SOMATULINE® – Tumor Growth Rate (TGR) a Better Indicator of Therapeutic Activity than RECIST in NeuroEndocrine Tumors

SUMMARY: NeuroEndocrine Tumors (NETs) arise from cells of the endocrine and nervous systems and produce biogenic amines and polypeptide hormones. NETs can be clinically symptomatic (functioning) or silent (nonfunctioning). The incidence is higher in African-Americans and is most frequently diagnosed in the small intestine, appendix, rectum, lungs and bronchi. NETs may be sporadic or may be a component of inherited genetic syndromes such as Multiple Endocrine Neoplasia (MEN) types 1 and 2. Majority of the NETs are nonfunctioning and are diagnosed incidentally but are clinically symptomatic following spread to the liver. Most NETs are classified based on tumor differentiation into 1) Well-differentiated, Low-grade (G1) 2) Well-differentiated, Intermediate-grade (G2) and 3) Poorly differentiated, High-grade (G3). Tumor differentiation and tumor grade often correlate with mitotic count and Ki-67 proliferation index. Even though surgery is curative when the tumor is detected early, this is often not the case, as most patients present with metastatic disease at the time of diagnosis.

SOMATULINE® (Lanreotide) is a synthetic analogue of Somatostatin, a naturally occurring inhibitory hormone, which blocks the release of other hormones, including Insulin, Glucagon, Growth hormone, Thyroid Stimulating Hormone, etc. The approval of SOMATULINE® by the FDA for the treatment of patients with unresectable, well or moderately differentiated, locally advanced or metastatic GastroEnteroPancreatic NeuroEndocrine Tumors (GEP-NETs), was based on the demonstration of improved Progression Free Survival (PFS) in the CLARINET trial, a multicenter, international, randomized placebo-controlled study. This study enrolled 204 patients of whom 55% (113/204) had NeuroEndocrine Tumors arising outside the pancreas. Patients were randomized to receive either SOMATULINE® 120 mg or placebo, subcutaneously every 28 days. This trial demonstrated a significant prolongation of PFS for the SOMATULINE® group compared to the placebo group (HR 0.47; P<0.001).

The authors now report an exploratory analysis of Tumor Growth Rate (TGR) with SOMATULINE® in patients with NeuroEndocrine Tumors from the CLARINET study. TGR has been proposed as a novel measure of tumor response. Target lesions were assessed by central radiologic review based on RECIST criteria. TGR was defined as the percentage of variation of tumor volume per month. This was calculated from sum-of-longest-diameters (SLD) of original target lesions (excluding new ones) on 2 CT scans during defined periods, which was 12-24 weeks prior to randomization versus baseline (pretreatment) and baseline versus each visit or between consecutive visits. TGR pre- and post-treatment were compared between treatment groups.

It was noted that even though all patients were classified as stable based on RECIST, a significant proportion of patients treated with SOMATULINE® showed changes in the TGR, following 12 weeks of treatment. This benefit was not seen in those on placebo. The TGR benefit with SOMATULINE® was significant compared to placebo and was maintained at subsequent study visits.

The authors concluded that in patients with NeuroEndocrine Tumors, Tumor Growth Rate provides an early and more precise characterization of therapeutic activity than RECIST and requires validation in prospective studies. Exploratory analysis of tumor growth rate (TGR) with lanreotide depot/autogel (LAN) in patients (pts) with neuroendocrine tumors (NETs) from the CLARINET study. Caplin ME, Pavel ME, Ruszniewski P, et al. J Clin Oncol 34, 2016 (suppl; abstr 4096)