Dataset Information

Efficacy of octreotide long-acting repeatable in neuroendocrine tumors: RADIANT-2 placebo arm post hoc analysis.

ABSTRACT: Somatostatin analogues (SSA) have demonstrated antiproliferative activity in addition to efficacy for carcinoid symptom control in functional neuroendocrine tumors (NET). A post hoc analysis of the placebo arm of the RAD001 In Advanced Neuroendocrine Tumors-2 (RADIANT-2) study was conducted to assess the efficacy of octreotide long-acting repeatable (LAR) on progression-free survival (PFS) and overall survival (OS) estimated using the Kaplan-Meier method. Out of 213 patients randomized to placebo plus octreotide LAR in RADIANT-2, 196 patients with foregut, midgut, or hindgut NET were considered for present analysis. Of these, 41 patients were SSA-treatment naïve and 155 had received SSA therapy before study entry. For SSA-naïve patients, median PFS by adjudicated central review was 13.6 (95% CI 8.2-22.7) months. For SSA-naïve patients with midgut NET (n=24), median PFS was 22.2 (95% CI 8.3-29.5) months. For patients who had received SSA previously, the median PFS was 11.1 (95% CI 8.4-14.3) months. Among the SSA-pretreated patients who had midgut NET (n=119), the median PFS was 12.0 (95% CI 8.4-19.3) months. Median OS was 35.8 (95% CI 32.5-48.9) months for patients in the placebo plus octreotide LAR arm; 50.6 (36.4 - not reached) months for SSA-naïve patients and 33.5 (95% CI 27.5-44.7) months for those who had received prior SSA. This post hoc analysis of the placebo arm of the large phase 3 RADIANT-2 study provides data on PFS and OS among patients with progressive NET treated with octreotide therapy.

SUBMITTER: Strosberg JR

PROVIDER: S-EPMC4609826 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Efficacy of octreotide long-acting repeatable in neuroendocrine tumors: RADIANT-2 placebo arm post hoc analysis.

Strosberg Jonathan R JR Yao James C JC Bajetta Emilio E Aout Mounir M Bakker Bert B Hainsworth John D JD Ruszniewski Philippe B PB Van Cutsem Eric E Öberg Kjell K Pavel Marianne E ME

Endocrine-related cancer 20150915 6

Somatostatin analogues (SSA) have demonstrated antiproliferative activity in addition to efficacy for carcinoid symptom control in functional neuroendocrine tumors (NET). A post hoc analysis of the placebo arm of the RAD001 In Advanced Neuroendocrine Tumors-2 (RADIANT-2) study was conducted to assess the efficacy of octreotide long-acting repeatable (LAR) on progression-free survival (PFS) and overall survival (OS) estimated using the Kaplan-Meier method. Out of 213 patients randomized to placeb ...[more]

PMID: 26373569

Similar Datasets

Project description:BackgroundIn the phase 3 RADIANT-2 study, everolimus plus octreotide long-acting repeatable (LAR) showed improvement of 5.1 months in median progression-free survival versus placebo plus octreotide LAR among patients with advanced neuroendocrine tumors associated with carcinoid syndrome. The progression-free survival P-value was marginally above the prespecified threshold for statistical significance. Here, we report final overall survival (OS) and key safety update from RADIANT-2.Patients and methodsThe RADIANT-2 trial compared everolimus (10 mg/day, orally; n = 216) versus placebo (n = 213), both in conjunction with octreotide LAR (30 mg, intramuscularly, every 28 days). Patients, unblinded at the time of progression or after end of double-blind core phase following primary analysis, were offered open-label everolimus with octreotide LAR (open-label phase). In the open-label phase, patients had similar safety and efficacy assessments as those in the core phase. For OS, hazard ratios (HRs) with 95% CIs using unadjusted Cox model and a Cox model adjusted for prespecified baseline covariates were calculated.ResultsA total of 170 patients received open-label everolimus (143 crossed over from the placebo arm; 27 in the everolimus arm continued to receive the same treatment after unblinding). The median OS (95% CI) after 271 events was 29.2 months (23.8-35.9) for the everolimus arm and 35.2 months (30.0-44.7) for the placebo arm (HR, 1.17; 95% CI, 0.92-1.49). HR adjusted for baseline covariates was 1.08 (95% CI, 0.84-1.38). The most frequent drug-related grade 3 or 4 AEs reported during the open-label phase were diarrhea (5.3%), fatigue (4.7%), and stomatitis (4.1%). Deaths related to pulmonary or cardiac failure were observed more frequently in the everolimus arm.ConclusionNo significant difference in OS was observed for the everolimus plus octreotide LAR and placebo plus octreotide LAR arms of the RADIANT-2 study, even after adjusting for imbalances in the baseline covariates.Clinical trial numberNCT00412061, www.clinicaltrials.gov.

