Lenvatinib Highly Beneficial in Advanced Thyroid Cancer

Roxanne Nelson

February 11, 2015

The investigational agent lenvatinib (developed by Eisai and currently awaiting approval) significantly improves progression-free survival in patients with differentiated thyroid cancer refractory to iodine-131, new research shows.

In the phase 3 SELECT trial, median progression-free survival was significantly better with lenvatinib than with placebo (18.3 vs 3.6 months); hazard ratio [HR] for progression or death, 0.21; 99% confidence interval, 0.14 - 0.31; P < .001).

The response rate was also dramatically better with lenvatinib than with placebo (64.8% vs 1.5%; P < .001).

"Based on these results, lenvatinib will probably become the standard of care in this population," said first author Martin Schlumberger, MD, from the Institut Gustave Roussy and University Paris-Sud in Villejuif, France.

"There is no need for more data," he told Medscape Medical News.

However, the toxic effects of lenvatinib were considerable, although most could be managed with dose modification and medical intervention, Dr. Schlumberger and colleagues report.

The study results were published in the February 12 issue of the New England Journal of Medicine. Early findings were presented last year at the American Society of Clinical Oncology (ASCO) annual meeting.

The manufacturer has submitted the SELECT results to regulatory authorities in Europe, Japan, and the United States.

Follow-up trials in development include a study of lenvatinib in other types of thyroid cancers and one in which lenvatinib is combined with other novel therapies in radioiodine-refractory patients.

No Survival Benefit, High Toxicity

Lenvatinib is an oral tyrosine kinase inhibitor that inhibits vascular endothelial growth factor receptors 1, 2, and 3; fibroblast growth factor receptors 1 to 4; platelet-derived growth factor receptor α; RET; and KIT signaling networks.

The 392 thyroid cancer patients involved in the SELECT trial were refractory to iodine-131; 261 were randomized to lenvatinib 24 mg daily in 28-day cycles, and 131 were randomized to placebo.

At disease progression, patients in the placebo group were permitted to receive open-label lenvatinib.

The primary end point was progression-free survival; secondary end points included response rate, overall survival, and safety.

Patients were stratified by age, sex, race or ethnic group, previous treatment with a tyrosine kinase inhibitor, geographic region, histologic findings, and baseline thyrotropin levels. In all prespecified subgroups, progression-free survival was better with lenvatinib.

There were more complete responses with lenvatinib than with placebo (4 vs 0), and more partial responses (165 vs 2).

Table. Outcomes

Outcome Lenvatinib Group, n (%) Placebo Group, n (%)
Durable stable disease for ≥23 weeks 40 (15.3) 39 (29.8)
Progressive disease 18 (6.9) 52 (39.7)

 

Median overall survival has not been reached in either group, but that is not surprising. "As expected from the trial design, which included a crossover, there was no benefit on overall survival," Dr. Schlumberger explained.

Treatment-related adverse effects of any grade experienced by more than 40% of the lenvatinib group included hypertension (67.8%), diarrhea (59.4%), fatigue or asthenia (59.0%), decreased appetite (50.2%), decreased weight (46.4%), and nausea (41.0%).

More patients in the lenvatinib group than in the placebo group discontinued the study drug because of adverse events (37 vs 3; 14.2% vs 2.3%).

Six of the 20 deaths that occurred during the treatment period were considered to be related to lenvatinib.

"The side-effect profile is actually quite typical for this class of drugs," said senior author Steven I. Sherman, associate vice-provost for clinical research and professor and chair of endocrine neoplasia and hormonal disorders at the University of Texas M.D. Anderson Cancer Center in Houston.

"We've learned over the years to be aggressive about dosing modifications and coming up with clever ways of helping patients tolerate the medication so that the effectiveness of the drug is maintained with a minimum of those side effects," he said in a statement. "It's paramount that patients are selected carefully and physicians giving the drug focus on symptom support."

Options Are Increasing

The SELECT results reflect the rapid advances 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, when the findings were first presented at the ASCO meeting.

At the time, he noted that sorafenib (Nexavar, Bayer) had been approved for this patient population after demonstrating progression-free survival of 10.8 months, but he cautioned that the sorafenib and lenvatinib trials "cannot be directly compared."

"Options for patients with refractory thyroid cancer have been very limited, but we now have two 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 highlight our collective ability to conduct large trials for relatively rare cancers," he added.

The study was funded by Eisai. Several of the authors report financial relationships with industry, including Eisai, as detailed in the publication.

N Engl J Med. 2015;372:621-630. Abstract

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