Impact of dose interruption on the efficacy of lenvatinib in a phase 3 study in patients with radioiodine- refractory differentiated thyroid cancer

Background: In the phase 3 Study of (E7080) Lenvatinib in Differentiated Cancer of the Thyroid (SELECT), lenvatinib significantly improved efficacy outcomes versus placebo in patients with radioiodine-refractory differentiated thyroid cancer (RR-DTC). Lenvatinib-treated patients had more adverse events (AEs), which were generally managed with dose modifications, including dose interruption. This exploratory post hoc analysis investigated the impact of dose interruption on lenvatinib efficacy. Methods: Dose modifications were required for grade 3 or intolerable grade 2 AEs in SELECT. Lenvatinib-treated patients were dichotomised based on the duration of dose interruption relative to total treatment duration: shorter dose interruption (<10% of total treatment duration) and longer dose interruption (>= 10%). Results: At the time of primary data cut-off (November 15, 2013; median follow-up, 17.1 months), the median progression-free survival (PFS) for the shorter dose-interruption group had not yet been reached, whereas median PFS for the longer dose-interruption group was 12.8 months (95% confidence interval [CI], 9.3-16.5). Compared with placebo, the hazard ratios for PFS in the shorter and longer dose-interruption groups were 0.14 (95% CI, 0.09-0.20) and 0.31 (95% CI, 0.22-0.43), respectively. In a multivariate model, dose interruption was significantly associated with lenvatinib efficacy, even after adjustment for patient characteristics. Conclusions: Lenvatinib improved efficacy outcomes versus placebo in patients with RR-DTC, regardless of the duration of dose interruption; however, those with shorter dose interruptions had a greater magnitude of benefit versus those with longer interruptions. This analysis highlights the importance of timely management of lenvatinib toxicities to minimise dose interruptions and maximise lenvatinib efficacy in patients with RR-DTC. ClinicalTrials.gov number: NCT01321554 (C) 2018 The Author(s). Published by Elsevier Ltd.