Lenvatinib 14-Month PFS Gain Reported for Radioiodine-Refractory Thyroid Cancer Patients

Multitargeted tyrosine kinase inhibitor therapy improves progression-free survival for thyroid cancer patients who do not response to radioiodine treatment

medwireNews: Lenvatinib significantly extends progression-free survival (PFS) in patients with differentiated thyroid cancer that has proven refractory to iodine-131 treatment, researchers report in The New England Journal of Medicine.

The tyrosine kinase inhibitor (TKI) is known to work on vascular endothelial growth factors 1, 2 and 3, and the fibroblast growth factor receptors 1, 2, 3 and 4, as well as the platelet-derived growth factor receptor α, and the RET and KIT signalling pathways, explain Martin Schlumberger, from Institut Gustave Roussy in Villejuif, France and co-authors.

In all, 64.8% of the 261 patients randomly assigned to receive lenvatinib 24 mg daily in 28-day cycles responded to treatment, including four complete responses, versus 1.5% of the 131 placebo-treated patients, a significant difference.

Moreover, PFS was a median of 18.3 months for lenvatinib-treated patients compared with 3.6 months for the controls, giving a significant hazard ratio of progression or death of 0.21.

“This improvement is longer than that observed in other placebo-controlled clinical trials involving patients with this disease”, write the researchers, adding that the PFS in the placebo group was significantly shorter than the expected 8 months, indicating aggressive disease.

Indeed, a significant PFS benefit was found for lenvatinib versus placebo for all the prespecified patient groups, regardless of whether they were defined by age, gender, race, geographical location, tumour histology, thyrotropin level and history of TKI therapy.

Nor did the PFS benefit associated with lenvatinib differ according to patient BRAF or RAS mutation status, prompting the team to say that “further investigation of biomarkers for lenvatinib efficacy is necessary.”

However, the researchers caution that lenvatinib was associated with a significantly higher rate of grade 3 or more severe treatment-related adverse events than placebo, at 75.9% versus 9.9%.

They highlight “special interest” adverse events at any grade or at grade 3 and above that were associated with lenvatinib, including hypertension, proteinuria, arterial thromboembolism, renal failure, hepatic failure and gastrointestinal fistula.

Deaths were reported for 27.2% of lenvatinib-treated patents and 35.9% of controls, three-quarters of which were associated with disease progression. However, 7.7% of patient deaths in the active arm occurred during treatment and 2.3% were considered to be associated with lenvatinib.

Over a median of 13.8 months of treatment, 14.2% of patients had to discontinue lenvatinib due to side effects compared with 2.3% of placebo-treated controls over 3.9 months.

Nevertheless, the team emphasizes: “Most adverse effects were managed with standard clinical interventions or dose modifications.”

Thus, lenvatinib was associated with a substantially higher rate of dose interruptions (82.4 vs 18.3%) and reductions (67.8 vs 4.6%) than placebo.


Schlumberger M, Tahara M, Wirth LJ, et al. Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med 2015; 372: 621–630. DOI: 10.1056/NEJMoa1406470

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