title: Effect of everolimus on the pharmacokinetics of octreotide long-acting repeatable in patients with advanced neuroendocrine tumors: An analysis of the randomized phase III RADIANT-2 trial.
abstract: In the RADIANT-2 trial, addition of everolimus to octreotide long-acting repeatable (LAR) exhibited a clinically meaningful 5.1-month improvement in progression-free survival (PFS) in patients with advanced functional neuroendocrine tumors. In this study, we characterized the effects of everolimus co-administration on octreotide LAR pharmacokinetics and its relationship with efficacy and safety. At least one evaluable blood everolimus and plasma octreotide predose minimum concentration (Cmin) was available for 182 patients and 294 patients, respectively. Concomitant everolimus administration increased octreotide Cminwith a geometric mean ratio (everolimus/placebo) of 1.47 (90% confidence interval [CI] = 1.32-1.64). Risk for progression was consistently reduced when everolimus Cminwas increased twofold, regardless of octreotide exposure (hazard ratio [HR] = 0.74; 95% CI = 0.46-1.18; HR = 0.54; 95% CI = 0.32-0.92 for 6 ng/mL and 4 ng/mL octreotide, respectively). Risk for pulmonary or metabolic events was associated with increased everolimus Cmin. Co-administration of everolimus plus octreotide LAR increased octreotide Cmin, which did not impact efficacy.
authors.affiliation: Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Campus Virchow Klinikum, Berlin, Germany.
authors.forename: M E
authors.initials: ME
authors.lastname: Pavel
authors.affiliation: Texas Oncology Charles A. Sammons Cancer Center at Baylor, Dallas, Texas, USA.
authors.forename: C
authors.initials: C
authors.lastname: Becerra
authors.affiliation: Novartis Pharmaceuticals Corporation, Basel, Switzerland.
authors.forename: K
authors.initials: K
authors.lastname: Grosch
authors.affiliation: Novartis Pharmaceuticals Corporation, Florham Park, New Jersey, USA.
authors.forename: W
authors.initials: W
authors.lastname: Cheung
authors.affiliation: Novartis Pharmaceuticals Corporation, Basel, Switzerland.
authors.forename: J
authors.initials: J
authors.lastname: Hasskarl
authors.affiliation: University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: J C
authors.initials: JC
authors.lastname: Yao
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology*; D017326:Clinical Trials, Phase III as Topic / Q000379:methods*; D003692:Delayed-Action Preparations; D018450:Disease Progression; D018572:Disease-Free Survival; D004311:Double-Blind Method; D004347:Drug Interactions; D023381:Endpoint Determination; D000068338:Everolimus / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008171:Lung Diseases / Q000139:chemically induced / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D018358:Neuroendocrine Tumors / Q000188:drug therapy* / Q000378:metabolism*; D015282:Octreotide / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D011446:Prospective Studies; D012306:Risk; D012449:Safety
chemical_list: D000970:Antineoplastic Agents; D003692:Delayed-Action Preparations; D000068338:Everolimus; D015282:Octreotide