Marianne E Pavel1, John D Hainsworth2, Eric Baudin3, Marc Peeters4, Dieter Hörsch5, Robert E Winkler6, Judith Klimovsky6, David Lebwohl6, Valentine Jehl7, Edward M Wolin8, Kjell Öberg9, Eric Van Cutsem10, James C Yao11. 1. Charité-Universitätsmedizin Berlin/Campus Virchow Klinikum, Berlin, Germany. 2. Sarah Cannon Research Institute, Nashville, TN, USA. 3. Oncologie Endocrinienne et Médecine Nucléaire, Institut Gustave Roussy, Villejuif, France. 4. Department of Oncology, Antwerp University Hospital, Edegem, Belgium. 5. Klinik für Innere Medizin, Gastroenterologie und Endokrinologie, Zentrum für Neuroendokrine Tumore, Zentralklinik Bad Berka GmbH, Bad Berka, Germany; Ochsner Kenner Medical Center, Kenner, LA, USA. 6. Novartis Oncology, Florham Park, NJ, USA. 7. Novartis Pharma AG, Basel, Switzerland. 8. Cedars Sinai Medical Center, Los Angeles, CA, USA. 9. Department of Endocrine Oncology, University Hospital, Uppsala, Sweden. 10. University Hospital Gasthuisberg, Leuven, Belgium. 11. University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: jyao@mdanderson.org.
Abstract
BACKGROUND:Everolimus, an oral inhibitor of the mammalian target of rapamycin (mTOR), has shown antitumour activity in patients with advanced pancreatic neuroendocrine tumours. We aimed to assess the combination of everolimus plus octreotide long-acting repeatable (LAR) in patients with low-grade or intermediate-grade neuroendocrine tumours (carcinoid). METHODS: We did a randomised, double-blind, placebo-controlled, phase 3 study comparing 10 mg per day oral everolimus with placebo, both in conjunction with 30 mg intramuscular octreotide LAR every 28 days. Randomisation was by interactive voice response systems. Participants were aged 18 years or older, with low-grade or intermediate-grade advanced (unresectable locally advanced or distant metastatic) neuroendocrine tumours, and disease progression established by radiological assessment within the past 12 months. Our primary endpoint was progression-free survival. Adjusted for two interim analyses, the prespecified boundary at final analysis was p≤0·0246. This study is registered at ClinicalTrials.gov, number NCT00412061. FINDINGS:429 individuals were randomly assigned to study groups; 357 participants discontinued study treatment and one was lost to follow-up. Median progression-free survival by central review was 16·4 (95% CI 13·7-21·2) months in the everolimus plus octreotide LAR group and 11·3 (8·4-14·6) months in the placebo plus octreotide LAR group (hazard ratio 0·77, 95% CI 0·59-1·00; one-sided log-rank test p=0·026). Drug-related adverse events (everolimus plus octreotide LAR vs placebo plus octreotide LAR) were mostly grade 1 or 2, and adverse events of all grades included stomatitis (62%vs 14%), rash (37%vs 12%), fatigue (31%vs 23%), and diarrhoea (27%vs 16%). INTERPRETATION:Everolimus plus octreotide LAR, compared with placebo plus octreotide LAR, improved progression-free survival in patients with advanced neuroendocrine tumours associated with carcinoid syndrome. FUNDING: Novartis Pharmaceuticals.
RCT Entities:
BACKGROUND:Everolimus, an oral inhibitor of the mammalian target of rapamycin (mTOR), has shown antitumour activity in patients with advanced pancreatic neuroendocrine tumours. We aimed to assess the combination of everolimus plus octreotide long-acting repeatable (LAR) in patients with low-grade or intermediate-grade neuroendocrine tumours (carcinoid). METHODS: We did a randomised, double-blind, placebo-controlled, phase 3 study comparing 10 mg per day oral everolimus with placebo, both in conjunction with 30 mg intramuscular octreotide LAR every 28 days. Randomisation was by interactive voice response systems. Participants were aged 18 years or older, with low-grade or intermediate-grade advanced (unresectable locally advanced or distant metastatic) neuroendocrine tumours, and disease progression established by radiological assessment within the past 12 months. Our primary endpoint was progression-free survival. Adjusted for two interim analyses, the prespecified boundary at final analysis was p≤0·0246. This study is registered at ClinicalTrials.gov, number NCT00412061. FINDINGS: 429 individuals were randomly assigned to study groups; 357 participants discontinued study treatment and one was lost to follow-up. Median progression-free survival by central review was 16·4 (95% CI 13·7-21·2) months in the everolimus plus octreotide LAR group and 11·3 (8·4-14·6) months in the placebo plus octreotide LAR group (hazard ratio 0·77, 95% CI 0·59-1·00; one-sided log-rank test p=0·026). Drug-related adverse events (everolimus plus octreotide LAR vs placebo plus octreotide LAR) were mostly grade 1 or 2, and adverse events of all grades included stomatitis (62%vs 14%), rash (37%vs 12%), fatigue (31%vs 23%), and diarrhoea (27%vs 16%). INTERPRETATION:Everolimus plus octreotide LAR, compared with placebo plus octreotide LAR, improved progression-free survival in patients with advanced neuroendocrine tumours associated with carcinoid syndrome. FUNDING: Novartis Pharmaceuticals.
Authors: Robert A Ramirez; Aman Chauhan; Juan Gimenez; Katharine E H Thomas; Ioni Kokodis; Brianne A Voros Journal: Rev Endocr Metab Disord Date: 2017-12 Impact factor: 6.514