A strong antiproliferative response was shown for the somatostatin analog lanreotide (subcutaneous, extended-release formulation, Somatuline Autogel [Somatuline Depot in the United States]) in patients with gastroenteropancreatic neuroendocrine tumors, in the large multinational prospective phase III CLARINET trial. Compared to placebo, lanreotide offered a highly significant advantage in progression-free survival, Philippe Ruszniewski, MD, Professor of Gastroenterology and Chief of the Division of Gastroenterology and Pancreatology at Beaujon Hospital in Clichy, France, reported at the 2013 European Cancer Congress.1
Growing Body of Evidence
CLARINET (Controlled study of Lanreotide Antiproliferative Response In NeuroEndocrine Tumors) adds to a growing body of evidence for these agents in neuroendocrine tumors, and supports their use in nonfunctioning tumors. The study’s first author was Martyn Caplin, MD, Professor of Gastroenterology and Gastrointestinal Neuroendocrinology, Royal Free Hospital, London.
In 2009, the PROMID trial was the first study to show that somatostatin analogs, in this case octreotide (Sandostatin) LAR, have antiproliferative effects.2 In PROMID, octreotide improved progression-free survival from 6.0 months to 14.3 months—a 66% reduction in risk (P < .00072). PROMID, however, was a small study of only 85 patients with well-differentiated midgut neuroendocrine tumors, and only two-thirds of these were nonfunctioning.
CLARINET was a larger international study of 204 patients with metastatic or locally advanced inoperable sporadic nonfunctioning gastroenteropancreatic neuroendocrine tumors (approximately 45% pancreas, 35% midgut). Patients with well- or moderately differentiated tumors with a low proliferative index (Ki67 < 10%) and naive to somatostatin analogs were randomized to receive lanreotide at 120 mg or placebo every 4 weeks for 96 weeks or until progression or death. Two baseline computed tomography (CT) scans at least 12 weeks apart were performed, followed by additional scans at intervals up to 96 weeks.
Primary and Secondary Endpoints
For the lanreotide arm, 30 of 101 patients developed progressive disease and 2 patients died. For the placebo arm, 58 of 103 had disease progression and 2 died. In addition, there were 18 withdrawals for various reasons in the lanreotide arm and 21 in the placebo arm. Ultimately, 53 patients treated with lanreotide completed the study “without events” compared to 26 in the placebo arm.
CLARINET met its primary endpoint, significantly improving progression-free survival at 2 years from 22% with placebo to 62% with lanreotide—a 53% reduction in risk (P = .0002). Median progression-free survival was not reached with lanreotide (after > 27 months) and was 18 months with placebo, Dr. Ruszniewski reported.
In a subgroup (intent-to-treat) analysis, the researchers looked separately at midgut (n = 73) and pancreatic (n = 91) neuroendocrine tumors. In midgut tumors, risk of progression was reduced by 65% with lanreotide (P = .0091); median progression-free survival was not reached with lanreotide but was 21.1 months with placebo. For the pancreatic neuroendocrine tumors, the risk reduction was 42% (P = .0637); again, median progression-free survival was not reached with lanreotide but was 12.1 months with placebo.
“Progression-free survival was substantially prolonged with lanreotide Autogel 120 mg for metastatic, well- to moderately differentiated enteropancreatic [neuroendocrine tumors],” he concluded. “The effect was observed in patients with grade 1 and grade 2 tumors, and in patients with low and high hepatic tumor load.”
Not surprisingly, overall survival was similar, with 19 deaths observed in the lanreotide arm and 17 in the placebo arm (P = .8791). The safety profile was consistent with previous studies.
Dr. Ruszniewski said the benefit of lanreotide in CLARINET, a clear antiproliferative effect, “may support its place in the treatment algorithm for enteropancreatic [neuroendocrine tumors].” ■
References
1. Caplin M, Ruszniewski P, Pavel M, et al: A randomized, double-blind, placebo-Controlled study of Lanreotide Antiproliferative Response in patients with gastroenteropancreatic NeuroEndocrine Tumors (CLARINET). 2013 European Cancer Congress. Abstract 3. Presented September 28, 2013.
2. Rinke A, Müller HH, Schade-Brittinger C, et al: Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: A report from the PROMID Study Group. J Clin Oncol 27:4656-4663, 2009.
