In patients with thyroid cancer that is refractory to radioactive iodine (I-131), lenvatinib improved progression-free survival and response rate when compared with placebo, according to data published in the New England Journal of Medicine.

In a previous phase 2 study of patients with differentiated thyroid cancer that was refractory to I-131, lenvatinib demonstrated clinical activity. Based on those results, the researchers conducted this pivotal phase 3 study to evaluate the drug’s effect on progression-free survival.

“For decades, in this patient population, the treatment was often to repeat ineffective doses of radioactive iodine, and possibly salvage therapy with chemotherapy,” senior author Steven I. Sherman, MD, of the University of Texas MD Anderson Cancer Center, said in a press release.

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“About 10 years ago, with the growing availability of novel targeted agents and multitargeted kinase inhibitors, we began to recognize potential for treating this subgroup of patients with anti-angiogenic therapy and sought to enroll those with refractory disease in clinical trials.”

In this double blind, multicenter study, the researchers randomly assigned patients with progressive thyroid cancer that was refractory to I-131 to receive lenvatinib 24 mg daily in 28-day cycles (n=261) or to receive placebo (n=131).

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At disease progression, the placebo group could receive open label lenvatinib.

Progression-free survival served as the primary endpoint, and secondary endpoints included response rate, overall survival and safety.

Results indicated that median progression-free survival was greater in the lenvatinib group vs. the placebo group (18.3 vs. 3.6 months; HR for progression or death=0.21; 99% CI, 0.14-0.31). This benefit associated with lenvatinib was also found in all prespecified subgroups.

Additionally, response rate was 64.8% with lenvatinib, with four complete responses and 165 partial responses in the treatment group, vs. 1.5% with placebo (P<.001).

Median overall survival was not reached in either group, according to the data.

“In our study, we not only saw a dramatic improvement in progression-free survival, there was also a 65% response rate — almost unprecedented results for thyroid cancer patients with such advanced disease,” Dr. Sherman said.

“We also found a strongly suggestive trend in how long patients lived, and a small number of patients had a complete response. While we couldn’t identify tumor mutations that might predict response, this represents a very exciting area of study going forward in hopes of possibly offering cure to a greater number of patients.”

More than 40% of patients in the lenvatinib group experienced any treatment-related adverse effects. These included hypertension (67.8%), diarrhea (59.4%), fatigue or asthenia (59.0%), decreased appetite (50.2%), decreased weight (46.4%) and nausea (41.0%).

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Thirty-seven patients who received lenvatinib and three patients who received placebo discontinued due to adverse events.

The researchers also reported that six of 20 deaths that occurred during the treatment period were deemed to be drug-related in the lenvatinib group.

“The side effect profile is actually quite typical for this class of drugs. We’ve learned over the years to be aggressive about dosing modifications and coming up with clever ways of helping patients tolerate the medication where drug effectiveness is maintained but with a minimum of those side effects. It’s paramount that patients are selected carefully and physicians giving the drug focus on symptom support,” Dr. Sherman said.

More studies of lenvatinib, including its use for treatment of other types of thyroid cancer and in combination with other novel therapies, are planned.


  1. Schlumberger, Martin, MD, et al. “Lenvatinib versus Placebo in Radioiodine-Refractory Thyroid Cancer.” The New England Journal of Medicine. DOI: 10.1056/NEJMoa1406470. February 12, 2015.