In the original phase III SELECT trial, no overall survival benefit was observed for lenvatinib (Lenvima) vs placebo in progressive radioactive iodine–refractory differentiated thyroid cancer. Overall survival was a secondary endpoint in that trial. However, in an updated analysis of SELECT, which was presented at the 2015 European Cancer Congress, investigators revisited the trial data using a sophisticated modeling computation that unearthed a survival benefit.¹ It is not clear whether this finding will translate to a real clinical benefit for patients.

“We did an updated analysis of overall survival to account for the high percentage of crossover [from placebo to lenvatinib] in SELECT. In this updated overall survival analysis, lenvatinib improved overall survival in iodine-refractory thyroid cancer,” said lead investigator Lori Wirth, MD, of the Department of Medicine, Massachusetts General Hospital, Boston.

Lenvatinib is approved by the U.S. Food and Drug Administration (FDA) for the treatment of radioactive iodine–refractory differentiated thyroid cancer. This type of cancer is a rare, aggressive, difficult-to-treat thyroid cancer with limited treatment options and a poor prognosis.

Original Analysis

SELECT is a multicenter, double-blind, placebo-controlled, phase III trial of 392 patients with radioactive iodine–refractory differentiated thyroid cancer who progressed on up to one prior VEGF (vascular endothelial growth factor) therapy within the past 13 months. They were randomized 2:1 to receive lenvatinib vs placebo and treated until disease progression. Placebo patients could cross over to lenvatinib at disease progression.

In the original analysis of SELECT, a significant progression-free survival benefit was observed for lenvatinib vs placebo: 18.3 months vs 3.3 months with placebo, representing a 79% improvement favoring lenvatinib (P < .001).

Overall survival, a secondary endpoint in the trial, was analyzed in 2013. Median overall survival was not reached in either arm at that time, and the survival data were immature.

At the time of the original analysis, 83% of the placebo arm crossed over to lenvatinib. In the adjusted analysis, 88% had crossed over. To account for the confounding effect of crossover, the investigators used a prespecified rank–preserving structural failure time adjustment, which is a model that calculated the effect of lenvatinib on survival without crossover. Overall survival curves were estimated using the Kaplan-Meier method, and the hazard ratio was estimated by a Cox proportional hazard model fitted to rank-preserving structural failure time–adjusted overall survival data, Dr. Wirth explained.

Updated Findings

The updated analysis found a significant survival effect for lenvatinib: 36% died in the lenvatinib arm vs 42% in the placebo arm. Median overall survival has not yet been reached in the lenvatinib arm vs 19.1 months for placebo (nominal P value = .005, hazard ratio, 0.53 [95% confidence interval: 0.34–0.82]).

“These patients had all progressed within the past 13 months. Lenvatinib does not cure patients, and like other drugs, it has toxicity. Other data show slightly better outcomes on the lenvatinib arm from the beginning compared with those who crossed over. This study suggests that we don’t want to wait too long to start treating patients. This study supports that. The prespecified analysis was approved by the FDA,” Dr. Wirth told listeners. ■

Disclosure: This study was funded by Eisai. Dr. Wirth disclosed financial relationships with Eisai and Novartis.

Reference

1. Guo M, Sherman S, Wirth L, et al: Overall survival gain with lenvatinib vs. placebo in radioactive iodine refractory differentiated thyroid cancer: An updated analysis. 2015 European Cancer Congress. Abstract 2805. Presented September 26, 2015.