Somatostatin Analogs Show Cumulative Benefit in NET Trials

The future of somatostatin analogs for neuroendocrine tumors (NETs) includes potential advances on several fronts, according to a presentation at the NANETS' 2015 Neuroendocrine Tumor Symposium.

One advance involves higher doses of somatostatin analogs, for example, a stronger formulation of lanreotide, which is in a phase II trial with optimal dosing not yet determined. That study illustrates the growing sentiment that higher doses of several somatostatin analogs will likely work better without increasing dangerous toxicities, said Martyn Caplin, BSc, DM, FRCP, a professor, consultant gastroenterologist, and neuroendocrine tumor physician at the Royal Free Hospital, London.

Speaking on somatostatin analogs' future and some important past studies, Caplin detailed other advances on the horizon including:

• The potential for blood measurement of neuroendocrine gene transcripts to predict progression. For example, Caplin cited a study by Irvin Medlin, MD. Medlin's poster at the 2015 ASCO Annual Meeting showed the sensitivity and specificity of a blood-based multianalyte NET gene transcript measurement for identifying small-intestinal and pancreatic NETs.

• Continuing study of vitamin D to help treat and prevent several cancers, including stabilizing NETs. After several years of treatment for NETs, patients often show vitamin D deficiencies. CAPLIN urged physicians to test patients for vitamin D and correct any deficiencies.

• Further research on peptide agonists that have some binding affinity for all five somatostatin receptors. Such drugs under continuing study include somatostatin 14, somatostatin 28, and KE 108.

The efficacy of somatostatin analogs and their limited side effects will increasingly move these agents into standard, first-line therapy for many NETs, Wouter de Herder, MD, PhD, toldTargeted Oncologyin an interview. de Hanerder is an endocrine oncology professor and physician at Erasmus MC in Rotterdam.

Gallstones are no longer a significant issue with somatostatin analogs, according to de Herder, who moderated a symposium session on the future of somatostatin analog therapy. He pointed out that gallstones seldom occur and are usually asymptomatic. He also noted that analogs are now far better than old treatment regimens that led surgeons to remove the gallbladder and the NETs at the same time.

These agents are being studied in higher oral dosing and in sustained-release formulations. Since administering somatostatin analogs can be complex, de Herder added that he looks forward to having more liquid dosing to make injections easier and eventually lead to self-dosing.

The future also includes the need for wider dissemination of existing knowledge. "Several significant NET studies have produced results that are too little known or utilized except by NET specialists," Caplin toldTargeted Oncology. The general message of these studies is that somatostatin analogs are often well-tolerated, effective treatments for grades 1 and 2 NETs.

One significant study was the open-label extension (OLE) of CLARINET, which studied the somatostatin analog, lanreotide 120 mg. Reinforcing CLARINET's results, the OLEstudy further illustrated lanreotide's antitumor effects because patients who had progressed on placebo gained an additional PFS of 14 months after switching to lanreotide, according to Caplin.The original phase III CLARINET study, published in theNew England Journal of Medicinein 2014, wasthe first randomized placebo-controlled trial investigating PFS with a somatostatin analog in a population that included patients with pancreatic NETs and with grade G2 tumors. The original study produced significantly prolonged PFS compared with placebo in patients with metastatic gastroenteropancreatic (GEP) NETs. Treatment with lanreotide improved PFS by 53% compared with placebo for patients with grade 1 or 2 GEP NETs.

Thanks to the CLARINET studies,several other speakers at the symposium had to add, "except for pancreatic tumors" when they discussed the many NETs still needing better treatment.

Caplin summarized another significant study, pasireotide LAR versus octreotide LAR in patients with metastatic NETs. The 2013 multicenter, randomized, blinded, phase III study by Wolin et al showed pasireotide produced PFS lasting 5 months longer than octreotide, with no differences in symptom response rates. The drugs had similar safety profiles, except for more hyperglycemia with pasireotide

The last significant study Caplin summarized was the PROMID study of somatostatin analog, octreotide LAR in patients with well-differentiated, metastatic midgut NETs. The phase III study in 2009 showed the median PFS with octreotide was 14.3 months versus 6 months with placebo. After 6 months of treatment, 67% of patients had stable disease with octreotide versus 37% with placebo.