CLARINET Results: Lanreotide First Line for Metastatic NETs

Veronica Hackethal, MD

July 16, 2014

The somatostatin analogue lanreotide (Somatuline, Ipsen) is significantly better than placebo for controlling progression of many types of metastatic neuroendocrine tumors (NETs), according to the phase 3 CLARINET trial.

"This double-blind randomized placebo-controlled study of lanreotide clearly demonstrates the significant antitumor benefit of lanreotide in patients, including those with intestinal and pancreatic neuroendocrine tumors, with excellent tolerability and side-effect profile," said first investigator Martyn Caplin, DM, FRCP, professor of gastroenterology and gastrointestinal neuroendocrinology at the Royal Free Hospital in London, United Kingdom.

The results were published in the July 17 issue of the New England Journal of Medicine.

At present, lanreotide is approved in Canada, the European Union, and the United States for use in the treatment of acromegaly, and is approved in the European Union for use in the treatment of NET-associated carcinoid syndrome.

The CLARINET trial paves the way for a new indication for the drug in the United States — use in the treatment of certain types of NETs, rare tumors that often start in the gastrointestinal system, but can also start in the lungs.

CLARINET can be considered a registration trial, Dr. Caplin told Medscape Medical News, that could be used "for additional approval for lanreotide as an antitumor agent."

Ipsen has announced that it has submitted a supplemental New Drug Application for lanreotide to the US Food and Drug Administration for the treatment of gastroenteropancreatic NETs. It has also submitted national marketing authorization variations for lanreotide (Somatuline Autogel) to 25 countries in the European Union, with plans for a worldwide roll-out.

CLARINET could change current practice and establish somatostatin analogues as first-line treatment, said Jonathon Strosberg MD, chair of the Gastrointestinal Department Research Program at the H. Lee Moffitt Cancer Center in Tampa, Florida. Dr. Strosberg was not involved in the CLARINET study, but is the author of a recent review of the treatment of NETs (Endocr Pract. 2014;20:167-175), which was highlighted on Medscape Oncology.

The treatment of NETs depends on where the tumors originate, their differentiation, their grade, and whether or not they produce hormones, Dr. Strosberg told Medscape Medical News.

Well-differentiated tumors are often treated with somatostatin analogues, he explained. In the United States, the somatostatin analogue that is primarily used is octreotide (Sandostatin, Novartis).

"The octreotide label is for acromegaly and control of carcinoid syndrome, even though it's used very widely for tumor-growth control in NETs," Dr. Strosberg said. "Lanreotide is not approved for carcinoid syndrome or tumor growth in the United States, [where] it's only approved is for acromegaly, and is therefore used quite rarely," he added.

"CLARINET is a very important trial," he emphasized. "It basically shows that somatostatin analogues can be used for tumor control in a variety of neuroendocrine tumors, not just midgut NETs."

The issue of how well somatostatin analogues can inhibit tumor growth was studied in the PROMID trial, which looked at octreotide in the treatment of well-differentiated low-grade carcinoid tumors that originated in the small intestine (J Clin Oncol. 2009;27:4656-4663).

"PROMID was an important randomized placebo-controlled study demonstrating the antitumor effect of octreotide in midgut intestinal NETs," said Dr. Caplin. He pointed out, however, that the CLARINET trial was much larger. In addition, somatostatin analogue treatment in CLARINET was expanded to a more diverse patient population, with tumors originating from throughout the gastrointestinal system.

Other treatments that have been used for NETs include the mTOR inhibitor everolimus (Afinitor, Novartis) and the VEGF inhibitor sunitinib (Sutent, Pfizer).

Dr. Caplin noted that "neither everolimus nor sunitinib have thus far shown definitive benefit in intestinal NET," although both drugs have "shown clear efficacy in randomized studies in pancreatic NETs with progressive disease."

But both are "considerably more toxic" than octreotide or lanreotide, and would be appropriate for patients with progressive tumors, Dr. Strosberg explained.

Some radiolabeled somatostatin analogues, which enable delivery of radiation to tumors, are "promising" treatments already being used or are available in Europe, and hopefully will be used in the future in the United States, he said.

For most patients, somatostatin analogues will be first-line treatment, although some patients might be better candidates than others, he noted. Patients with somatostatin-receptor-positive tumors, for example, would probably be better candidates for somatostatin analogues than those with tumors lacking such receptors.

Based on the CLARINET trial, I think the pattern of practice is changing.

"Based on the CLARINET trial, I think the pattern of practice is changing," Dr. Strosberg concluded. "For many patients, especially those with well-differentiated slow-growing tumors, I think somatostatin analogues are the appropriate first-line choice."

Details of the CLARINET Results

The CLARINET trial involved 204 patients recruited from 48 care centers in Europe, India, and the United States from June 2006 to April 2013. Patients had NETs that originated in the pancreas, midgut, or hindgut, or were of unknown origin. Tumors were grade 1 or 2, well or moderately differentiated, nonfunctioning (<10% proliferative index), and were somatostatin-receptor positive.

Dr. Caplin and colleagues randomized 101 participants to extended-release aqueous-gel lanreotide 120 mg and 103 participants to placebo (sodium chloride). Participants received treatments once every 28 days for 96 weeks.

At 96 weeks, the risk for disease progression decreased by 53% in the lanreotide group (hazard ratio for progression or death, 0.47). Median progression-free survival was significantly longer in the lanreotide group than in the placebo group (not reached vs 18.0 months; 95% confidence interval, 0.30 - 0.73; P < .001).

However, overall survival did not differ significantly between the 2 groups, which could be related to the slow-growing tumors in this trial, the investigators note. In addition, after disease progression, participants from the placebo group crossed over to lanreotide, which could have muddied the results.

The lanreotide and placebo groups had similar rates of adverse events (88% vs 90%), most of which were mild or moderate, the investigators report.

The most frequent adverse event linked to treatment was diarrhea (26% in the lanreotide group vs 9% in the placebo group). Patients in the 2 groups had similar quality of life.

The study was supported by Ipsen, the manufacturer of lanreotide. Several of the study authors report receiving research grants and consultancy fees from the company. Dr. Strosberg has disclosed no relevant financial relationships.

N Engl J Med. 2014;371:224-233. Abstract


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