FDA Approval Sought for Lenvatinib in Differentiated Thyroid Cancer

Martin Schlumberger, MD

Eisai has submitted a New Drug Application for lenvatinib (E7080) as a treatment for patients with progressive, radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC), based on findings from the phase III SELECT trial that was presented at the 2014 ASCO Annual Meeting. The FDA will review the application by mid-October, at which point a decision timeline under the Prescription Drug User Fee Act will be established. The fastest review under this program provides a decision within 6 months.

In the SELECT trial, 392 patients with advanced RAI-refractory DTC were randomized in a 2:1 ratio to lenvatinib or placebo. The median progression-free survival (PFS) with lenvatinib was 18.3 months versus 3.6 months with placebo (HR = 0.21; P <.0001). The median PFS with lenvatinib in the second-line setting following treatment with a prior VEGF therapy was 15.1 months. The objective response rate (ORR) with lenvatinib was 64.7% versus 1.5% with placebo.

The lenvatinib dose (24 mg per day) was reduced for 78.5% of patients, and 14.2% of patients discontinued due to side effects. Six treatment-related deaths occurred in the lenvatinib arm of the trial. The most common grade 3 side effect was hypertension, which occurred in 42% of patients. The most common lenvatinib-related side effects were hypertension, diarrhea, fatigue, decreased appetite, decreased weight, and nausea/vomiting.

In November 2013, the FDA approved sorafenib (Nexavar) as a treatment for patients with RAI-refractory DTC. In the pivotal phase III DECISION trial, the median PFS with sorafenib was 10.8 months versus 5.8 months for placebo (HR = 0.587; P <.0001). The ORR with sorafenib was 12.2%. Dose modifications were needed in 77.8% patients and 18.8% discontinued due to adverse events.

The treatment landscape for patients with RAI-refractory DTC has undergone a dramatic transformation in recent years, with the approval of sorafenib and the application for lenvatinib. To gain further insight into this growing space, OncLive interviewed the SELECT trial lead author, Martin Schlumberger, MD, a professor of Oncology at the University Paris Sud in Paris, France, at the ASCO Annual Meeting in June.

OncLive: Can you compare the Efficacy and Safety of lenvatinib and sorafenib?

Schlumberger: Obviously, lenvatinib is more efficient than sorafenib in terms of PFS prolongation and also in terms of objective response rate. Sixty-five percent of patients had an objective response on lenvatinib, including complete responses. With sorafenib in the DECISION trial, we observed only 20% of objective responses. Now sorafenib also induces toxicities but no deaths. So probably, lenvatinib is more efficient than sorafenib but when it comes to comparing the toxicity of lenvatinib to sorafenib, it is difficult because there is no head-to-head comparison.

Can you discuss the treatment-related deaths in the SELECT trial?

So we have observed a number of deaths due to thyroid carcinoma in the placebo arm. About one-third of the patients died from thyroid carcinoma overall, while 22 patients died of thyroid carcinoma in the treatment arm. Six patients who died on the trial died from treatment-related toxicities due to lenvatinib. These six deaths are too many, but we have to compare that to the hundred of lives that were saved from treatment of the drug. So you have efficacy, but you also have toxicities and usually these go together.

Looking ahead, could you discuss potential sequencing strategies for lenvatinib with sorafenib?

When patients with distant metastasis or locally advanced disease progress, they progress slowly so they can be treated with one of these two drugs. Some will respond and then progress but still be alive and in good condition. So most of these patients will require two lines of treatment. So we may start with sorafenib, or we may start with lenvatinib but in the end they will receive both drugs.