Roxanne Nelson

May 31, 2014

CHICAGO — A new targeted agent has shown high response rates and delayed disease progression in patients with radioiodine-resistant advanced differentiated thyroid cancer. This is a patient population for which, only a year ago, there were no treatment options.

Sorafenib (Nexavar) was recently approved by the US Food and Drug Administration for this indication, and now the investigational agent lenvatinib (under development by Eisai) has shown promising activity.

In the SELECT study, highlighted today during a press briefing here at the 2014 Annual Meeting of the American Society of Clinical Oncology®, nearly two-thirds of patients responded to treatment with lenvatinib. In addition, treatment with lenvatinib significantly delayed disease progression, compared with placebo.

"There was a very significant progression-free survival, and the response rate was very high — at 65%," said investigator Lori J. Wirth, MD, assistant professor of medicine at Harvard Medical School and medical director of the Center for Head and Neck Cancer at Massachusetts General Hospital in Boston.

"We don't see numbers that high in oncology very often," she added. "With these kinds of results, I am hoping that this drug will soon be in our arsenal."

According to Eisai, results from the SELECT trial will be submitted to regulatory authorities in the Europe, Japan, and the United States.

Differentiated thyroid cancer is the most common subtype of thyroid cancer, and accounts for approximately 85% of the thyroid cancer cases diagnosed each year in the United States. "About 90% of patients will do very well," Dr. Wirth told Medscape Medical News. "But 10% will go on to develop refractory disease, so we do need more treatment options."

Options Needed

SELECT reflects the rapid advancement in the field of refractory thyroid cancer, said Stephen Liu, MD, assistant professor of medicine at the Georgetown Lombardi Comprehensive Cancer Center, in Washington, DC, who was not involved in the study.

"Sorafenib was recently approved in this patient population after demonstrating a progression-free survival of 10.8 months," he said, but noted that the sorafenib trial and SELECT "cannot be directly compared."

"Interestingly, the response rate of lenvatinib was over 60%, whereas sorafenib had only a 12% response rate in its phase 3 study," he reported.

"Options for patients with refractory thyroid cancer have been very limited, but we now have 2 agents that have shown a clear benefit in large phase 3 studies reported within the past year," Dr. Liu said. Both drugs are oral tyrosine kinase inhibitors.

"These studies shighlight our collective ability to conduct large trials for relatively rare cancers," he added.

High Response Rates, Delayed Progression

In the SELECT trial, Dr. Wirth and colleagues randomized 392 patients in a 2:1 ratio to lenvatinib (24 mg/day in 28-day cycles) or placebo. The median patient age was 63 years, and all participants had documented disease progression within 13 months.

The cohort was stratified by age (younger or older than 65 years), region, and number of previous VEGFR-targeted therapies (0 or 1, or more than 1).

Patients in the placebo group could cross over to open-label lenvatinib on disease progression.

Median progression-free survival was significantly longer with lenvatinib than with placebo (18.3 vs 3.6 months; hazard ratio, 0.21; P < .0001).

A progression-free survival benefit was also seen in predefined subgroups. It was 15.1 months in the 66 patients who had received previous VEGF therapy, and 18.7 months in the 195 patients who had received no previous VEGF therapy.

The complete responses rate was higher in the lenvatinib group than in the placebo group (1.5% vs 0.0%), as was the partial response rate (63.2% vs 1.5%).

Median exposure was longer in the lenvatinib group than in the placebo group (13.8 vs 3.9 months), and median time to response in the lenvatinib group was 2 months.

Median overall survival has not been reached and, because of the study's crossover design, these data might be difficult to interpret, Dr. Wirth reported.

To date, the mortality rate is lower in the lenvatinib group than in the placebo group (27.2% vs 35.9%). "The study is ongoing and we are continuing to follow patients," she explained.

The most common adverse events of any grade were hypertension (68%), diarrhea (59%), appetite decreased (50%), weight loss (46%), and nausea (41%). Events of grade 3 or higher that occurred in more than 5% of patients included hypertension (42%), proteinuria (10%), weight loss (10%), diarrhea (8%), and decreased appetite (5%). Dose reduction was needed for 78.5% of patients, and 14.2% of patients discontinued because of adverse events.

The study was funded by Eisai. Several of the authors have financial relationships with industry, including Eisai, as noted in the abstract.

2014 Annual Meeting of the American Society of Clinical Oncology (ASCO): Abstract LBA6008. To be presented June 2, 2014.

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