Philippe B. Ruszniewski

348 Background: Neuroendocrine tumor progression is associated with decline in quality of life, both due to tumor and hormone-related symptoms. The Phase III NETTER-1 trial randomized patients with advanced, progressive midgut NETs to receive treatment with ¹⁷⁷Lu-DOTATATE (¹⁷⁷Lu; Lutathera) versus high-dose (60 mg) Octreotide LAR (Oct). EORTC questionnaires C30 and GINET21 were assessed during the trial in order to determine the impact of treatment on health-related quality of life (HRQoL). Methods: Patients completed EORTC QLQ-30 and QLQ-G.I.NET21 questionnaires at baseline and every 12 weeks thereafter until disease progression. Raw scores were converted to a 100-point scale and individual changes from baseline scores were assessed. Clinically relevant ( ≥ 10 point) deterioration/improvement was considered clinically significant. Results: Clinically and statistically significant improvements in QoL were observed in the ¹⁷⁷Lu arm versus the Oct arm at certain time points in key domains of HRQoL including global health status and diarrhea. In mean, global health status improved in 28% of patients on ¹⁷⁷Lu arm vs. 15% on Oct, and worsened in 18% of patients on ¹⁷⁷Lu vs. 26% on Oct. Diarrhea improved in 39% of patients on ¹⁷⁷Lu vs. 23% on Oct, and worsened in 19% of patients on ¹⁷⁷Lu vs. 23% on Oct. There was a trend towards improvement in pain that was not statistically significant. Flushing appeared to improve compared to baseline in both arms of the study with no clear advantage to treatment with ¹⁷⁷Lu vs. Oct. Conclusions: QoL analysis suggests benefit in important domains associated with ¹⁷⁷Lu treatment compared to high-dose octreotide in patients with advanced midgut NETs, and confirms the treatment value of ¹⁷⁷Lu on patient QoL, in addition to the meaningful increase in progression-free survival already reported. Clinical trial information: NCT01578239.

4005 Background: There are limited therapeutic options for patients with advanced midgut NETs progressing on first-line somatostatin analog therapy. The purpose of this phase III trial was to evaluate the efficacy and safety of ¹⁷⁷Lu-DOTA⁰-Tyr³-Octreotate (Lutathera) in patients with advanced, progressive sstr positive midgut NETs. Methods: 230 patients with grade 1-2 metastatic midgut NETs were randomized to Lutathera, 7.4 GBq every 8 weeks (x 4 administrations) vs Octreotide LAR 60 mg every 4 weeks. Primary endpoint was PFS (RECIST 1.1) with tumor assessment every 12 weeks. Secondary objectives included ORR, OS, toxicity and QoL. Results: In the intent-to-treat population (ITT), the median PFS was not reached for Lutathera and was 8.4 months with control (p < 0.0001, HR 0.21). There were 23 centrally confirmed disease progressions or deaths in the Lutathera arm and 67 in the Octreotide LAR 60 mg arm. The objective radiographic response rate (ORR) was 18% with Lutathera and 3% with control (p = 0.0008). Besides the scintigraphic ¹¹¹In-pentetreotide tumor uptake score (Krenning scale > = 2), tumor burden and Ki67 grade had no significant effect on clinical efficacy outcomes (PFS, OS, TTP) in the Cox regression models. Interim OS analysis (13 deaths in Lutathera group and 22 in control group; p = 0.019) strongly suggests an improvement in OS. Only 5% (6 patients) experienced dose modifying toxicity with Lutathera. Grade 3 or 4 adverse events of neutropenia, thrombocytopenia and lymphopenia occurred in 1%, 2% and 9% of patients in Lutathera arm vs. none in controls. Conclusions: The NETTER-1 trial provides evidence for a clinically meaningful and statistically significant increase in PFS and ORR, and suggests a potential survival benefit in patients with advanced midgut NETs treated with Lutathera in both ITT and PP analyses. Lutathera safety profile was found to be very favorable. Clinical trial information: NCT01578239.

