Eva Sedlackova

380 Background: Sunitinib was approved by the FDA in 2011 for treatment of progressive, well-differentiated, advanced pancreatic neuroendocrine tumors (pNETs) based on a pivotal phase III study (NCT00428597) that showed a significant increase in progression-free survival (PFS) over placebo following early study termination. Subsequently, the FDA requested a post-approval study to support these findings. Methods: In this open-label, phase IV clinical trial (NCT01525550), patients with progressive, well-differentiated, unresectable advanced/metastatic pNETs received continuous sunitinib 37.5 mg once daily. Eligibility criteria were similar to the phase III study. Primary endpoint was investigator-assessed PFS per RECIST 1.0. This study is ongoing. Results: Sixty one treatment-naïve and 45 previously treated patients with progressive pNETs were treated with sunitinib: mean age, 54.6 years; males, 59.4%; white, 63.2%; ECOG PS 0, 65.1% or PS 1, 34.0%; and prior somatostatin analog, 48.1% (treatment-naïve, 39.3%; previously treated, 60.0%). At the data cutoff date, 82 (77%) patients discontinued treatment, mainly due to disease progression (46%). Median duration of treatment was ~11.9 months. Investigator-assessed median PFS (mPFS) was 13.2 months (95% CI, 10.9–16.7) in the overall population, with comparable mPFS in treatment-naïve and previously treated patients (13.2 vs 13.0 months). mPFS per independent radiologic review was 11.1 months (95% CI, 7.4–16.6). Objective response rate (ORR) per RECIST was 24.5%: 21.3% in treatment-naïve and 28.9% in previously treated patients. Median overall survival, although not yet mature, was 37.8 months. Treatment-emergent, all-causality adverse events (AEs) reported by ≥ 20% of all patients included neutropenia, diarrhea, leukopenia, fatigue, hand–foot syndrome, hypertension, abdominal pain, dysgeusia, and nausea. Most common grade 3/4 AEs were neutropenia (22%) and diarrhea (9%). Conclusions: The mPFS of 13.2 months and ORR of 24.5% observed in this study support the outcomes of the pivotal phase III study of sunitinib in pNETs and confirm its activity in this setting. AEs were consistent with known safety profile of sunitinib. Clinical trial information: NCT01525550.

In the CLARINET study, lanreotide Autogel (depot in USA) significantly prolonged progression-free survival (PFS) in patients with metastatic pancreatic/intestinal neuroendocrine tumours (NETs). We report long-term safety and additional efficacy data from the open-label extension (OLE). Patients with metastatic grade 1/2 (Ki-67 ≤10%) non-functioning NET and documented baseline tumour-progression status received lanreotide Autogel 120 mg (n=101) or placebo (n=103) for 96 weeks or until death/progressive disease (PD) in CLARINET study. Patients with stable disease (SD) at core study end (lanreotide/placebo) or PD (placebo only) continued or switched to lanreotide in the OLE. In total, 88 patients (previously: lanreotide, n=41; placebo, n=47) participated: 38% had pancreatic, 39% midgut and 23% other/unknown primary tumours. Patients continuing lanreotide reported fewer adverse events (AEs) (all and treatment-related) during OLE than core study. Placebo-to-lanreotide switch patients reported similar AE rates in OLE and core studies, except more diarrhoea was considered treatment-related in OLE (overall diarrhoea unchanged). Median lanreotide PFS (core study randomisation to PD in core/OLE; n=101) was 32.8 months (95% CI: 30.9, 68.0). A sensitivity analysis, addressing potential selection bias by assuming that patients with SD on lanreotide in the core study and not entering the OLE (n=13) had PD 24 weeks after last core assessment, found median PFS remaining consistent: 30.8 months (95% CI: 30.0, 31.3). Median time to further PD after placebo-to-lanreotide switch (n=32) was 14.0 months (10.1; not reached). This OLE study suggests long-term treatment with lanreotide Autogel 120 mg maintained favourable safety/tolerability. CLARINET OLE data also provide new evidence of lanreotide anti-tumour benefits in indolent and progressive pancreatic/intestinal NETs.

E15181 Background: CLARINET was a large 96-week phase 3 study showing that LAN 120 mg significantly improved progression-free survival vs PBO in patients with intestinal and pancreatic NETs. Here, we analyze the safety/tolerability data in greater detail, quantifying the relative risk (RR) of adverse events (AEs). Methods: Patients withmetastatic grade 1/2 (Ki-67 post hoc for any AE occurring in ≥5% of patients in either group. Results: The incidence of AEs overall was similar for LAN and PBO (88% vs 90%). Gastrointestinal disorders were the most common AE class (67% vs 63%; RR 1.1 [0.9, 1.3]) and diarrhea the most common individual AE (35% vs 35%; RR 1.0 [0.7, 1.4]); based on RR, these incidences were not significantly different for LAN vs PBO (lower CIs were ≤1). Furthermore, there were no significant differences for any AE occurring in ≥5% in either group (see Table for the subset occurring in ≥10% in either group), although CIs for RRs were wide in a number of cases. Conclusions: There were no significant safety signals for LAN in the CLARINET study, highlighting its favorable benefit–risk profile in patients with intestinal and pancreatic NETs. For significant difference between treatment groups, lower CIs would need to be >1. Clinical trial information: NCT00353496.

E15182 Background: CLARINET showed antitumor effects with LAN 120 mg in metastatic intestinal/pancreatic NETs. Here, we characterize treatment effects within subgroups defined post hoc by baseline BMI. Methods: CLARINET was a 96-wk randomized trial of patients with metastatic grade 1/2 (Ki-67 <10%) non-functioning intestinal/pancreatic NETs (NCT00353496). Patients received LAN 120 mg (N=101) or placebo (PBO; n=103) every 4 wks. Patient subgroups are based on well-known WHO BMI categories. Median progression-free survival (PFS) [95% CI] was determined by Kaplan–Meier method, and HRs and CIs with Cox proportional hazards model with single term for treatment (both intent-to-treat population); summary statistics were used for adverse events (AEs) (safety population). PFS analyses investigated only consistency of treatment effects across subgroups as the study was not otherwise powered for such analyses. Results: LAN median PFS was not reached in any BMI subgroup (vs 13–24 months for PBO); HRs favored LAN and ...

E15177 Background: The somatostatin analog LAN 120 mg significantly prolonged progression-free survival (PFS) vs. placebo (PBO) in patients with metastatic grade 1 or 2 (Ki-67 65 years. Methods: In this 96-week randomized double-blind trial, patients received LAN 120 mg or PBO every 4 weeks by deep subcutaneous injection (NCT00353496). Subgroup analyses were undertaken to investigate only the consistency of treatment effects, the study was not designed or powered for such analyses. Results: Median age (range) was 57 years (30–65 years) for those ≤65 years old, and 71 years (66–92 years) for those >65 years old. Other baseline characteristics were similar between groups, including tumor origins (≤65 years: pancreatic 43%, midgut 34%; >65 years: pancreatic 46%, midgut 38%) and hepatic tumor loads (>25%: 30% and 37% for ≤65 and >65 years, respectively). Disease was predominantly stable at baseline (94% vs. 98%, respectively). Therapeutic effects of LAN 120 mg on PFS were similar for the two groups and there were no consistent differences in tolerability (Table). Overall, the most common adverse event was diarrhea (≤65 years: LAN 36%, PBO 32%; >65 years: LAN 33%, PBO 40%). Conclusions: Treatment effect with LAN 120 mg in terms of PFS was consistent across age groups. LAN tolerability/safety was favorable. Clinical trial information: NCT00353496.