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CLARINET Study in Metastatic Enteropancreatic NETs Published in the New England Journal of Medicine

ESMO @ ECC 2013: Phase III trial results favour Lanreotide therapy in patients with gastroenteropancreatic neuro-endocrine tumours. New and compelling evidence for the antiproliferative effect of lanreotide
17 Jul 2014
Endocrine and neuroendocrine tumours;  Anticancer agents & Biologic therapy

A strong anti-proliferative response was demonstrated for the somatostatin analogue lanreotide in patients with gastroenteropancreatic neuro-endocrine tumours. The final analyses of data from a phase III trial showed that treatment with lanreotide significantly prolonged progression-free survival in patients with gastroenteropancreatic (GEP) neuroendocrine tumours (NETs) compared to treatment with placebo.

Lead investigator Dr. Martyn Caplin, Professor of Gastroenterology & Gastrointestinal Neuroendocrinology, Royal Free Hospital, London, UK presented late breaking results on 28 September from the CLARINET study (Abstract E17-7103), which was completed in June of this year, during the Presidential Session I of the 17th ECCO – 38th ESMO – 32nd ESTRO European Cancer Congress.

In search for antiproliferative response of lanreotide

The CLARINET (LanreotideAntiproliferativeResponse in patients with GEP-NET) is until now a largest phase III, randomised, double-blind, placebo-controlled, multinational study that evaluated the anti-proliferative effect of the somatostatin analogue lanreotide in patients with GEP-NETs. Although somatostatin analogues have been indicated for treating patients with GEP-NET, there were limited data on their antiproliferative activity. It had been shown previously in just one prospective trial in patients who had midgut tumours and limited liver tumor burden.

The CLARINET (CT. gov NCT00353496; EudraCT 2005-004904-35) is the first large phase III prospective trial to evaluate the antiproliferative effects of lanreotide Autogel (Autogel is a lanreotide preparation preloaded in a syringe) in patients with non-functioning GEP-NET. The study enrolled 204 patients with well or moderately differentiated non-functioning GEP-NETs, including pancreatic and gastrointestinal tumours, and defined as having less than 10% of proliferation marker Ki67. All patients were 18 or more years with no hormone-related symptoms and had not received somatostatin analogues, interferon, chemoembolisation or chemotherapy with six months prior to study entry.

CLARINET is a large phase III trial assessing the anti-proliferative effect of lanreotide scheduled for a total of 24 monthly injections in neuroendocrine tumours (NETs). Compared to placebo, there was a highly significant advantage in progression-free survival (PFS) with the use of lanreotide. Data from CLARINET were both confirmatory and instructive. PROMID study was the first study to show somatostatin analogues (SSA), octreotide LAR in this case, had anti-proliferative effect in NETs (Rinke et al J Clin Oncol 2009). However, only 85 patients were randomised in PROMID study constituting a very small clinical trial dataset. Furthermore, only patients with well differentiated/Ki67 ≤2% midgut primary or unknown primary NETs were eligible. Three-quarters of patients had ≤10% liver involvement and nearly 40% of patients had functional tumours. In contrast, CLARINET study recruited NETs of both GI and pancreatic origins and in particular 45% had primary pancreatic NETs – an important subgroup not included in the PROMID study. Both well- and moderately differentiated NETs were recruited and one-third of patients had >25% liver involvement. The anti-proliferative effect of SSA was confirmed in the CLARINET study, but also appeared to apply to a wider group of NET patients – a conundrum often faced by clinicians in routine clinical practice armed with only PROMID data to decide what to do with other groups of patients.

Progression-free survival has been recommended as the primary endpoint for phase III trials as overall survival was not deemed to be a practical endpoint for most advanced NETs trials in the recent Consensus Report of the National Cancer Institute Neuroendocrine Tumor Clinical Trials Planning Meeting (Kulke et al J Clin Oncol 2011). This recommendation was attributed to long survival after progression and the wide variability of salvage regimens in many patients with NETs who are often of excellent performance status still. Unlike other solid tumours, there is no definitive evidence in NETs that radiographic progression equates to symptom deterioration or worsening of quality of life. In some occasions, clinicians may consider minor tumour growth with worsening of carcinoid symptoms as disease progression. This would not be the case in the CLARINET study as patients had non-functioning NETs. Data are not currently available for the proportion of patients with disease progression who are also symptomatic with pain, weight loss or deterioration of performance status within CLARINET. Furthermore, it is unclear how many patient had progressing disease on study entry, despite this factor was stratified at randomisation.

Several areas within the CLARINET study would be of interests. Firstly, the proliferative behaviour of NETs when lanreotide was stopped after 96 weeks. Did the patients experience accelerated tumour growth or continuing tumour control? Secondly, did patients on placebo crossed over to octreotide LAR and did tumour achieve control with octroetide salvage? Thirdly, if eventually no overall survival advantage is demonstrated with lanreotide, does this PFS advantage matter? Patient reported outcome would be of great importance and we shall wait to see the completeness of quality of life data as this is an area clearly deficient from PROMID, RADIANT II & III and sunitinib A6181111 studies.

Lanreotdie will provide a new treatment option for patients with wider spectrum of GEP NETs. Both patients and clinicians will however need to decide whether this delay in radiographic disease progression is a worthwhile clinical gain.

Ian Chau*
ESMO Comments bubble

*Ian Chau, ESMO spokesperson who was not involved in the study

The patients were randomised to receive either 120 mg lanreotide Autogel (n=101) or placebo (n=103) every 4 weeks for 96 weeks or until progressive disease (PD) or death. The trial’s primary endpoint was progression-free survival (PFS) by RECIST criteria. Secondary endpoints were the percentage of patients who died or showed PD and safety. Computed tomography (CT) scans taken at baseline and at restaging timepoints throughout the study were centrally assessed.

At baseline 45% of patients had primary tumours located in the pancreas, 36% in the midgut, 7% in the hindgut and 13% of patients had tumours in unknown locations. The majority of patients, 96%, had stable disease (SD) and 81% were treatment-naive (81%). Levels of Ki67 between 3% and 10% (WHO grade 2) were recorded in 22% of patients and 33% had a hepatic tumour load greater than 25%.

The study met its endpoints

The CLARINET trial of lanreotide Autogel met both primary and secondary endpoints. At a time-point of two years following initiation of treatment, median PFS was not reached with lanreotide compared to 18 months with placebo, hazard ratio (HR) 0.47; 95% confidence interval (CI) 0.30, 0.73 (p = 0.0002). Neither disease progression nor death occurred in 62% of lanreotide patients compared to 22% of placebo patients.

The safety results showed lanreotide had favourable safety and tolerability that was consistent with its known safety profile. Treatment-related adverse events (AEs) occurred in 50% of patients receiving lanreotide and 28% of placebo patients, with diarrhea being the most frequently reported AE in 26% versus 9% of patients receiving lanreotide and placebo, respectively. Serious AEs were reported in 3% patients receiving lanreotide and in 1% of placebo patients. Adverse events led to withdrawal from the study for a total of six patients, three from each treatment group.

The authors concluded that lanreotide Autogel can substantially prolong PFS for GEP-NET patients. Furthermore, these results from the first large-scale, multinational, prospective study on somatostatin analogue therapy in patients with several types of neuroendocrine tumours offer new and compelling evidence for the antiproliferative effect of lanreotide.

Last update: 17 Jul 2014

The authors disclosed study sponsorship from Ipsen.

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