Lenvatinib versus Placebo in Radioiodine-Refractory Thyroid Cancer

Schlumberger, Martin M.D.
Tahara, Makoto M.D., Ph.D.
Wirth, Lori J. M.D.
Robinson, Bruce M.D.
Brose, Marcia S. M.D., Ph.D.
Elisei, Rossella M.D.
Habra, Mouhammed Amir M.D.
Newbold, Kate M.D.
Shah, Manisha H. M.D.
Hoff, Ana O. M.D.
Gianoukakis, Andrew G. M.D.
Kiyota, Naomi M.D., Ph.D.
Taylor, Matthew H. M.D.
Kim, Sung-Bae M.D., Ph.D.
Krzyzanowska, Monika K. M.D., M.P.H.
Dutcus, Corina E. M.D.
de las Heras, Begoña M.D.
Zhu, Junming Ph.D.
Sherman, Steven I. M.D.

The authors' affiliations are listed in the Appendix.

Address reprint requests to Dr. Schlumberger at the Department of Nuclear Medicine and Endocrine Oncology, Centre de Référence Tumeurs Réfractaires de la Thyroïde, Institut Gustave Roussy and University Paris-Sud, Villejuif, France, or at [email protected].

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

Presented in part at the 50th Annual Meeting of the American Society of Clinical Oncology, Chicago, May 30–June 3, 2014; and in part at the 12th Annual Scientific Meeting of the Japanese Society of Medical Oncology, Fukuoka City, Japan, July 17–19, 2014.

New England Journal of Medicine 372(7):p 621-630, February 12, 2015. | DOI: 10.1056/NEJMoa1406470

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.)