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Phase II Study of Everolimus and Octreotide LAR in Patients with Nonfunctioning Gastrointestinal Neuroendocrine Tumors: The GETNE1003_EVERLAR Study.

ABSTRACT: BACKGROUND:Antitumor activity of the combination of somatostatin analogues (SSAs) and the mammalian target of rapamycin (mTOR) inhibitor everolimus in patients with neuroendocrine tumors (NETs) has been reported but not confirmed in prospective trials. MATERIALS AND METHODS:This prospective, multicenter, single-arm phase II EVERLAR study evaluated everolimus 10 mg/day and the SSA octreotide 30 mg every 28 days in patients with advanced nonfunctioning well-differentiated gastrointestinal NETs (GI-NETs) that progressed in the last 12 months (ClinicalTrials.gov NCT01567488). Prior treatment with SSAs and any systemic or locoregional therapy was allowed except for mTOR inhibitors. Patients continued treatment until disease progression or unacceptable adverse events (AEs). The primary endpoint was progression-free survival (PFS) at 12 months; secondary endpoints included early biochemical response, objective response rate (ORR) by RECIST v1.0, overall survival (OS), AEs, activation of mTOR pathway (insulin-like growth factor 1 receptor [IGF1R] and phosphoS6 [pS6] expression). RESULTS:Forty-three patients were included in the intent-to-treat analyses. After 12 months of treatment, 62.3% (95% confidence interval [CI] 48%-77%) of patients had not progressed or died. The 24-month PFS rate was 43.6% (95% CI 29%-58%). The confirmed ORR was 2.3%, and stable disease was 58.1%. Median OS was not reached after 24 months of median follow-up. Dose reductions and temporary interruptions due to AEs were required in 14 (33%) and 33 (77%) patients, respectively. The most frequent AEs were diarrhea, asthenia, mucositis, rash, and hyperglycemia. No correlation was observed between IGFR1 and pS6 expression and PFS/OS. CONCLUSION:The everolimus-octreotide combination provided clinically relevant efficacy in nonfunctioning GI-NETs, similar to the results of RADIANT-2 in functioning setting. IMPLICATIONS FOR PRACTICE:The EVERLAR study reports prospective data of somatostatin analogue in combination with everolimus in nonfunctioning gastrointestinal neuroendocrine tumors suggesting meaningful activity and favorable toxicity profile that supports drug combination in this setting.

SUBMITTER: Capdevila J

PROVIDER: S-EPMC6324631 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Phase II Study of Everolimus and Octreotide LAR in Patients with Nonfunctioning Gastrointestinal Neuroendocrine Tumors: The GETNE1003_EVERLAR Study.

Capdevila Jaume J Teulé Alexandre A Barriuso Jorge J Castellano Daniel D Lopez Carlos C Manzano Jose Luis JL Alonso Vicente V García-Carbonero Rocío R Dotor Emma E Matos Ignacio I Custodio Ana A Casanovas Oriol O Salazar Ramon R

The oncologist 20180523 1

<h4>Background</h4>Antitumor activity of the combination of somatostatin analogues (SSAs) and the mammalian target of rapamycin (mTOR) inhibitor everolimus in patients with neuroendocrine tumors (NETs) has been reported but not confirmed in prospective trials.<h4>Materials and methods</h4>This prospective, multicenter, single-arm phase II EVERLAR study evaluated everolimus 10 mg/day and the SSA octreotide 30 mg every 28 days in patients with advanced nonfunctioning well-differentiated gastrointe ...[more]

PMID: 29794066

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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:BackgroundSeveral studies have demonstrated the antitumor activity of first-generation somatostatin analogs (SSAs), primarily targeting somatostatin receptor (sstr) subtypes 2 and 5, in neuroendocrine tumors (NET). Pasireotide, a second-generation SSA, targets multiple sstr subtypes. We compared the efficacy and safety of pasireotide plus everolimus to everolimus alone in patients with advanced, well-differentiated, progressive pancreatic NET.Patients and methodsPatients were randomized 1 : 1 to receive a combination of everolimus (10 mg/day, orally) and pasireotide long-acting release (60 mg/28 days, intramuscularly) or everolimus alone (10 mg/day, orally); stratified by prior SSA use, and baseline serum chromogranin A and neuron-specific enolase. The primary end point was progression-free survival (PFS). Secondary end points included overall survival, objective response rate, disease control rate, and safety. Biomarker response was evaluated in an exploratory analysis.ResultsOf 160 patients enrolled, 79 were randomized to the combination arm and 81 to the everolimus arm. Baseline demographics and disease characteristics were similar between the treatment arms. No significant difference was observed in PFS: 16.8 months in combination arm versus 16.6 months in everolimus arm (hazard ratio, 0.99; 95% confidence interval, 0.64-1.54). Partial responses were observed in 20.3% versus 6.2% of patients in combination arm versus everolimus arm; however, overall disease control rate was similar (77.2% versus 82.7%, respectively). No significant improvement was observed in median overall survival. Adverse events were consistent with the known safety profile of both the drugs; grade 3 or 4 fasting hyperglycemia was seen in 37% versus 11% of patients, respectively.ConclusionsThe addition of pasireotide to everolimus was not associated with the improvement in PFS compared with everolimus alone in this study. Further studies to delineate mechanisms by which SSAs slow tumor growth in NET are warranted.

Dataset Information

Phase II Study of Everolimus and Octreotide LAR in Patients with Nonfunctioning Gastrointestinal Neuroendocrine Tumors: The GETNE1003_EVERLAR Study.

Publications

Phase II Study of Everolimus and Octreotide LAR in Patients with Nonfunctioning Gastrointestinal Neuroendocrine Tumors: The GETNE1003_EVERLAR Study.

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