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

Eur J Cancer. 2019 Jan;106:61-68. doi: 10.1016/j.ejca.2018.10.002. Epub 2018 Nov 22.

Abstract

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.

Keywords: Disease-free survival; Lenvatinib; MeSH terms; Thyroid neoplasms.

Publication types

  • Clinical Trial, Phase III
  • Comparative Study
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / adverse effects
  • Cell Differentiation
  • Disease Progression
  • Disease-Free Survival
  • Double-Blind Method
  • Drug Administration Schedule
  • Female
  • Humans
  • Iodine Radioisotopes / adverse effects
  • Iodine Radioisotopes / therapeutic use*
  • Male
  • Middle Aged
  • Phenylurea Compounds / administration & dosage*
  • Phenylurea Compounds / adverse effects
  • Protein Kinase Inhibitors / administration & dosage*
  • Protein Kinase Inhibitors / adverse effects
  • Quinolines / administration & dosage*
  • Quinolines / adverse effects
  • Radiation Tolerance*
  • Risk Assessment
  • Risk Factors
  • Thyroid Neoplasms / mortality
  • Thyroid Neoplasms / pathology
  • Thyroid Neoplasms / therapy*
  • Time Factors

Substances

  • Antineoplastic Agents
  • Iodine Radioisotopes
  • Phenylurea Compounds
  • Protein Kinase Inhibitors
  • Quinolines
  • lenvatinib

Associated data

  • ClinicalTrials.gov/NCT01321554