The efficacy of lower doses of everolimus in patients with advanced neuroendocrine tumors

BackgroundEverolimus 10mg daily is approved for patients (pts) with advanced G1/G2 neuroendocrine tumors (NET) but it leads to significant toxicity. In phase I trials, everolimus 5mg daily efficiently inhibited mTOR and offered better tolerance. Our objective was to evaluate the efficacy of everolimus with lower doses.MethodsRetrospective multicenter study that compared the time to treatment failure (TTF) in NET pts who received a mean daily dose of 6.1 – 10mg (higher dose [HD]) or 6mg or less (lower dose [LD]) of everolimus. The primary endpoint was TTF - from C1D1 until tumor progression, treatment change for toxicity/intolerance or death. TTF and overall survival (OS) were compared between the dose groups. Dose reduction was decided by the treating physician, and it could be upfront (for frailty, older age) or during treatment due to toxicities. Cox regression multivariable analyses for TTF and OS were performed to adjust for prognostic variables (age at C1D1 of everolimus), NET grade [3 v 1 and 2], line of everolimus (3 or more v 1 or 2) and everolimus dose [LD v HD]).ResultsFrom Aug/2011 to Sep/2023, 92 pts were included: 74 (80%) in HD and 18 (20%) in LD group. The mean daily doses in HD and LD groups were: 9.6mg (range: 6.8 – 10) and 5.3mg (4.7 – 6), respectively. In the HD, 24% of pts required dose reductions and 23% had permanent discontinuation. At a median follow up of 4.2 years, median TTF was 9.2 months (IQR: 3.7 – 32) for pts on HD and 7.2 months (IQR: 3.9 – 27) for those on LD (log rank p = 0.85). TTF was also not significantly different according to LD v HD (HR: 1.24, 95% CI: 0.68 - 2.25; p = 0.47), after adjusting for age at C1D1 of everolimus (HR: 1.02; 95% CI: 1.01 - 1.04; p = 0.002), NET grade (HR: 1.27, 95% CI: 0.95 - 1.71; p = 0.11), or treatment line (HR: 1.55, 95% CI: 0.92 – 2.62; p = 0.09). In the LD v HD groups, median OS was 3.6 years (IQR: 1.4 – 6) and 6.5 years (IQR: 1.37 - 9.98; log rank p = 0.57), respectively. In the Cox model, age (HR: 1.03, 95% CI: 1.01 - 1.05; p = 0.007), NET grade (HR: 1.68, 95% CI: 1.15 – 2.47; p = 0.008), and line of everolimus (HR: 2.1; 95% CI: 1.05 - 4.13; p =0.036), but not everolimus mean daily dose (HR: 1.32, 95% CI: 0.56 – 3.13; p = 0.53), were independently associated with OS.ConclusionsEverolimus 5 to 6mg/day leads to similar efficacy than higher doses but offers less toxicity and cost.Legal entity responsible for the studyR. Riechelmann.FundingHas not received any funding.DisclosureAll authors have declared no conflicts of interest.