Lanreotide autogel/depot in advanced enteropancreatic neuroendocrine tumours: final results of the CLARINET open-label extension study

Abstract

Purpose: In the phase III CLARINET study (NCT00353496), lanreotide autogel/depot (lanreotide) significantly improved progression-free survival (PFS) vs placebo in patients with non-functioning intestinal or pancreatic neuroendocrine tumours (NETs). The aim of CLARINET open-label extension (OLE) (NCT00842348) was to evaluate long-term safety and efficacy of lanreotide in these patients.

Methods: Patients from the CLARINET study were eligible for the OLE if they had stable disease (irrespective of treatment group) or progressive disease (PD) (placebo-treated patients only). All patients in the OLE received lanreotide 120 mg every 28 days. Computed tomography or magnetic resonance imaging scans were conducted every 6 months and assessed locally for PD (the final scan was also assessed centrally).

Results: Overall, 89 patients took part in the OLE (lanreotide, n = 42; placebo, n = 47). Median (range) exposure to lanreotide in patients who received lanreotide in the core study and OLE (LAN-LAN group) was 59.0 (26.0-102.3) months. In this group, the overall incidences of adverse events (AEs) and treatment-related AEs were lower in the OLE than in the core study. Median [95% CI] PFS in the LAN-LAN group was 38.5 [30.9; 59.4] months. In placebo-treated patients with PD at the end of the core study, time to death or subsequent PD during the OLE was 19 [10.1; 26.7] months.

Conclusions: This study provides new evidence on the long-term safety profile and sustained anti-tumour effects of lanreotide autogel/depot in indolent and progressive metastatic intestinal or pancreatic NETs.

Keywords: Lanreotide autogel; Lanreotide depot; Neuroendocrine tumours; Progression-free survival; Safety.

Fig. 1

Flow of patients through the OLE. ‘Completed’ means the patient had had no PD events during the OLE at the time that the OLE was terminated. ^aOne patient was enroled by the investigator before centrally assessed PD was confirmed (the patient was withdrawn when the confirmation was received). ^bIncludes 1 patient who was withdrawn from the core study due to investigator judgement of PD but had an a posteriori central assessment of SD—this patient was then enroled in the OLE. ^cIncluding 1 patient who was withdrawn from the core study due to a centrally assessed PD, but was erroneously classified as having SD at the time of the core study database lock—this subject was censored in the primary analysis of PFS in the core study, but was included as an event in the analysis of PFS in the OLE. ^dWithdrawal from the OLE due to ‘PD’ did not always represent an event in the analysis of PFS: part-way through the study, the sponsor sent additional clarification to all sites on how to complete local tumour evaluations in order to have a standardised approach for the assessment of progression status across the study sites; all radiological scans that had already been evaluated were re-evaluated at this time. ^eOnly the PD event was included in the analysis of PFS. ^fIncludes 1 patient with PD at the final study visit. OLE open-label extension, LAN–LAN group patients receiving lanreotide autogel/depot in core study as well as the OLE study, PBO–LAN group patients receiving placebo in the core study before crossing over to lanreotide in the OLE study, AE adverse event, SD stable disease, PFS progression-free survival

Fig. 2

PFS for lanreotide autogel/depot from the CLARINET core study and the OLE and PFS for placebo from the core study: overall (a) and for subgroups according to primary tumour origin (b, c) and prior therapy (d). Events were PD (according to RECIST version 1.0) or death. Data are from the intention-to-treat population with months approximated based on 4 weeks per month. Core-study data are from all patients randomly allocated to double-blind treatment (lanreotide autogel/depot or placebo). The OLE data are only for patients originally randomly allocated to lanreotide in the core study who then continued into the OLE. The PFS data previously reported for placebo were based on 60 events at the time of database lock in the core study [1]; however, one patient with PD had been erroneously reported as having centrally assessed SD. This additional event been included in the analysis of the OLE data. For the pancreas and midgut data, primary tumour type is the basis for the analyses and results are based on the combination of the various primary tumour locations. OLE open-label extension, PD progressive disease, NET neuroendocrine tumour, NR not reached, PFS progression-free survival, RECIST Response Evaluation Criteria In Solid Tumours, SD stable disease

Fig. 3

Time to death or subsequent PD in patients with PD, while receiving placebo in the core study who switched to lanreotide autogel/depot in the OLE. Data are from a subset of the intention-to-treat population with months approximated based on 4 weeks per month. OLE open-label extension, PD progressive disease