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6540 Background: Multikinase inhibitors (MKI) targeting angiogenesis, including pazopanib (P), have shown efficacy in progressive radioiodine refractory thyroid cancers (RAIR-TC) but are accompanied by adverse effects, leading to dose adjustments/interruptions. We aimed to investigate the efficacy and tolerance of a discontinuous scheme of pazopanib administration in this situation. Methods: This randomized phase II study enrolled RAIR-TC patients (pts) in first or second-line of MKI with documented disease progression within 12 months (m). After a 6-m pazopanib continuous induction phase, pts with stable disease (SD) or tumor response were randomly assigned in a 1:1 ratio to receive continuous pazopanib (CP) or intermittent pazopanib (IP) until progression and restart. They were stratified by best tumor response [stable disease vs. objective response] and prior MKI treatment [yes vs. no]). Primary endpoint was time to treatment failure (TTF) defined as time between randomization and permanent discontinuation of pazopanib (either for disease progression or intolerance); secondary endpoints included overall response rate (ORR), progression-free survival (PFS) and safety. Results: 168 pts (66.5 years median age; 51.8% female) were included and 100 pts randomized (CP: 50, IP: 50). The median number of metastatic sites was 2.0 (1-7) and 50 pts (29.8%) were pretreated with MKI. With a median follow-up of 31.3 m, we did not show any statistically significant difference in the TTF, 80% (66.0-88.7%)] of the pts being under P at 6 m after randomization in the IP arm versus 78% (63.8-87.2%) in the CP arm. Median TTF was 14.7 m 95% CI [9.3; 17.4] and 11.9 m 95% CI [7.5; 15.6] respectively (HR 0.79 [0.49-1.27]). The best response with P was 35.6% (95% CI [28.2; 43.6]) and the disease control rate was 89.4% 95% CI [83.5; 93.7]. Median time to progression under P was not statistically different between 2 arms (5.7m 95% CI [4.8;7.8] in the IP arm vs. 9.2m 95% CI [7.3;11.1] in the CP arm (HR 1.36 [0.88; 2.12]). 36/100 pts (36%) experienced pazopanib-related grade 3/4 AEs (CP:17; IP: 19) mainly represented by gastrointestinal disorders, hypertension, cardiac disorders and asthenia. Five pazopanib-related deaths were reported (CP:1;IP: 4). Conclusions: The intermittent administration of pazopanib study did not significantly demonstrate superiority in efficacy or tolerance over continuous treatment. Continuous administration of MKI remains the standard in RAIR-TC. Clinical trial information: NCT01813136 .

274 Background: Angiogenesis is extensively developed in well-differentiated pancreatic neuroendocrine tumors (PNET) where sunitinib was showed to prolong progression-free survival leading to FDA and EMA approval. However, clinical experience in pts with well-differentiated G3 & PD-NEN remains limited. Methods: This prospective phase II trial evaluate potential biomarkers correlating with sunitinib activity in pts with advanced well differentiated G3 or PD-NEN. Sunitinib was given at the dose of 37.5 mg/d as a continuous daily dosing until progression or unacceptable toxicity. Evaluation of activity was based on RECIST1.1. Safety was evaluated according to NCI-CTCAEv4. Pharmacokinetics (PK) of sunitinib and SU12662 (main active metabolite) were evaluated. Tumor biomarkers (PDGFR-b, VEGFR2, Carbonic Anhydrase 9, Ki67 and p-AKT) were evaluated in tumor tissues, quantified in tumor cells and stroma (vessels, fibroblasts) using immunohistochemistry and correlated with response by RECIST. Results: Among 31 pts (M/F: 18/13, median age 61), 13 pancreatic, 5 gastric, 5 rectal, 4 colonic, and 4 other G3 & PD-NEN were entered. 27 pts had previous treatment with chemotherapy (mainly platinum/VP16). Among 26 pts evaluable for safety and activity, 7 pts (23%, 95%CI: 6.9%-39.3%), including 3 pts classified as well-differentiated G3 neoplasms) experienced partial responses and tumor stabilizations (clinical benefit). Safety and PK exposure to sunitinib and SU12662 in those pts was consistent with that experienced in PNET. Among the above evaluated tumor biomarkers, only Ki67 correlated with sunitinib activity. The median Ki67 was 20% and 77.5% in pts with CB versus non-responders (p=.002), respectively. ROC curves showed correlations between lower Ki67 in tumors and sunitinib activity (OR:0.9; IC95%:0.831-0.9, p=.039). With a threshold value of Ki67 of 47%, sensitivity and specificity were 80%, the predictive positive value was 67% and the negative predictive value was 86%. Conclusions: In pts with well-differentiated G3 & PD-NEN, sunitinib showed evidence of activity that was more pronounced in pts with Ki67

