BSc, DM, FRCP
The somatostatin analog lanreotide (Somatuline Depot) significantly prolonged progression-free survival (PFS) compared with placebo for patients with metastatic gastroenteropancreatic (GEP) neuroendocrine tumors (NETs), according to phase III results published in the New England Journal of Medicine
In the phase III CLARINET study, treatment with lanreotide improved PFS by 53% compared with placebo for patients with grade 1 or 2 GEP NETs. Additionally, quality of life was similar between the two arms. Based on these findings, Ipsen, the company developing the drug, submitted a supplemental New Drug Application to the FDA for lanreotide in GEP NETs on July 1, 2014.
“The CLARINET data are compelling, since no similar GEP NET progression-free survival data exist for a somatostatin analog in such a large, multinational study population,” the study's lead author Martyn Caplin, BSc, DM, FRCP, a professor of gastroenterology & gastrointestinal neuroendocrinology at the Royal Free Hospital in London, England, said in a release.
In the study, 204 patients were randomized to lanreotide at 120 mg (n = 101) or placebo (n = 103). Treatment was administered once a month for 24 months. The primary endpoint of the study was PFS, with secondary endpoints focused on overall survival (OS) and quality of life.
The median PFS was not reached with lanreotide versus 18 months with placebo (HR = 0.47; 95% CI, 0.30-0.73; P
<.001). At the end of 24 months, the estimated PFS rate was 65% in the lanreotide arm compared with 33% with placebo.
The HR for PFS in patients with midgut tumors (n = 73) was 0.35 for lanreotide and placebo. Patients with hindgut tumors (n = 14) experienced better PFS outcomes with placebo compared with lanreotide (HR = 1.47). For patients with tumors located in the pancreas (n=91), the HR for PFS was 0.58, favoring lanreotide.
A significant difference in OS was not demonstrated in the trial. There were 19 deaths observed in patients randomized to lanreotide compared with 17 with placebo (P
= .88). After the 24-month study period, patients in the placebo arm were allowed to crossover to receive lanreotide. In total, 47 patients randomized to placebo received lanreotide during the follow-up period.
Treatment with lanreotide was associated with a higher rate of gastrointestinal adverse events. The most commonly observed was diarrhea (26% vs 9%). Other adverse events included hyperglycemia (5% vs 0%) and cholelithiasis (10% vs 3%). For patients who developed cholelithiasis, 4 patients had new gallbladder sludge (3% vs 1%) and 10 patients had new lithiasis (7% vs 3%).
The FDA initially approved lanreotide in 2007 as a long-term treatment for patients with acromegaly. Somatostatin analogs have traditionally been used for symptom control in patients with NETs, although lanreotide is not currently approved for this indication.
In 2009, results from the phase IIIb PROMID study demonstrated a significant extension in PFS with the somatostatin analog octreotide LAR in patients with well-differentiated metastatic midgut NETs. In this trial, the median PFS with octreotide was 14.3 months versus 6 months with placebo (HR = 0.34; P
= .000072). After 6 months of treatment, 66.7% patients had stable disease with octreotide versus 37.2% with placebo.
"One of the perhaps most surprising observations of the past few years has been that somatostatin analogs, which we typically think of as using to control hormone symptoms, also seem to have an antiproliferative effect," Matthew H. Kulke, MD, director of the Program in Neuroendocrine and Carcinoid Tumors at the Dana-Farber Cancer Institute, explained in a recent OncLive Peer Exchange
discussion. "These drugs are very well tolerated but there are some side effects. You need to watch blood sugar a little bit and they can cause some cholestasis, and there’s a slightly higher risk of developing gallstones."