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

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 predoseminimum concentration (C-min) was available for 182 patients and 294 patients, respectively. Concomitant everolimus administration increased octreotide C-min with a geometricmean ratio (everolimus/placebo) of 1.47 (90% confidence interval [CI] = 1.32-1.64). Risk for progression was consistently reduced when everolimus C-min was 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 ormetabolic events was associated with increased everolimus C-min. Co-administration of everolimus plus octreotide LAR increased octreotide C-min, which did not impact efficacy.