A large, multi-center phase 3 study (SELECT trial) has found that patients with progressive, iodine refractory differentiated thyroid cancer have markedly improved progression free survival (PFS) when treated with lenvatinib, an oral tyrosine kinase inhibitor. Multiple ITOG members participated in the study, including lead author, Dr. Martin Schlumberger and senior author, Dr. Steven I. Sherman, current Chairman of ITOG.  The study, funded by the Eisai, the manufacturer of lenvatinib, was published in the New England Journal of Medicine, on February 12, 2015.On February 13th the FDA approved lenvatinib (Lenvima) for patients with progressive, differentiated thyroid cancer (DTC) whose disease progressed despite receiving radioactive iodine therapy.  

You can read more about the FDA approval here: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm434288.htm

The ten-year survival rate from the time of metastasis detection among patients with differentiated thyroid cancer that is refractory to radioiodine (iodine 131) is only 10%. Complications include metastases to bone or lung tissue. Patients with radioiodine-refractory thyroid cancer have traditionally had limited treatment options, but recent efforts have focused on targeting vascular endothelial growth factor (VEGF) and its receptor (VEGFR), as VEGF signaling contributing to increased angiogenesis has been implicated in aggressiveness and metastasis of thyroid cancers. Additional signaling pathways are also involved in tumor progression, and thus testing inhibitors that target multiple tyrosine kinases has been a central focus for the discovery of effective therapeutic strategies for these aggressive tumor types.

Lenvatinib is an oral molecularly targeted agent that inhibits multiple tyrosine kinases including VEGFR 1, 2, and 3, in addition to other pro-angiogenic and oncogenic pathway-related receptor tyrosine kinases involved in tumor proliferation (including fibroblast growth factor (FGF) receptors FGFR1- 4; the platelet-derived growth factor (PDGF) receptor PDGFRα; KIT; and RET). In the SELECT trial patients were randomized to treatment with either 24 mg once daily dosing of lenvatinib or a placebo in 28 day cycles.  Treatment assignment was double-blinded; neither physicians nor patients were aware of which medication they were receiving. Crossover from placebo to lenvatinib at the time of disease progression was permitted.

In the study reported by Dr. Schlumberger and colleagues, thyroid cancer patients were enrolled if they had evidence of progressive metastatic, radioiodine-refractory disease over the prior 13 months. Confirmation of progressive disease by a centralized radiology team was required at the time of enrollment. Some patients enrolled in the study had received one prior therapy with a tyrosine kinase inhibitor. A total of 392 patients were enrolled in 21 countries.  Patients were randomized in a 2:1 ratio to receive lenvatinib (261 patients) or placebo (131 patients).

The study's primary outcome was improvement in progression free survival, which favored treatment with lenvatinib. The median progression-free survival was 18.3 months in the lenvatinib group, in comparison with 3.6 months in the placebo group (hazard ratio of 0.21, 99% confidence interval between 0.14 and 0.31). The progression-free survival benefit with lenvatinib was observed across all patient groups, including those who had previously received one tyrosine-kinase inhibitor treatment. This is significant from a clinical standpoint as other tyrosine kinase inhibitors such as the FDA approved agent sorafenib are likely to be used with increased frequency for the treatment of iodine-131-refractive thyroid cancers. Additionally, there were four patients with a complete response to lenvatinib, and 165 patients (63.2%) with a partial response. Lenvatinib appears to confer an advantage for patients with existing bony metastases who experienced a decrease in the rate of progression of these lesions, compared with patients treated with placebo.

The most common treatment-related adverse events reported in the lenvatinib group were hypertension, diarrhea, fatigue, decreased appetite, and nausea. These side effects are consistent with those observed in patients receiving other VEGFR inhibitors. While the toxic effects of therapy were considerable in some patients, most adverse effects were managed with standard medications or dose modifications. There were six deaths in the lenvatinib treatment group that were deemed potentially or definitely related to treatment.

Based on the results published in the SELECT trial, lenvatinib is under consideration by the FDA in the US as well as regulatory authorities in Europe and Japan for approval for treatment of patients with progressive, radioiodine-refractory differentiated thyroid cancer. If lenvatinib is approved it would become the second kinase inhibitor approved for this patient population. Lenvatinib is also currently undergoing clinical investigation as a potential therapy for a range of other solid tumors.

Eisai funded performance of the clinical trial at each of the co-authors’ institutions.  In addition, Drs. Gianoukakis, Robinson, Shah, Schlumberger, Sherman, and Wirth have reported receiving personal fees such as honoraria or consulting fees from Eisai.  ITOG received an unrestricted educational grant to support expenses associated with its 2015 annual scientific meeting.