• Oncology Clinical Trials
• Thyroid Disorders
• Head & Neck Cancers

• Oncology Clinical Trials
• Oncology
• Thyroid Disorders
• Head & Neck Cancers

Martin Schlumberger, MD, University of Paris-Sud, Orsay, France, reported outcomes from A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial of Lenvatinib (E7080) in ¹³¹I-Refractory Differentiated Thyroid Cancer (SELECT; NCT01321554) [Schlumberger M et al. J Clin Oncol 2014]. The trial compared the progression-free survival (PFS) of subjects with ¹³¹I-refractory differentiated thyroid cancer who were treated with lenvatinib versus placebo.

Lenvatinib (E7080) is an oral multi–tyrosine kinase inhibitor of VEG1–3, FGFR1–4, PDGFRa, RET, and KIT. It demonstrated clinical activity in a Phase 2 study of patients with radioiodine-refractory differentiated thyroid cancer [Sherman S et al. J Clin Oncol 2011].

In the SELECT trial, 392 patients aged ≥18 years from 136 study locations were randomly assigned to either 24 mg of the investigational tyrosine kinase inhibitor lenvatinib orally once daily (on a 28-day cycle) or a matching 24-mg placebo tablet. All had radiographic evidence of disease progression within the prior 13 months.

In total, 261 patients in the SELECT trial received the study drug compared with 131 who received the placebo. Patients were treated until confirmed disease progression. They could cross over to open-label lenvatinib treatment if their disease progressed.

Treatment with lenvatinib resulted in substantial gains in PFS. Patients who received lenvatinib had median PFS of 18.3 months, whereas those taking the placebo had median PFS of 3.6 months—a significant 14.7-month difference (p<0.0001). At Year 2, progression events occurred in 86% of subjects in the placebo arm and in only 41% of those in the treatment arm. Complete responses were seen in 2% of patients.

Gains were not seen in overall survival. The lack of improvement in overall survival compared with placebo might have been an artifact of the crossover design of the study, such that those who started on placebo but required lenvatinib after clinical progression may not have derived the same benefit. This would lower overall survival rates.

Within the trial population, 66 of the 261 patients in the lenvatinib group and 27 of the 131 in the placebo group had received prior vascular endothelial growth factor–targeted therapy. However, this did not affect study outcomes. In addition, findings from subgroup analyses did not differ on the basis of baseline tumor burden, histology, or the status of bone or lung metastasis.

A large number of adverse events were seen in almost every patient. Treatment-related adverse events were reported in 260 (>99%) of the patients in the lenvatinib group and 118 (90%) of those in the placebo group. Most often these were hypertension, diarrhea, fatigue, and decreased appetite.

These adverse events were managed with dose modification and medication. However, 68% of the patients on lenvatinib required dose reduction, 82% required dose interruption, and 14% of patients were taken off the drug.

In the active-treatment arm, there were 20 fatalities, compared with 6 in the placebo arm. Investigators attributed 6 fatalities (2%) directly to the use of lenvatinib. One person died of a pulmonary embolism, 1 died because of hemorrhagic stroke, and 4 others died because of general health deterioration. Still, the study is considered a breakthrough for a fatal cancer with few treatment options [Stjepanovic N et al. Biologics 2014].

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