Approval of Lenvatinib for Advanced Thyroid Cancer: Clinical Implications

On February 13, 2015, the FDA approved lenvatinib (Lenvima) for treatment of locally recurrent or metastatic differentiated thyroid cancer (DTC) that is refractory to radioactive iodine therapy (RAI).¹The approval gives clinicians a therapy to treat a common form of advanced thyroid cancer that is often resistant to conventional treatment.

Mechanism of Action

R. Michael Tuttle, MD, an endocrinologist at Memorial Sloan Kettering Cancer Center in New York City, discussed the results of the phase III SELECT trial that led to the approval of lenvatinib and how this agent will influence future treatment of advanced thyroid cancer.Lenvatinib is a tyrosine kinase inhibitor (TKI) that potently inhibits activity of vascular endothelial growth factor (VEGF) receptors (VEGFR1, VEGFR2, and VEGFR3), as well as fibroblast growth factor (FGF) receptors 1-4, platelet-derived growth factor receptor alpha (PDGFRα), KIT, and RET. According to Tuttle, the multitargeted nature of lenvatinib and other TKIs is beneficial in targeting a broad patient population that may have distinct mutations in their tumors.

“If [the patient] fails to respond to one [TKI] inhibitor, you can just move onto the next one,” said Tuttle. “Even though [the drugs are] in the same group of kinase inhibitors, [the receptors] they inhibit can be different.”

Mutations within the tumor itself also likely play a role in the effectiveness of lenvatinib. Before choosing a drug to use, Tuttle’s institution performs sequencing of the tumor to predict whether or not a particular agent may be effective.

“We have found 351 mutations, all of which have a targetable drug to use against that mutation,” said Tuttle. “We’re trying to be smarter about which one of these drugs to use.”

SELECT Trial

However, Tuttle also indicated that all potent VEGF inhibitors, including lenvatinib, tend to produce hypertension and proteinuria, which will have to be followed in ongoing safety analyses. Furthermore, lenvatinib likely interacts with other targets that are not fully understood, which may explain differences in toxicity profile, tolerability, and activity among patients.The SELECT trial²was a phase III, multicenter, randomized, double-blind, placebo-controlled study that investigated the efficacy of lenvatinib in patients with progressive RAI-refractory DTC. A negative RAI scan with structural disease was a straightforward indication of RAI-refractory disease and fulfilled the inclusion criteria for the trial. However, patients also qualified if they had a positive RAI scan with evidence of progression within 12 months of RAI therapy or a cumulative RAI activity greater than 600 mCi with the last RAI dose administered at least 6 months prior to study entry.

According to Tuttle, these last 2 inclusion criteria were important considerations for identifying refractory disease. He indicated that even though some of the lesions were ‘RAI-avid,’ the RAI therapy was not sufficient to halt progression of the disease in these patients. Furthermore, patients who required treatment with high doses of radioactive iodine were likely to be refractory to RAI. Therefore, both of these groups of patients should be considered RAI-refractory and thus, candidates for lenvatinib, Tuttle suggested.

A total of 261 patients received lenvatinib (24 mg/day in 28-day cycles), and 131 received placebo with an opportunity to receive lenvatinib upon disease progression. The median age among all patients was 63 years, and 99% of them had metastasis (89% in the lungs, 52% in the lymph nodes, 39% in the bone, 18% in the liver, and 4% in the brain).

Patients who received lenvatinib had a median progression-free survival (PFS) of 18.3 months, which was significantly longer than the 3.6 months in the placebo group. Objective response rates (the sum of the partial and complete response rates) were 65% for the lenvatinib-treated group versus 2% for the placebo group. Tuttle noted that these substantial differences between the treatment and placebo groups highlights the effectiveness of lenvatinib in treating patients with rapidly progressing, treatment-refractory thyroid cancer.

Safety of Lenvatinib

“The patients in this trial are probably the sickest you’d find in practice,” said Tuttle. “It makes the PFS data in the treatment group that much more impressive.”The most common adverse reactions (AEs) associated with lenvatinib included hypertension, fatigue, diarrhea, decreased appetite, and proteinuria. Hypertension was particularly common, occurring in 73% of patients on lenvatinib and required dose reductions in 13% of patients. Therefore, Tuttle emphasized the importance of normalizing the patient’s blood pressure before lenvatinib treatment and monitoring it at weekly or biweekly intervals.

Tuttle also emphasized that many patients who will take lenvatinib are likely to have health complications and take other drugs unrelated to their thyroid cancer diagnosis. Therefore, the oncologist must be aware of patients’ changing clinical status when monitoring their response to lenvatinib and adjust the dosage accordingly if an AE occurs.

“It’s important to see the big picture when treating these patients,” said Tuttle.

Tuttle also indicated that lenvatinib is intended to be a ‘static agent,’ and patients should continue to take it as long as it is effective and does not result in serious AEs. However, dose interruptions from AEs is common and a single occurrence of an AE should not preclude usage permanently, Tuttle said.

“We don’t give up on it,” said Tuttle. “We want to keep patients on a dose as long as we can, because that is probably the best way to treat them.”

Factors to Consider When Prescribing Lenvatinib

Tuttle indicated that serious AEs may require a patient to take a lower dose (for example, a decrease from 24 mg to 20 mg after the first occurrence of an AE) but that the dose can be titrated back up as long as it is tolerable for the patient.Tuttle stated that identifying whether the patient is truly refractory to RAI is important, because incorrect or inappropriate methods of test administration can falsely identify patients as refractory. Tuttle indicated that radioactive iodine is still preferable for patients who respond to it because it has been used successfully for a longer time than has lenvatinib.

Patients who take lenvatinib should also have progressive disease and the drug is not recommended for those who have no or very slow progression. One of the clinical challenges, according to Tuttle, is determining when a clinician should administer lenvatinib during disease progression. Generally, other methods of management, such as surgery and external beam radiation, are preferred for disease that is localized in the neck area, according to Tuttle. Other contraindications for lenvatinib include rising thyroglobulin levels, tumors that can be surgically resected, or use in those patients who have a single metastasis that can be targeted with external beam radiation.

“[Tyrosine kinase inhibitors] are great drugs,” said Tuttle. “But if I can keep patients off of them for as long as possible, that is what I would like to do.”

References

1. U.S. Department of Health and Human Services. FDA News Release: FDA approves Lenvima for a type of thyroid cancer. Available at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm434288.htm. Accessed March 6, 2015.
2. Schlumberger M, Tahara M, Wirth LJ, et al. Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med. 2015;372(7):621-630