309 Background: In 2010, the pivotal double blind Phase III study met its primary endpoint with a median progression-free survival (PFS) of 11.4 months (mo) for sunitinib vs. 5.5 mo for placebo (PBO) (HR=0.42; 95% CI 0.26-0.66; P

4111^ Background: Somatostatin analogs can provide CS symptom relief, but associated PROs in clinical practice, in particular patient (pt) treatment satisfaction, are less clear. Methods: SymNET was a large multinational observational study of PRO after >3 months’ LAN for CS-related diarrhea (NCT01234168). At a routine clinic visit (CV), 273 pts reported their satisfaction with diarrhea control (primary endpoint) on a 5-point Likert scale. Secondary endpoints included health-related quality of life (HRQoL) assessed with EORTC QLQ-C30 and G.I.NET 21 questionnaires completed by pts. HRQoL scores were transformed for some items/scales so that all had a range 0–100. Summary statistics were derived from evaluable data (enrolled population). Results: 58% (157/273) of pts were >60 yrs, 66% (176/267) had small-bowel primary tumors, and 80% (217/271) had liver metastases. At the CV, median LAN treatment duration was 11 months and 76% (203/268) [95% CI: 70–81%] were satisfied with diarrhea control (primary endpoint...

4118 Background: In a double-blind phase III trial, sunitinib (Sutent; SU) improved progression-free survival (PFS) vs placebo (PBO; 11.4 vs 5.5 mos; HR: 0.42, 95% CI: 0.26–0.66; P=0.0001) and was well tolerated in patients (pts) with unresectable, well-differentiated pancreatic NET that had progressed ≤12 mos before baseline. Initial overall survival (OS) revealed a benefit for SU vs PBO, although median OS had not been reached. We now report PFS assessed by blinded independent central review (BICR) and updated OS. Methods: Pts were randomized 1:1 to SU 37.5 mg or PBO on a continuous daily dosing schedule, each with best supportive care. The primary endpoint was investigator-assessed PFS; OS was a secondary endpoint to be evaluated every 2 yrs for 5 yrs, or until 95% of pts had died. Additionally, BICR was performed retrospectively; baseline and on-study CT/MRI scans were evaluated by a 2-reader, 2-time-point lock, followed by a sequential locked-read, batch-mode paradigm by blinded, third-party radiologists. Results: 171 pts were randomized (SU, n=86; PBO, n=85) from Jun 2007 to Apr 2009. The trial ended when an independent data monitoring committee noted efficacy favoring SU and more serious AEs and deaths with PBO. The study was unblinded at closure; pts were offered open-label SU and followed for survival. Median PFS by BICR was 12.6 mos (SU) vs 5.8 mos (PBO) (HR: 0.32, 95% CI: 0.18–0.55; P=0.00001). At study closure, there were 9 and 21 deaths in the SU and PBO arms (HR: 0.41, 95% CI: 0.19–0.89; P=0.02). By Apr 2011 (2 yrs additional follow-up) a total of 87 deaths occurred (51%), median OS was estimated at 33.0 mos in the SU arm, and 26.7 mos in the PBO arm (HR: 0.71, 95% CI: 0.47–1.09; P=0.11 [Table]). 69% of pts crossed over to SU on progression. Conclusions: BICR confirmed investigator assessment of PFS and demonstrated a 6.8-mo improvement in median PFS with SU. Updated OS favors SU, although this result is non-significant for reasons that may include crossover of treatment and limited statistical power. [Table: see text]

4000 Background: SU has shown activity against pancreatic NET in preclinical and phase I/II studies, leading to its investigation in this double-blind, PBO-controlled trial (NCT00428597). Methods: Eligible pts had advanced, well- differentiated pancreatic endocrine tumors and disease progression in the past 12 months, and were randomized (1:1) to SU 37.5 mg/day continuous daily dosing (CDD) or PBO, each with best supportive care. Primary endpoint: progression-free survival (PFS). Target enrolment: 340 pts to detect 50% improvement in PFS (90% power, 2-sided unstratified log-rank test). Results: This trial ended early based on recommendations of the independent Data Monitoring Committee, which noted more serious adverse events (AEs) and deaths in the PBO arm and differences in efficacy. 171 pts were randomized to SU (n = 86) or PBO (n = 85) from Jun 2007 to Apr 2009. At baseline, 49% of pts had functioning tumors, Ki-67 index was ≤ 5% in 60% of evaluable pts, and 95% had distant metastases. Most pts had un...