367 Background: The somatostatin analog lanreotide Autogel 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 s.c. injection (NCT00353496). Subgroup analyses were undertaken to investigate only the consistency of treatment effects as the study was not otherwise designed or powered for such analyses. Results: Median age (range) was 57 years (30, 65) for thegroup aged ≤65 years and 71 years (66, 92) for the group aged >65 years. Other baseline characteristics were similar between age 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 on PFS were similar for the age groups and there were no consistent differences in tolerabilities between age groups (Table). The most common AE was diarrhea irrespective of age and treatment (≤65 years: LAN 36%, PBO 32%; >65 years: LAN 33%, PBO 40%). Conclusions: The treatment effect with LAN in terms of PFS was consistent across age groups and LAN tolerability/safety was favorable in both cases. Clinical trial information: NCT00353496. [Table: see text]

4107^ Background: The CLARINET core study showed that the long-acting somatostatin analog (SSA) LAN 120 mg significantly prolonged PFS vs placebo (PBO) in patients (pts) with metastatic enteropancreatic NETs (p=0.0002). Median PFS not reached with LAN vs 18.0 months with PBO. This study was the first randomized PBO-controlled trial investigating PFS with an SSA in a population that included pts with pancreatic NETs and pts with grade G2 tumors (Ki-67 <10%). Here, we report PFS data and safety findings from the open-label extension (OLE) to CLARINET. Methods: Pts enrolled in CLARINEThad: well/moderately differentiated non-functioning enteropancreatic NETs with Ki-67 <10%; no prior SSAs, or other medical therapies in last 6 months; metastatic disease. In CLARINET, pts were randomized to LAN 120 mg (n=101) or PBO (n=103) every 28 days for 96 wks or until death/disease progression (PD; according to RECIST 1.0). LAN pts with stable disease and PBO pts with/without PD could then enter the single-arm (LAN) OLE (NCT00842348, max. expected duration 5 yrs). The primary objective of the OLE was safety (safety population). The main efficacy endpoint was PFS (i.e. time from randomization in core study to death/PD) for the core study intent-to-treat population, using survival analysis based on Kaplan–Meier estimates. Results: 88 pts from the CLARINET core study (LAN arm, 41; PBO arm, 47) participated in OLE. At core study enrollment, 96% of OLE patients did not have tumor progression; 38% had pancreatic primary tumors, 39% had midgut, and 8% hindgut. The median PFS for LAN was reached during the OLE: 32.8 months. For subset of pts who had PD while on PBO in the core study, median time to further PD with LAN in the OLE was 14.0 months. During the OLE, 27% who continued LAN vs 40% switched to LAN had treatment-related adverse events (TRAE); most frequent TRAE was diarrhea. No new safety concerns were identified in the extension. Conclusions: CLARINET extension data suggest there were antitumor effects with LAN 120 mg in enteropancreatic NET patients with progressive disease. Long-term safety/tolerability of lanreotide in the extension was consistent with its known profile. Clinical trial information: NCT00842348.

Introduction: Somatostatin analogues are widely used to reduce the incidence and severity of carcinoid syndrome symptoms. However, their impact on patients’ satisfaction with symptom control needs further investigation. SYMNET was a large international multicentre observation study that assessed PROs during LAN-ATG treatment of carcinoid syndrome in gastroenteropancreatic neuroendocrine tumour (GEP–NET) patients. Methods: At routine clinic visit, patients with diarrhoea related to carcinoid syndrome and receiving LAN-ATG for >3 months were asked to complete PRO questionnaires on satisfaction and symptoms associated with their treatment. Investigators also assessed patients’ medical records to identify patient characteristics that were potential predictors of treatment satisfaction. Results: Of 273 patients enrolled, 56% were males, 57% were aged >60 years, 66% had small bowel primary tumours, and 80% had liver metastases. Prior to the study, 66% had surgery and 23% other anti-tumour therapy within last 3 months. Mean time since diagnosis was 4.4 years. Mean LAN-ATG treatment duration was 21.7 months and median dose 120 mg/month on study day. Most patients (76%) were satisfied with diarrhoea control, and flushing control (73%). More patients indicated no, minimal, or mild diarrhoea at study visit (75%) than did before treatment (33%). Most (79%) patients reported diarrhoea was improved overall with LAN-ATG. Investigators identified a clinically relevant decrease in stool frequency since treatment initiation (median: 4–2 episodes/day). Statistically significant decreases (McNemar paired tests, P<0.001) were seen in the proportion of patients with urgency (73–41%), leakage (21–9%), and associated pain (37–4%). Predictors of satisfaction with diarrhoea control were initial stool leakage and non-small bowel primary localization. Conclusions: GEP–NET patients reported favourable symptom control with LAN-ATG treatment. Improvements in PROs were consistent with those on investigators’ medical assessments. Patients’ satisfaction with symptom control on LAN-ATG may be supported by associated factors.