Phase II study of sunitinib in Japanese patients with unresectable or metastatic, well-differentiated pancreatic neuroendocrine tumor

Abstract

Background: Pancreatic neuroendocrine tumors (NETs) are rare but are frequently diagnosed at advanced stages and require systemic therapy.

Patients and methods: This multicenter, open-label, phase II study evaluated sunitinib in Japanese patients with well-differentiated pancreatic NET. Patients received sunitinib 37.5 mg/day on a continuous daily dosing (CDD) schedule. The primary endpoint was clinical benefit rate (CBR; percentage of complete responses [CRs] plus partial responses [PRs] plus stable disease [SD] ≥ 24 weeks). Secondary endpoints included objective response rate (ORR), tumor shrinkage, progression-free survival (PFS) probability, safety, pharmacokinetics, and biomarkers.

Results: Twelve patients received treatment. The CBR was 75 % (95 % confidence interval [CI], 43-94) and included 6 patients with a PR and 3 with SD. The ORR was 50 % (95 % CI, 21-79). PFS probability was 91 % (95 % CI, 54-99) at 6 months and 71 % (95 % CI, 34-90) at 12 months. Commonly reported treatment-emergent (all-causality), any-grade adverse events included diarrhea (n=10), hand-foot syndrome and hypertension (both n=8), fatigue and headache (both n=7), and neutropenia (n=6). No deaths on study were reported; one death due to disease progression occurred >28 days after end of treatment. Sunitinib on a CDD schedule resulted in sustained drug concentrations without accumulation across cycles. Tumor responses in all 12 patients did not appear to correlate with decreases in chromogranin A levels.

Conclusions: Sunitinib 37.5 mg/day on a CDD schedule demonstrated antitumor activity in Japanese patients with unresectable, well-differentiated pancreatic NET. Commonly reported adverse events were consistent with the known safety profile of sunitinib.

Trial registration: ClinicalTrials.gov NCT01121562.

Figures

Fig. 1

Maximum percentage reduction from baseline in target lesion size by patient (N = 12). Although one patient had a maximum percentage change in target tumor size from baseline of −100 %, non-target lesions remained and therefore this was not classified as a complete response. Asterisk stable disease of ≥24 weeks in duration; RECIST Response Evaluation Criteria in Solid Tumors

Fig. 2

Individual patient profiles and response to treatment (N = 12). a Summary of patient profiles and changes in tumor-size and chromogranin A levels. b Percentage change from baseline in target lesion size over time in individual patients. a Maximum % change = [(minimum value after dosing – baseline)/baseline] x 100; b Based on censored data; F female; M male; PD progressive disease; PFS progression-free survival; PR partial response; SD stable disease

Fig. 3

Trough concentrations of sunitinib, active metabolite SU12662, and total drug (sunitinib plus SU12662) in Japanese patients with pancreatic neuroendocrine tumor (NET; n = 11; present study) or gastrointestinal stromal tumor (GIST; n = 30) [21] and renal cell carcinoma (RCC; n = 38; pooled data) [25], and in predominantly Western patients with pancreatic NET; n = 57 [17]. The sunitinib dose in each study was dose-corrected to 37.5 mg. The upper and lower box boundaries denote the 75th and 25th percentiles, respectively, with the median shown as a line within the box. Whiskers indicate minimum and maximum values. Outlying values are denoted as circles