Lenvatinib Shows Promise for Patients With Radioiodine-Refractory Thyroid Cancer in Phase III Study
In a phase III study led by researchers at The University of Texas MD Anderson Cancer Center, the oral antiangiogenic therapy lenvatinib has shown dramatic improvement in progression-free survival in patients with advanced radioiodine-refractory thyroid cancer. Their findings are published by Schlumberger et al in The New England Journal of Medicine.
The global study, led by Steven I. Sherman, MD, Associate Vice-Provost for Clinical Research and Professor and Chair of Endocrine Neoplasia and Hormonal Disorders at MD Anderson, could offer a new treatment paradigm for a group of patients for whom, until recently, there has been no new effective treatment since the 1940s. Preliminary findings were first reported at last year’s ASCO Annual meeting; the published study includes updated data.
History of Treatment Options
According to the American Cancer Society, 62,450 people will be diagnosed with thyroid cancer in 2015, and 1,950 will die of the disease. It’s the fastest-growing cancer type, said Dr. Sherman, with rates of refractory disease also on the rise. Until recent therapeutic advances, radioactive iodine has been the only treatment available to patients with metastatic thyroid disease, explained Dr. Sherman. Although it does offer cure to a select group of patients, more than half do not respond to the therapy.
“For decades in this patient population, the treatment was often to repeat ineffective doses of radioactive iodine, and possibly salvage therapy with chemotherapy,” said Dr. Sherman. “About 10 years ago, with the growing availability of novel targeted agents and multitargeted kinase inhibitors, we began to recognize the potential for treating this subgroup of patients with antiangiogenic therapy. We sought to enroll those with refractory disease in clinical trials.”
MD Anderson led the global phase III trial, and Mouhammed Habra, MD, Associate Professor of Endocrine Neoplasia and Hormonal Disorders, was the institution’s principal investigator.
Study Findings
The international, randomized, phase III, double-blind study enrolled 392 patients from 21 countries, all of whom had progressive, refractory disease. Patients were randomly assigned at a two-to-one ratio to receive either the study drug or a placebo, respectively. In total, 261 patients received lenvatinib, and 131 received a placebo. At the time of disease progression, patients in the placebo arm could receive lenvatinib. The primary endpoint was progression-free survival, and secondary endpoints tested response rate, overall survival, and safety.
For patients who received lenvatinib, the median progression-free survival rate was 18.3 months, compared with 3.6 months in those who received the placebo. The overall response rate in the study arm group was 64.8% (with 4 complete and 165 partial responses), and 1.5% in the placebo arm. The median overall survival was not reached in either group.
For patients with advanced and metastatic disease, this class of drugs is the first with potential for improved overall survival.
“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. We also found a strongly suggestive trend in how long patients lived. 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 Dr. Sherman.
Side Effects
Lenvatinib is not without side effects. More than 40% of patients who received lenvatinib experienced some reaction, with manageable hypertension being the most common. Other side effects included diarrhea, fatigue, nausea, and decreased appetite. Thirty-seven patients discontinued the drug because of adverse effects. Also, 6 of 20 deaths that occurred during the treatment period were determined to be drug-related by treating physicians.
“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,” said Dr. Sherman.
A number of follow-up studies with lenvatinib are in development, including its use in other types of thyroid cancers and in combination with other novel therapies for radioiodine-refractory patients.
Martin Schlumberger, MD, of Institut Gustave Roussy, is the corresponding author for The New England Journal of Medicine article.
The study was supported by Eisai, and Dr. Sherman has served as a consultant for the company. For full disclosures of the study authors, visit www.nejm.org.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
