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.
*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.
The authors disclosed study sponsorship from Ipsen.