agreed with the recommendation of the IDMC and notified investigators in March 2009 that the study would be closed and all patients should be offered open-label sunitinib. The final PFS analysis was based on an April 15, 2009 data cutoff, at which time there were 171 patients enrolled and 81 events observed. These 171 randomized patients (sunitinib, n 86; placebo, n 85) comprise the intent-to-treat population. Six patients, three in each arm, were randomized but not treated and were excluded from the “as treated” safety population. A total of 42 centers in 11 countries enrolled patients into this study. The majority of patients were from Europe (67%), followed by North America (20%). Fourteen patients (8%) were enrolled in the U.S. Table 1 summarizes the baseline patient demographics and disease characteristics. An imbalance in certain baseline characteristics between the treatment groups (such as performance status, number of disease sites, number with distant extrahepatic metastasis, and number with prior liver directed therapies) could have favored the sunitinib arm. However, the results of a post hoc sensitivity analysis of PFS outcomes performed by the FDA adjusting for these potential imbalances were consistent with the primary PFS analysis. Primary Endpoint The applicant reported a difference in the median investigatordetermined PFS interval of 5.9 months with sunitinib (11.4 months versus 5.5 months; HR, 0.42; 95% confidence interval [CI]; 0.26–0.66; p .001). However, the FDA conducted an in-depth review of the submitted raw tumor measurements and case report forms and found certain discrepancies, including cases of improper use of RECIST and instances of improper 1109 Blumenthal, Cortazar, Zhang et al. www.TheOncologist.com by gest on July 1, 2017 http://thologist.alpham edpss.org/ D ow nladed from