Phase II clinical trial of pasireotide long-acting repeatable in patients with metastatic neuroendocrine tumors

Abstract

Pasireotide long-acting repeatable (LAR) is a novel somatostatin analog (SSA) with avid binding affinity to somatostatin receptor subtypes 1, 2, 3 (SSTR1,2,3) and 5 (SSTR5). Results from preclinical studies indicate that pasireotide can inhibit neuroendocrine tumor (NET) growth more robustly than octreotide in vitro. This open-label, phase II study assessed the clinical activity of pasireotide in treatment-naïve patients with metastatic grade 1 or 2 NETs. Patients with metastatic pancreatic and extra-pancreatic NETs were treated with pasireotide LAR (60 mg every 4 weeks). Previous systemic therapy, including octreotide and lanreotide, was not permitted. Tumor assessments were performed every 3 months using Response Evaluation Criteria in Solid Tumors (RECIST) criteria. The primary endpoint was progression-free survival (PFS). The secondary endpoints included overall survival (OS), overall radiographic response rate (ORR), and safety. Twenty-nine patients were treated with pasireotide LAR (60 mg every 4 weeks) and 28 were evaluable for response. The median PFS was 11 months. The most favorable effect was observed in patients with low hepatic tumor burden, normal baseline chromogranin A, and high tumoral SSTR5 expression. Median OS has not been reached; the 30-month OS rate was 70%. The best radiographic response was partial response in one patient (4%), stable disease in 17 patients (60%), and progressive disease in ten patients (36%). Although grade 3/4 toxicities were rare, pasireotide LAR treatment was associated with a 79% rate of hyperglycemia including 14% grade 3 hyperglycemia. Although pasireotide appears to be an effective antiproliferative agent in the treatment of advanced NETs, the high incidence of hyperglycemia raises concerns regarding its suitability as a first-line systemic agent in unselected patients. SSTR5 expression is a potentially predictive biomarker for response.

Trial registration: ClinicalTrials.gov NCT01253161.

Keywords: carcinoid; neuroendocrine tumors; pasireotide; somatostatin analogs; somatostatin receptors.

Figure 1

Kaplan–Meier estimate of progression-free survival (PFS). (A) For all 29 patients, 6- and 12-month PFS rates were 66.9% (±9) and 41.9% (±9.9) respectively. (B) PFS by primary site, (C) PFS by tumor grade, and (D) PFS by hepatic tumor burden.

Figure 2

Biochemical and radiological response following pasireotide treatment. (A) In patients with elevated baseline CgA, median CgA concentrations decreased from 189 to 73.5 ng/ml. The decrease was statistically significant (P=0.02) according to the Wilcoxon-matched pairs signed rank test. Paired row values, median change, and interquartile range are represented. (B) Waterfall plot illustrating best radiographic response (percentage change) in each enrolled patient. *Decrease not confirmed at subsequent assessment, thus failing to match RECIST criteria for partial response.

Figure 3

Examples of positive immunohistochemical staining for SSTR_1–5 subtypes (magnification: ×40). A full colour version of this figure is available at http://dx.doi.org/10.1530/ERC-14-0360.