Author(s): Schlumberger M, Tahara M, Wirth LJ, Robinson B, Brose MS,
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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.).
This article was published in N Engl J Med
and referenced in Journal of Cancer Science & Therapy