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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.

SUBMITTER: Wolin EM

PROVIDER: S-EPMC4562767 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Phase III study of pasireotide long-acting release in patients with metastatic neuroendocrine tumors and carcinoid symptoms refractory to available somatostatin analogues.

Wolin Edward M EM Jarzab Barbara B Eriksson Barbro B Walter Thomas T Toumpanakis Christos C Morse Michael A MA Tomassetti Paola P Weber Matthias M MM Fogelman David R DR Ramage John J Poon Donald D Gadbaw Brian B Li Jiang J Pasieka Janice L JL Mahamat Abakar A Swahn Fredrik F Newell-Price John J Mansoor Wasat W Öberg Kjell K

Drug design, development and therapy 20150903

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 epis ...[more]

PMID: 26366058

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Project description:In recent decades, the incidence of neuroendocrine tumors (NETs) has steadily increased. Due to the slow-growing nature of these tumors and the lack of early symptoms, most cases are diagnosed at advanced stages, when curative treatment options are no longer available. Prognosis and survival of patients with NETs are determined by the location of the primary lesion, biochemical functional status, differentiation, initial staging, and response to treatment. Somatostatin analogue (SSA) therapy has been a mainstay of antisecretory therapy in functioning neuroendocrine tumors, which cause various clinical symptoms depending on hormonal hypersecretion. Beyond symptomatic management, recent research demonstrates that SSAs exert antiproliferative effects and inhibit tumor growth via the somatostatin receptor 2 (SSTR2). Both the PROMID (placebo-controlled, prospective, randomized study in patients with metastatic neuroendocrine midgut tumors) and the CLARINET (controlled study of lanreotide antiproliferative response in neuroendocrine tumors) trial showed a statistically significant prolongation of time to progression/progression-free survival (TTP/PFS) upon SSA treatment, compared to placebo. Moreover, the combination of SSA with peptide receptor radionuclide therapy (PRRT) in small intestinal NETs has proven efficacy in the phase 3 neuroendocrine tumours therapy (NETTER 1) trial. PRRT is currently being tested for enteropancreatic NETs versus everolimus in the COMPETE trial, and the potential of SSTR-antagonists in PRRT is now being evaluated in early phase I/II clinical trials. This review provides a synopsis on the pharmacological development of SSAs and their use as antisecretory drugs. Moreover, this review highlights the clinical evidence of SSAs in monotherapy, and in combination with other treatment modalities, as applied to the antiproliferative management of neuroendocrine tumors with special attention to recent high-quality phase III trials.

Project description:IntroductionLong-acting somatostatin analogues such as lanreotide autogel (LAN) and octreotide long-acting release (OCT) are recommended as first-line treatment for patients with neuroendocrine tumors (NETs). However, only few real-world studies have compared the two medications. This retrospective, observational cohort study used a French claims database to compare patterns of use with LAN vs. OCT in patients with NETs.MethodsData on LAN and OCT patterns of use were obtained retrospectively from the National System of Health Data (SNDS), a national French claims database. Patients 18 years of age or older who initiated treatment for NETs between 2009 and 2016, and who received at least six subsequent dispensings of first-line LAN or OCT during the first year of treatment, were included. A subgroup analysis was performed on patients with gastroenteropancreatic (GEP)-NETs.ResultsPatients receiving LAN (n = 2327) vs. OCT (n = 2090) had greater median treatment duration (31.8 months vs. 22.1 months, respectively; p < 0.0001; log-rank test) and were less likely to discontinue treatment; adjusted hazard ratio (HR) 0.74 (95% confidence interval [CI] 0.69-0.80). In year 1, a significantly lower percentage of patients receiving LAN vs. OCT switched treatments (10.4% vs. 22.2%, respectively; p < 0.0001), received an average monthly dose per trimester above recommended dose (3.0% vs. 7.3%, respectively; p < 0.0001), and used rescue medication (3.1% vs. 10.0%, respectively; p < 0.0001). Dispensing of pancreatic enzymes was significantly higher in patients receiving LAN than OCT (16.4% vs. 13.9%, respectively). In the subgroup of patients with GEP-NETs, those receiving LAN (n = 1478) vs. OCT (n = 1278) had greater treatment duration and less treatment discontinuation, switching, dosage above the recommended dose, and rescue medication use, but no significant difference in dispensing of pancreatic enzymes or time to second-line treatment.ConclusionThese real-world data suggest potential clinical and economic advantages of LAN over OCT in the management of patients with NETs in the French population.

Project description:PurposeEvaluate patients' and nurses' experiences, including injection problem frequency, with the somatostatin analogues (SSAs) lanreotide autogel® (Somatuline® autogel®, deep subcutaneous) and octreotide long-acting release (LAR) (Sandostatin® LAR®, intramuscular) when treating gastroenteropancreatic neuroendocrine tumors (GEP-NETs).MethodsAn observational, cross-sectional study across 2 NET centers in Sweden. Questionnaires based on participants' most recent injection experience were sent to patients with GEP-NETs treated with octreotide or lanreotide, and to nurses administering these treatments. Nurses were identified via patients completing their questionnaires. Resource use was sourced from Swedish prescription registry records. The planned sample size was 200, based on an estimated proportion of 0.50 and ±7% precision.Results119/156 patients (n=53, lanreotide; n=66, octreotide) and 43/53 nurses (n=22, lanreotide; n=21, octreotide) completed questionnaires. Despite smaller recruitment than planned, the endpoint precision was ±9% with 119 participants, and still considered reasonable. More octreotide-treated patients reported problems (18% vs none; P=0.001) and experienced moderate-to-high anxiety pre-injection (11% vs 2%). Patients had similar physical HRQoL scores overall (Short Form-12 mean composite scores: physical: 39.4 vs 37.6; mental: 50.7 vs 49.6). The mean number of lanreotide and octreotide doses dispensed per year were 11.1 and 12.6, respectively (P<0.05). In the lanreotide group, 28% self-injected, while 29% were not aware they could self-inject. In the octreotide group, 3% self-injected and 73% were unaware of the availability of an SSA for self-injection. Most patients (61%) felt well-informed about their disease and treatment. Nurses were generally experienced and felt confident and well-informed about giving SSA injections; however, only 12% felt well-informed about the disease and treatment.ConclusionThose treated with lanreotide reported fewer injection problems and experienced less pre-injection anxiety than those treated with octreotide. SSA choice did not appear to affect patients' HRQoL. Some patients treated with octreotide were unaware of an SSA with the flexibility of self-injection.

Dataset Information

Phase III study of pasireotide long-acting release in patients with metastatic neuroendocrine tumors and carcinoid symptoms refractory to available somatostatin analogues.

Publications

Phase III study of pasireotide long-acting release in patients with metastatic neuroendocrine tumors and carcinoid symptoms refractory to available somatostatin analogues.

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