Lenvatinib improves survival in radioiodine-refractory thyroid cancer

by Bruce Sylvester: Lenvatinib treatment has resulted in significant improvement in progression-free survival among patients with advanced radioiodine-refractory thyroid cancer, researchers from a Phase III trial reported in the NEJM/New England Journal of Medicine on Feb. 12, 2015.

“For decades, in this patient population, the treatment was often to repeat ineffective doses of radio-active iodine, and possibly salvage therapy with chemotherapy,” said lead investigator Steven Sherman, M.D., associate vice-provost for Clinical Research, and professor and chair, Endocrine Neoplasia and Hormonal Disorders, MD Anderson Cancer Center in Houston, Texas. “About 10 years ago, with the growing availability of novel targeted agents and multi-targeted 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,” he added.

Sherman noted that rates of refractory disease have been rising, with radioactive iodine remaining the only available treatment. Over 50 percent of patients do not respond to iodine therapy.

In the international, randomized, Phase III double-blind study, researchers enrolled 392 patients diagnosed with progressive, refractory disease.

They randomized the subjects at a two-to-one ratio to receive either the lenvatinib or placebo, with  261 receiving lenvatinib and 131 receiving a placebo. At the time of disease-progression, placebo subjects could switch to lenvatinib.

The primary endpoint was progression-free survival. Secondary endpoints were response rate, overall survival and safety.

Among levatinib subjects, median progression-free survival rate was 18.3 months, compared with 3.6 months among placebo subjects. Overall response was 64.8 percent in the levatinib group, and 1.5 percent in the placebo group. Neither group reached measurable median overall survival.

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

Over 40 percent of lenvatinib-treated subjects reported some side-effect reaction, most commonly  manageable hypertension. Other side effects included diarrhea, fatigue, nausea, decreased appetite and weight.

Notably, 37 patients discontinued lenvatinib treatment due to adverse effects. And six of 20 deaths during the treatment period appeared to be drug-related.

“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,” added Sherman.