Lenvatinib Likely to Become Standard in Resistant Differentiated Thyroid Cancer

Martin Schlumberger, MD

Lenvatinib, a novel multityrosine kinase inhibitor, is highly effective against differentiated thyroid cancer that has become resistant to standard radioiodine (RAI) therapy, according to phase III study results reported during a May 31 press briefing at the 2014 American Society of Clinical Oncology (ASCO) Annual Meeting.

The oral drug delayed disease progression by 14.7 months, and nearly two-thirds of patients in the multicenter, randomized, double-blinded SELECT trial experienced tumor shrinkage; median overall survival had not been reached, said lead study author Martin Schlumberger, MD, a professor of Oncology at the University Paris Sud in Paris, France.

“We are confident that, based on our findings, lenvatinib will eventually become a standard treatment for radioiodine-resistant thyroid cancer,” Schlumberger said, adding that it will probably be used sequentially with other anticancer drugs. “As little as a year ago, this group of patients had no effective treatment options. It’s remarkable that we now have two active drugs in this setting, both of them tyrosine kinase inhibitors.”

Another targeted agent, sorafenib (Nexavar), was approved by the FDA in November 2013 to treat this same patient population. Although it is difficult to compare the results of two trials, Schlumberger said, the progression-free survival (PFS) and response rate numbers were higher in the lenvatinib trial than in the DECISION trial that led to sorafenib’s approval.

Differentiated thyroid cancer is the most common subtype of thyroid cancer, accounting for about 85% of the 60,000 thyroid cancer cases diagnosed each year in the United States, according to an ASCO press release. Although differentiated thyroid cancer is generally curable with standard treatment—surgery and RAI—roughly 5% to 15% of patients develop RAI resistance, the press release stated.

Those resistant patients have a 10-year survival rate of 10% from the time metastasis is detected, Schlumberger said.

The SELECT trial was developed based on positive efficacy results of lenvatinib in a phase II trial, the study authors wrote. Lenvatinib blocks several targets, including VEGFR1-3, FGFR1-4, PDGFR-α, KIT, and RET, Schlumberger said, adding that the VEGF-signaling networks are associated with aggressiveness and metastasis in thyroid cancer. Lenvatinib is also being explored in phase II and phase III clinical trials as a potential treatment for liver, lung, and kidney cancers and other types of solid tumors, according to ASCO.

In the SELECT study, 392 patients with advanced, RAI-resistant, differentiated thyroid cancer that had progressed within a year were randomly assigned to treatment with either lenvatinib or placebo in a 2:1 ratio. Patients received 24 mg per day of the drug or placebo in 28-day cycles until disease progression. Patients in the placebo arm were allowed to cross over to the lenvatinib arm upon disease progression.

The primary endpoint of the trial was PFS, and secondary endpoints included overall response rate, overall survival, and safety.

A median PFS of 18.3 months in the lenvatinib arm represented an “extraordinary improvement” over a PFS of 3.6 months in the placebo arm (hazard ratio [HR] = 0.21; 99%CI, 0.14-0.31; P <.0001), Schlumberger said. Median PFS for patients on lenvatinib differed depending upon prior VEGF therapy status; patients who had received prior VEGF therapy had a median PFS of 15.1 months (n = 66), while those who had not been given previous VEGF therapy experienced a median PFS of 18.7 months (n = 195), researchers said in the abstract.

Approximately 65% of patients experienced tumor shrinkage in the lenvatinib arm, compared with 2% in the placebo arm. The majority of responses occurred quickly, within 2 months of starting treatment, Schlumberger said.

Total deaths in the lenvatinib and placebo arms occurred at rates of 27.2% (71 patients) and 35.9% (47 patients), respectively, the authors wrote.

Among those were 6 treatment-emergent deaths in the placebo group. Of 20 treatment-emergent deaths in the lenvatinib arm, 6 were considered by investigators to be treatment-related: 1 due to pulmonary embolism, 1 to hemorrhagic stroke, and 4 to general health deterioration, Schlumberger reported. There were no treatment-related deaths in the placebo arm, he said.

Toxicities of lenvatinib were “considerable,” but manageable with dose modification and medication, Schlumberger said.

The most common side effects of lenvatinib were hypertension, diarrhea, fatigue, decreased appetite, decreased weight, and nausea/vomiting, he said. Although the side effects necessitated dose reductions in 68% of patients and dose interruption in 82% of patients, the benefit of lenvatinib persisted with decreased dose, Schlumberger noted. The drug was discontinued due to side effects in 14% of patients, he said.

“The progress we’re seeing with targeted agents for uncommon cancers is encouraging,” said the moderator of the press briefing, Gregory A. Masters, MD, director of Medical Oncology Fellowship at Christiana Care’s Helen F. Graham Cancer Center in Delaware and an associate professor at Thomas Jefferson University Medical School in Philadelphia. “Patients with differentiated thyroid cancer have historically had limited options when the disease progresses despite radioactive iodine therapy. Now this new drug, lenvatinib, offers an effective option with reasonable side effects and can help patients live longer before the disease worsens.”

Schlumberger noted that thyroid cancer rarely gives rise to distant metastases, and that refractory cases number 4 to 5 patients per million people, “so it’s a very rare disease. To include 392 patients in the trial was a real success.”

Schlumberger M, Tahara M, Wirth LJ, et al. A phase 3, multicenter, double-blind, placebo-controlled trial of lenvatinib (E7080) in patients with ¹³¹I-refractory differentiated thyroid cancer (SELECT). Presented at the 50th Annual Meeting of the American Society of Clinical Oncology; May 30-June 3, 2014; Chicago, IL. Abstract LBA6008.

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