Project description:Lessons learnedRate of progression-free survival at a particular point in time, i.e., a landmark analysis, is a difficult endpoint for a heterogenous malignancy such as neuroendocrine cancer.Landmark analyses can also be complicated by evolution in the standard of care during the conduct of a clinical trial.Improvements in biomarker development would be useful in developing future clinical trials in NET to better tailor individualized therapies and assess for possible efficacy endpoints.BackgroundNeuroendocrine tumors (NETs) are rare malignancies of the gastrointestinal (GI) tract that are highly vascularized and overexpress vascular-endothelial growth factor (VEGF). Sunitinib has demonstrated efficacy in the pancreatic subset of NET. This study explored the activity of another oral VEGF inhibitor, AMG 706 or motesanib, a multikinase inhibitor that targets receptor tyrosine kinases, including VEGFR1, VEGFR2, VEGFR3, KIT, RET, and PDGFR (IC50s = 2, 3, 6, 8, 59, and 84 nM, respectively).MethodsThis was a single-arm, first-line, phase II study run through the Eastern Cooperative Oncology Group. Patients with low-grade NET (as defined by central confirmation of Ki-67 of 0%-2%) were administered a flat dose of 125 mg per day orally combined with octreotide long acting-repeatable (LAR) for patients who had been on a stable dose. The primary objective was to determine the 4-month progression-free survival (PFS).ResultsForty-four patients were evaluated per protocol. The 4-month PFS was 78.5%. The partial response rate was 13.6% (6/44), stable disease was 54.5% (24/44), 9.1% (4/44) had progressive disease, and 10/44 were not evaluable for response. Common toxicities included fatigue, hypertension, nausea, and headache, and most were grade 1-2. Median PFS was 8.7 months, and overall survival was 27.5 months.ConclusionMotesanib (AMG 706) demonstrated a 4-month PFS that met the per-protocol definition of efficacy. Fatigue and hypertension were the most common toxicities, and few grade 3-4 toxicities were encountered. The progression-free survival of 8.7 months in all NETs merits further study.

Project description:The management of neuroendocrine tumors (NETs) is very variable, depending on many specific aspects, such as the type of tumor, spread and patient general health. Several advances have been made with the newly developed somatostatin analogues to cure this type of malignancies. Somatostain analogues such as octreotide have been used in clinic to treat patients with neuroendocrine tumors (NETs). However, the molecular mechanism leading either to successful therapy or acquired resistance to the analogues is still to large extent unclear. Patients develop drugs resistance during a long term treatment. Therefore, to identify the pivotal regulatory genes involved in the development of drug resistance is an actual challenge. We studied five human neuroendocrine tumor cell lines, CNDT2.5, KRJ1, QGP-1, NCI H720 and NCI H727. We also investigated a long-term treated CNDT2.5 by using octreotide. We performed gene expression profiling in all the human neuroendocrine cell lines. Keywords: Gene Expression profiling, treatment comparison We investigated 5 human neuroendocrine cell lines, CNDT2.5 and KRJ1, established from ileum NETs, QGP1 by a pancreatic NET, NCI H720 and NCI H727 from bronchopulmonary NETs. CNDT2.5 cell were constantly treated with 1M-BM-5M octreotide for 10 and 16 months. We isolated total RNA (Ambion, PARISM-bM-^DM-" Kit) from 5 WT cell lines and CNDT2.5 treated with octreotide (Santostatin, Novartis). Total RNA was hybridized onto the Affymetrix Human Gene 1.0 ST Array by Affymetrix Uppsala Platform, UU. SE (Uppsala, Sweden). We first wanted to verify whether the different cell lines may become reliable models to study neuroendocrine signaling pathways. The main objective of this project aimed at understanding the mechanisms by which octrotide (Sandostatin, Novartis) alter cellular growth and differentiation of CNDT2.5 cells. We therefore focused on intermediate (10 months) and long stimulation (16 months) events triggered by sandostatin, which lead variation of CNDT.2.5 cells gene expression to identify potential pivotal genes involved in the development of drug resistance in neuroendocrine cells.

Dataset Information

Efficacy of octreotide long-acting repeatable in neuroendocrine tumors: RADIANT-2 placebo arm post hoc analysis.

Publications

Efficacy of octreotide long-acting repeatable in neuroendocrine tumors: RADIANT-2 placebo arm post hoc analysis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure