title: A Phase II Trial of the Multitargeted Tyrosine Kinase Inhibitor Lenvatinib (E7080) in Advanced Medullary Thyroid Cancer.
abstract: OBJECTIVE
  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).
  
  
  METHODS
  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.
authors: Department of Nuclear Medicine and Endocrine Oncology, Institut Gustave-Roussy and University Paris-Sud, Villejuif, France. martin.schlumberger@gustaveroussy.fr.
authors: Martin
authors: M
authors: Schlumberger
authors: Department of Nuclear Medicine and Endocrine Oncology, Centrum Onkologii Instytut im. M. Sklodowskiei-Curie, Gliwice, Poland.
authors: Barbara
authors: B
authors: Jarzab
authors: Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Maria E
authors: ME
authors: Cabanillas
authors: Department of Endocrinology, Royal North Shore Hospital, Sydney, Australia.
authors: Bruce
authors: B
authors: Robinson
authors: Department of Medical, Surgical and Neurological Sciences, Azienda Ospedaliera Universitaria Senese, Siena, Italy.
authors: Furio
authors: F
authors: Pacini
authors: Division of Endocrinology and Metabolism, Johns Hopkins Medical Institute, Baltimore, Maryland.
authors: Douglas W
authors: DW
authors: Ball
authors: Department of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
authors: Judith
authors: J
authors: McCaffrey
authors: NIHR Royal Marsden Hospital and Institute of Cancer Research BRC, London, UK.
authors: Kate
authors: K
authors: Newbold
authors: Cancer Care Services, The Royal Brisbane and Women's Hospital, Herston, Australia.
authors: Roger
authors: R
authors: Allison
authors: Division of Clinical Research, Seattle Cancer Care Alliance, Seattle, Washington.
authors: Renato G
authors: RG
authors: Martins
authors: Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors: Lisa F
authors: LF
authors: Licitra
authors: Department of Medical Oncology, The Ohio State University School of Medicine, Columbus, Ohio.
authors: Manisha H
authors: MH
authors: Shah
authors: Department of Otolaryngology-Head and Neck Surgery, University of Arkansas, Little Rock, Arkansas.
authors: Donald
authors: D
authors: Bodenner
authors: Endocrine Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
authors: Rossella
authors: R
authors: Elisei
authors: Department of Medicine, University of Minnesota, Minneapolis, Minnesota.
authors: Lynn
authors: L
authors: Burmeister
authors: Eisai, Andover, Massachusetts.
authors: Yasuhiro
authors: Y
authors: Funahashi
authors: Eisai Inc., Woodcliff Lake, New Jersey.
authors: Min
authors: M
authors: Ren
authors: Eisai Inc., Woodcliff Lake, New Jersey.
authors: James P
authors: JP
authors: O'Brien
authors: Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Steven I
authors: SI
authors: Sherman
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D015415:Biomarkers; D018278:Carcinoma, Neuroendocrine / Q000097:blood / Q000188:drug therapy* / Q000473:pathology*; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D010671:Phenylurea Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000090063:Proto-Oncogene Mas; D011804:Quinolines / Q000494:pharmacology / Q000627:therapeutic use*; D019233:Retreatment; D013964:Thyroid Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; C000715470:MAS1 protein, human; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D000090063:Proto-Oncogene Mas; D011804:Quinolines; C531958:lenvatinib