The Efficacy of Lower Doses of Everolimus in Patients with Advanced Neuroendocrine Tumors

Everolimus 10 mg daily is approved to treat patients with advanced grade 1/2 neuroendocrine tumors (NET), although it may lead to significant toxicity. Grade 3 or higher drug-related adverse events and drug discontinuation occur in approximately one-fourth of the cases. However, phase I trials demonstrated that doses from 5 mg daily efficiently inhibit NET cell signaling. This multicenter retrospective study compared the time to treatment failure (TTF) in patients with NET who received a mean daily dose of 7 – 10mg (higher dose [HD]) or ≤ 6 mg (lower dose [LD]) of everolimus. Ninety-two patients were included: 74 (80%) in the HD group and 18 (20%) in the LD group. At a median follow-up of 4.2 years, the median time to treatment failure (TTF) was 9.2 months for HD and 7.2 months for LD (p = 0.85). TTF did not significantly differ between LD and HD (HR: 1.24, 95% CI: 0.68 - 2.25; p = 0.47), even after adjusting for age at treatment initiation, NET grade, or treatment line. Everolimus doses from 5 to 6 mg/day seem to be equally effective as higher doses, but lower doses are potentially associated with less toxicity and costs. These findings support validation through a randomized clinical trial.