FDA Approves Lenvatinib in Differentiated Thyroid Cancer

Richard Pazdur, MD

The FDA has granted approval to lenvatinib (Lenvima) as a treatment for patients with progressive, radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC), based on findings from the phase III SELECT trial. The approval comes 2 months ahead of the FDA's scheduled decision date.

In the SELECT trial, treatment with the multikinase inhibitor lenvatinib reduced the risk of disease progression by 79% (HR = 0.21; 99% CI, 0.14-0.31; P <.0001).

“The development of new therapies to assist patients with refractory disease is of high importance to the FDA,” said Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Today’s approval gives patients and healthcare professionals a new therapy to help slow the progression of DTC.”

The SELECT trial randomized 392 patients with advanced RAI-refractory DTC in a 2:1 ratio to oral lenvatinib at 24-mg daily in 28-day cycles (n = 262) or placebo (n = 131). Pretreatment with one prior TKI regimen was allowed. Baseline characteristics were similar between the two arms.

At a median treatment duration of 13.8 months with lenvatinib and 3.9 months with placebo, the median progression-free survival was 18.3 months versus 3.6 months, respectively.

The objective response rate with lenvatinib was 64.8% versus 1.5% with placebo. Four patients in the lenvatinib arm had complete responses versus none in the placebo group, with partial responses in 165 and 2 patients, respectively.

“I think based on the results of this study, that this could become the drug of choice for first-line therapy for patients with progressive, radioactive iodine-refractory, differentiated thyroid cancer,” said the senior investigator of SELECT, Steven I. Sherman, MD, in an interview with OncLive.

Sherman, who is associate vice-provost for Clinical Research, and professor and chair, Endocrine Neoplasia and Hormonal Disorders, at MD Anderson Cancer Center, added, “The adverse events that were seen were fairly typical of what has been seen in the earlier studies with lenvatinib and anticipated for other antiangiogenic drugs.”

Specifically, 97.3% of patients receiving lenvatinib and 59.5% of patients on placebo experienced a treatment-related adverse event (AE), with grade ≥3 AE rates of 75.9% and 9.9%, respectively.

The most frequently reported grade ≥3 AEs reported in the lenvatinib group included hypertension (42.9% vs 2.3%), proteinuria (10.0% vs 0), decreased weight (9.6% vs 0), fatigue (9.2% vs 2.3%), and diarrhea (8.0% vs 0).

Sherman also noted that it was significant that the rate of grade ≥3 palmar—plantar erythrodysesthesia syndrome was 3.4%. He said that sorafenib (Nexavar), the other TKI approved in this setting in recent years, “had a very high frequency of palmar-plantar erythrodysesthesia in the pivotal phase III DECISION study.”

There were six patient deaths in the lenvatinib arm considered to be treatment related. These included one pulmonary embolism, one hemorrhagic stroke, one related to a general deterioration of health, and three in which no specific cause was identified.

Martin Schlumberger, MD, lead author of the SELECT trial, commented on these treatment-related deaths in an interview with OncLive at the 2014 ASCO Annual Meeting.

“These six deaths are too many, but we have to compare that to the hundreds of lives that were saved from treatment with the drug. So you have efficacy, but you also have toxicities and usually these go together,” said Schlumberger, a professor of Oncology at the University Paris Sud in Paris, France.

With sorafenib and lenvatinib both now both available for RAI-refractory DTC, the issue of sequencing now arises. Sherman, for his part, said he would use lenvatinib first.

“The degree of improvement and progression-free survival would appear to be markedly higher with lenvatinib than sorafenib. So I personally think that the effectiveness of lenvatinib is going to be superior to that of sorafenib in this patient cohort.”

Schlumberger, however, did not express a first-line preference.

“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.”