Abstract
PurposeOnce-daily lenvatinib 24 mg is the approved dose for radioiodine-refractory differentiated thyroid cancer. In a phase 3 trial with lenvatinib, the starting dose of 24 mg was associated with a relatively high incidence of adverse events that required dose reductions. We used an exposure–response model to investigate the risk–benefit of different dosing regimens for lenvatinib.MethodsA population pharmacokinetics/pharmacodynamics modeling analysis was used to simulate the potential benefit of lower starting doses to retain efficacy with improved safety. The seven lenvatinib regimens tested were: 24 mg; and 20 mg, 18 mg, and 14 mg, all with or without up-titration to 24 mg. Exposure–response models for efficacy and safety were created using a 24-week time course.ResultsThe approved dose of lenvatinib at 24 mg, predicted the best efficacy. However, the lenvatinib dosing regimens of 14 mg with up-titration or 18 mg without up-titration potentially provides comparable efficacy (objective response rate at 24 weeks) and a better safety profile.ConclusionsTreatment with lenvatinib at starting doses lower than the approved once-daily 24 mg dose could provide comparable antitumor efficacy and a similar or better safety profile. Based on the results from this modeling and simulation study, a comparator dose of lenvatinib 18 mg without up-titration was selected for evaluation in a clinical trial.
Highlights
Of the various thyroid cancers, advanced differentiated thyroid cancer (DTC) represents a small, but difficult-totreat patient population, when the disease becomes radioiodine refractory (RR) [1]
CV coefficient of variation, Emax maximum effect of lenvatinib on tumor suppression, EC50 lenvatinib average area under the concentration–time curve that results in 50% of Emax, IIV interindividual variability, KG tumor growth rate, SD standard deviation; % RSE percent relative standard error of the estimate = SE/parameter estimate × 100, λ resistance term
B1 baseline odds for experiencing an adverse event leading to dose interruption, B2–B1 baseline odds for experiencing an adverse event leading to dose reduction/withdrawal, Emax maximum effect of lenvatinib, EC50 lenvatinib area under the concentration–time curve that results in 50% of Emax, IIV interindividual variability, RR-DTC radioiodine-refractory differentiated thyroid cancer, SD standard deviation, %RSE percent relative standard error of the estimate = SE/parameter estimate × 100 or observed as early in the time course of treatment, when compared with the approved 24 mg dose (Fig. 3b)
Summary
Of the various thyroid cancers, advanced differentiated thyroid cancer (DTC) represents a small, but difficult-totreat patient population, when the disease becomes radioiodine refractory (RR) [1]. Associated with the development and progression of thyroid cancer has offered a new strategy to these patients [1]. In the phase 3 Study of (E7080) Lenvatinib in Differentiated Cancer of the Thyroid (SELECT) that enrolled patients with RR-DTC, lenvatinib, at a maximum starting dose of 24 mg once daily, significantly prolonged progression-free survival (PFS) vs placebo (median 18.3 vs 3.6 months, respectively; hazard ratio 0.21; 99% confidence interval, 0.14–0.31; P < 0.001) and was associated with a significantly better response rate (64.8% vs 1.5%, respectively) [5].
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
