title: Phase III study of pasireotide long-acting release in patients with metastatic neuroendocrine tumors and carcinoid symptoms refractory to available somatostatin analogues.
abstract: In a randomized, double-blind, Phase III study, we compared pasireotide long-acting release (pasireotide LAR) with octreotide long-acting repeatable (octreotide LAR) in managing carcinoid symptoms refractory to first-generation somatostatin analogues. Adults with carcinoid tumors of the digestive tract were randomly assigned (1:1) to receive pasireotide LAR (60 mg) or octreotide LAR (40 mg) every 28 days. Primary outcome was symptom control based on frequency of bowel movements and flushing episodes. Objective tumor response was a secondary outcome. Progression-free survival (PFS) was calculated in a post hoc analysis. Adverse events were recorded. At the time of a planned interim analysis, the data monitoring committee recommended halting the study because of a low predictive probability of showing superiority of pasireotide over octreotide for symptom control (n=43 pasireotide LAR, 20.9%; n=45 octreotide LAR, 26.7%; odds ratio, 0.73; 95% confidence interval [CI], 0.27-1.97; P=0.53). Tumor control rate at month 6 was 62.7% with pasireotide and 46.2% with octreotide (odds ratio, 1.96; 95% CI, 0.89-4.32; P=0.09). Median (95% CI) PFS was 11.8 months (11.0 - not reached) with pasireotide versus 6.8 months (5.6 - not reached) with octreotide (hazard ratio, 0.46; 95% CI, 0.20-0.98; P=0.045). The most frequent drug-related adverse events (pasireotide vs octreotide) included hyperglycemia (28.3% vs 5.3%), fatigue (11.3% vs 3.5%), and nausea (9.4% vs 0%). We conclude that, among patients with carcinoid symptoms refractory to available somatostatin analogues, similar proportions of patients receiving pasireotide LAR or octreotide LAR achieved symptom control at month 6. Pasireotide LAR showed a trend toward higher tumor control rate at month 6, although it was statistically not significant, and was associated with a longer PFS than octreotide LAR.
authors.affiliation: Markey Cancer Center, University of Kentucky, Lexington, KY, USA.
authors.forename: Edward M
authors.initials: EM
authors.lastname: Wolin
authors.affiliation: Department of Nuclear Medicine and Endocrine Oncology, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch, Gliwice, Poland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Jarzab
authors.affiliation: Department of Medical Sciences, Endocrine Oncology Unit, University Hospital, Uppsala, Sweden.
authors.forename: Barbro
authors.initials: B
authors.lastname: Eriksson
authors.affiliation: Department of Medical Oncology, Edouard Herriot Hospital, Lyon, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Walter
authors.affiliation: Gastroenterology and Neuroendocrine Tumours, Royal Free Hospital, London, UK.
authors.forename: Christos
authors.initials: C
authors.lastname: Toumpanakis
authors.affiliation: Department of Medical Oncology, Duke University Medical Center, Durham, NC, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Morse
authors.affiliation: Department of Medical and Surgical Sciences, University Hospital St Orsola, Bologna, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Tomassetti
authors.affiliation: Medizinische Klinik und Poliklinik, Johannes Gutenberg-Universität Mainz, Mainz, Germany.
authors.forename: Matthias M
authors.initials: MM
authors.lastname: Weber
authors.affiliation: Department of Gastrointestinal Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Fogelman
authors.affiliation: Gastroenterology Unit, North Hampshire Hospital, Basingstoke, UK.
authors.forename: John
authors.initials: J
authors.lastname: Ramage
authors.affiliation: Department of Medical Oncology, Raffles Hospital and Duke-NUS Graduate Medical School, Singapore.
authors.forename: Donald
authors.initials: D
authors.lastname: Poon
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Gadbaw
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: Jiang
authors.initials: J
authors.lastname: Li
authors.affiliation: Surgery and Oncology Faculty of Medicine, Foothills Hospital, Calgary, AB, Canada.
authors.forename: Janice L
authors.initials: JL
authors.lastname: Pasieka
authors.affiliation: Department of Gastrointestinal Oncology, CHU de Nice Hôpital de l'Archet 1, Nice, France.
authors.forename: Abakar
authors.initials: A
authors.lastname: Mahamat
authors.affiliation: Department of Clinical Science, Intervention and Technology, Karolinska Universitatssjukhuset, Huddinge, Stockholm, Sweden.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Swahn
authors.affiliation: Department of Human Metabolism, School of Medicine and Biomedical Science, The University of Sheffield, and Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.
authors.forename: John
authors.initials: J
authors.lastname: Newell-Price
authors.affiliation: Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK.
authors.forename: Wasat
authors.initials: W
authors.lastname: Mansoor
authors.affiliation: Department of Medical Sciences, Endocrine Oncology Unit, University Hospital, Uppsala, Sweden.
authors.forename: Kjell
authors.initials: K
authors.lastname: Öberg
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D002276:Carcinoid Tumor / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D003692:Delayed-Action Preparations; D004067:Digestive System Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D018572:Disease-Free Survival; D004311:Double-Blind Method; D019008:Drug Resistance, Neoplasm; D057915:Drug Substitution; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D015282:Octreotide / Q000009:adverse effects / Q000627:therapeutic use*; D016017:Odds Ratio; D016016:Proportional Hazards Models; D013004:Somatostatin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D013997:Time Factors; D016896:Treatment Outcome; D047368:Tumor Burden
chemical_list: D000970:Antineoplastic Agents; D003692:Delayed-Action Preparations; D013004:Somatostatin; C517782:pasireotide; D015282:Octreotide
keywords: carcinoid syndrome; neuroendocrine tumors; pasireotide; progression-free survival; somatostatin analogues; symptom control