Priority Review Granted to Lenvatinib for RAI-Refractory DTC

The FDA has granted a priority review to the oral multiple tyrosine kinase receptor inhibitor lenvatinib as a treatment for patients with progressive, radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC).

The FDA has granted a priority review to the oral multiple tyrosine kinase receptor inhibitor lenvatinib as a treatment for patients with progressive, radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC), according to the manufacturer of the drug, Eisai. Under the Prescription Drug User Fee Act, the FDA is scheduled to make a decision by April 14, 2015.

The new drug application for lenvatinib was based on promising findings from the phase III SELECT trial that were presented at the 2014 ASCO Annual Meeting. In this study, the risk of progression was reduced by 79% in patients treated with lenvatinib compared with placebo.

"We are confident that, based on our findings, lenvatinib will eventually become a standard treatment for radioiodine-resistant thyroid cancer,” Martin Schlumberger, MD, a professor of Oncology at the University Paris Sud in Paris, France, said when the data was presented. “As little as a year ago, this group of patients had no effective treatment options. It’s remarkable that we now have two active drugs in this setting, both of them tyrosine kinase inhibitors.”

In the SELECT trial, 392 patients with advanced RAI-refractory DTC were randomized in a 2:1 ratio to lenvatinib or placebo. Lenvatinib was administered orally at 24 mg per day in 28-day cycles. Following disease progression, patients in the placebo arm were allowed to crossover to the lenvatinib arm. The primary endpoint of the study was progression-free survival (PFS).

The median 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. Median overall survival has not been reached.

The objective response rate (ORR) with lenvatinib was 64.8% versus 1.5% with placebo. Four patients in the lenvatinib arm experienced a complete response (1.5%).

Lenvatinib inhibits VEGF receptors 1, 2, 3 and FGF receptors 1, 2, 3, and 4, in addition to PDGFR&alpha;, KIT, and RET. Consistent with this mechanism, the most common grade 3 side effect was hypertension, which occurred in 41.8% of patients. The most common all-grade lenvatinib-related side effects were hypertension (67.8%), diarrhea (59.4%), decreased appetite (50.2%), weight loss (46.4%), and nausea (41.0%).

The lenvatinib dose 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.

"Six patients who died on the trial died from treatment-related toxicities due to lenvatinib," Schlumberger said when the data was presented. "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."

The treatment landscape for patients with RAI-refractory advanced DTC has undergone a dramatic transformation in recent years. 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.

"Obviously, lenvatinib is more efficient than sorafenib in terms of PFS prolongation and also in terms of objective response rate," Schlumberger said. "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."