A Phase II Trial of the Multitargeted Tyrosine Kinase Inhibitor Lenvatinib (E7080) in Advanced Medullary Thyroid Cancer

Clin Cancer Res. 2016 Jan 1;22(1):44-53. doi: 10.1158/1078-0432.CCR-15-1127. Epub 2015 Aug 26.

Abstract

Purpose: Positive results of phase I studies evaluating lenvatinib in solid tumors, including thyroid cancer, prompted a phase II trial in advanced medullary thyroid carcinoma (MTC).

Experimental design: Fifty-nine patients with unresectable progressive MTC per Response Evaluation Criteria In Solid Tumors (RECIST) v1.0 within the prior 12 months received lenvatinib (24-mg daily, 28-day cycles) until disease progression, unmanageable toxicity, withdrawal, or death. Prior anti-VEGFR therapy was permitted. The primary endpoint was objective response rate (ORR) by RECIST v1.0 and independent imaging review.

Results: Lenvatinib ORR was 36% [95% confidence interval (CI), 24%-49%]; all partial responses. ORR was comparable between patients with (35%) or without (36%) prior anti-VEGFR therapy. Disease control rate (DCR) was 80% (95% CI, 67%-89%); 44% had stable disease. Among responders, median time to response (TTR) was 3.5 months (95% CI, 1.9-3.7). Median progression-free survival (PFS) was 9.0 months (95% CI, 7.0-not evaluable). Common toxicity criteria grade 3/4 treatment-emergent adverse events included diarrhea (14%), hypertension (7%), decreased appetite (7%), fatigue, dysphagia, and increased alanine aminotransferase levels (5% each). Ret proto-oncogene status did not correlate with outcomes. Low baseline levels of angiopoietin-2, hepatocyte growth factor, and IL8 were associated with tumor reduction and prolonged PFS. High baseline levels of VEGF, soluble VEGFR3, and platelet-derived growth factor BB, and low baseline levels of soluble Tie-2, were associated with tumor reduction.

Conclusions: Lenvatinib had a high ORR, high DCR, and a short TTR in patients with documented progressive MTC. Toxicities were managed with dose modifications and medications.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • Biomarkers
  • Carcinoma, Neuroendocrine / blood
  • Carcinoma, Neuroendocrine / drug therapy*
  • Carcinoma, Neuroendocrine / pathology*
  • Disease Progression
  • Female
  • Humans
  • Male
  • Middle Aged
  • Molecular Targeted Therapy*
  • Neoplasm Metastasis
  • Neoplasm Staging
  • Phenylurea Compounds / pharmacology
  • Phenylurea Compounds / therapeutic use*
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use*
  • Proto-Oncogene Mas
  • Quinolines / pharmacology
  • Quinolines / therapeutic use*
  • Retreatment
  • Thyroid Neoplasms / blood
  • Thyroid Neoplasms / drug therapy*
  • Thyroid Neoplasms / pathology*
  • Treatment Outcome
  • Young Adult

Substances

  • Antineoplastic Agents
  • Biomarkers
  • MAS1 protein, human
  • Phenylurea Compounds
  • Protein Kinase Inhibitors
  • Proto-Oncogene Mas
  • Quinolines
  • lenvatinib

Supplementary concepts

  • Thyroid cancer, medullary