title: Lenvatinib versus placebo in radioiodine-refractory thyroid cancer.
abstract: BACKGROUND
  Lenvatinib, an oral inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, fibroblast growth factor receptors 1 through 4, platelet-derived growth factor receptor α, RET, and KIT, showed clinical activity in a phase 2 study involving patients with differentiated thyroid cancer that was refractory to radioiodine (iodine-131).
  
  
  METHODS
  In our phase 3, randomized, double-blind, multicenter study involving patients with progressive thyroid cancer that was refractory to iodine-131, we randomly assigned 261 patients to receive lenvatinib (at a daily dose of 24 mg per day in 28-day cycles) and 131 patients to receive placebo. At the time of disease progression, patients in the placebo group could receive open-label lenvatinib. The primary end point was progression-free survival. Secondary end points included the response rate, overall survival, and safety.
  
  
  RESULTS
  The median progression-free survival was 18.3 months in the lenvatinib group and 3.6 months in the placebo group (hazard ratio for progression or death, 0.21; 99% confidence interval, 0.14 to 0.31; P<0.001). A progression-free survival benefit associated with lenvatinib was observed in all prespecified subgroups. The response rate was 64.8% in the lenvatinib group (4 complete responses and 165 partial responses) and 1.5% in the placebo group (P<0.001). The median overall survival was not reached in either group. Treatment-related adverse effects of any grade, which occurred in more than 40% of patients in the lenvatinib group, were hypertension (in 67.8% of the patients), diarrhea (in 59.4%), fatigue or asthenia (in 59.0%), decreased appetite (in 50.2%), decreased weight (in 46.4%), and nausea (in 41.0%). Discontinuations of the study drug because of adverse effects occurred in 37 patients who received lenvatinib (14.2%) and 3 patients who received placebo (2.3%). In the lenvatinib group, 6 of 20 deaths that occurred during the treatment period were considered to be drug-related.
  
  
  CONCLUSIONS
  Lenvatinib, as compared with placebo, was associated with significant improvements in progression-free survival and the response rate among patients with iodine-131-refractory thyroid cancer. Patients who received lenvatinib had more adverse effects. (Funded by Eisai; SELECT ClinicalTrials.gov number, NCT01321554.).
authors: The authors' affiliations are listed in the Appendix.
authors: Martin
authors: M
authors: Schlumberger
authors: Makoto
authors: M
authors: Tahara
authors: Lori J
authors: LJ
authors: Wirth
authors: Bruce
authors: B
authors: Robinson
authors: Marcia S
authors: MS
authors: Brose
authors: Rossella
authors: R
authors: Elisei
authors: Mouhammed Amir
authors: MA
authors: Habra
authors: Kate
authors: K
authors: Newbold
authors: Manisha H
authors: MH
authors: Shah
authors: Ana O
authors: AO
authors: Hoff
authors: Andrew G
authors: AG
authors: Gianoukakis
authors: Naomi
authors: N
authors: Kiyota
authors: Matthew H
authors: MH
authors: Taylor
authors: Sung-Bae
authors: SB
authors: Kim
authors: Monika K
authors: MK
authors: Krzyzanowska
authors: Corina E
authors: CE
authors: Dutcus
authors: Begoña
authors: B
authors: de las Heras
authors: Junming
authors: J
authors: Zhu
authors: Steven I
authors: SI
authors: Sherman
mesh_terms: D000328:Adult; D000368:Aged; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007457:Iodine Radioisotopes / Q000627:therapeutic use; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D010671:Phenylurea Compounds / Q000009:adverse effects / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D011804:Quinolines / Q000009:adverse effects / Q000627:therapeutic use*; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy
chemical_list: D007457:Iodine Radioisotopes; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011804:Quinolines; C531958:lenvatinib