Lenvatinib in Advanced Radioiodine-Refractory Differentiated Thyroid Cancer


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Lenvatinib in Thyroid Cancer

In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.

 

On February 13, 2015, lenvatinib (Lenvima) was approved for the treatment of patients with locally recurrent or metastatic, progressive, radioactive iodine–refractory differentiated thyroid cancer.1,2

Supporting Trial

Approval was based on the finding of increased progression-free survival for lenvatinib vs placebo in a double-blind trial in which 392 patients with disease progression within the prior 12 months were randomly assigned to lenvatinib at 24 mg per day in 28-day cycles (n = 261) or placebo (n = 131).2,3 Patients in the placebo group could receive lenvatinib following independent radiologic confirmation of disease progression.

Among all patients, median age was 63 years (40% > 65 years), 51% were male, 79% were white, 54% had Eastern Cooperative Oncology Group performance status of 0, and 24% had received one prior vascular endothelial growth factor (VEGF)/VEGF receptor–targeted therapy. Metastases were present in 99%, including in lungs in 89%, lymph nodes in 52%, bone in 39%, liver in 18%, and brain in 4%.

Histologic diagnoses were papillary in 66% and follicular in 34%; of those with follicular histology, 44% had Hürthle cell and 11% had clear cell subtypes. No iodine uptake on any radioiodine scan was observed in 67% of patients in the lenvatinib group and 77% in the placebo group.

Median progression-free survival was 18.3 months (95% confidence interval [CI] = 15.1 months to not estimable) in the lenvatinib group vs 3.6 months (95% CI = 2.2–3.7 months) in the placebo group (hazard ratio [HR] = 0.21, P < .001). Objective response rates were 65% (complete response in 2%) vs 2% (P < .001). Median overall survival was not reached in either group (HR = 0.73, P = .10). At disease progression, 109 placebo patients (83%) received open-label lenvatinib.

How It Works

Lenvatinib is a receptor tyrosine kinase inhibitor that inhibits the kinase activities of VEGF receptors 1, 2, and 3. It also inhibits other receptor tyrosine kinases implicated in pathogenic angiogenesis, tumor growth, and cancer progression as well as normal cellular functions, including fibroblast growth factor (FGF) receptors 1, 2, 3, and 4, platelet-derived growth factor (PDGF) receptor α, KIT, and RET.

How It Is Given

The recommended dose of lenvatinib is 24 mg/d, continued until disease progression or unacceptable toxicity. In patients with severe renal impairment or severe hepatic impairment, the recommended dose is 14 mg/d.

Treatment should be interrupted for grade 4 clinical adverse events; at present, there are no recommendations on resumption of dosing in patients with grade 4 reactions that resolve. In general, for persistent and intolerable grade 2 adverse events, grade 3 adverse events, and grade 4 laboratory abnormalities, treatment should be interrupted until resolution to grade 0 or 1 or baseline status and resumed at doses of 20, 14, and 10 mg/d for successive interruptions.

With regard to specific adverse reactions, lenvatinib should be withheld for grade 3 hypertension that persists despite optimal antihypertensive therapy and resumed at a reduced dose when hypertension is controlled to grade ≤ 2. Treatment should be discontinued for life-threatening hypertension.

In addition, treatment should be discontinued for grade 4 cardiac dysfunction or hemorrhage; it should be withheld for grade 3 events until improvement to grade 0 or 1 or baseline status and can be resumed at a reduced dose or discontinued depending on the severity and persistence of the reaction. Lenvatinib should be discontinued after an arterial thrombotic event.

Lenvatinib should be discontinued for hepatic failure. For grade 3 or 4 renal failure/impairment or hepatotoxicity, it should be withheld until resolution to grade 0 or 1 or baseline status and can be resumed at a reduced dose or discontinued depending on the severity and persistence of the reaction. For proteinuria ≥ 2 g/24 hours, treatment should be withheld and can be resumed at a reduced dose when proteinuria is < 2 g/24 hours; treatment should be discontinued for nephrotic syndrome.

Lenvatinib should be discontinued for gastrointestinal perforation or life-threatening fistula. Treatment should be withheld for grade ≥ 3 QT-interval prolongation and can be resumed at a reduced dose when QT prolongation resolves to grade 0 or 1 or baseline status. Lenvatinib should be withheld for reversible posterior leukoencephalopathy syndrome until complete resolution; it can be resumed at a reduced dose or discontinued depending on the severity and persistence of neurologic symptoms.

Safety Profile

In the randomized trial, median treatment duration was 16.1 months in the lenvatinib group and 3.9 months in the placebo group. The most common adverse events of any grade in the lenvatinib group occurring at an incidence ≥ 5% higher vs the placebo group were hypertension (73% vs 16% in the placebo group), fatigue (67% vs 35%), diarrhea (67% vs 17%), arthralgia/myalgia (62% vs 28%), decreased appetite (54% vs 18%), decreased weight (51% vs 15%), nausea (47% vs 25%), and stomatitis (41% vs 8%).

The most common grade 3 or 4 adverse events were hypertension (44% vs 4%), decreased weight (13% vs 1%), fatigue (11% vs 4%), proteinuria (11% vs 0%), and diarrhea (9% vs 0%). The most common grade 3 or 4 laboratory abnormalities were hypocalcemia (9% vs 2%), hypokalemia (6% vs 1%), increased aspartate aminotransferase levels (5% vs 0%), increased alanine aminotransferase levels (4% vs 0%), and increased lipase (4% vs 1%). The most common serious adverse events in lenvatinib patients were pneumonia (4%), hypertension (3%), and dehydration (3%).

Adverse events led to dose reductions in 68% of lenvatinib recipients vs 5% of placebo recipients, with the most common causes in lenvatinib recipients being hypertension (13%), proteinuria (11%), decreased appetite (10%), and diarrhea (10%). Adverse events led to discontinuation of treatment in 18% vs 5%, with the most common cause in lenvatinib patients being hypertension (1%) and asthenia (1%).

Lenvatinib carries warnings/precautions for hypertension, cardiac failure, arterial thrombotic events, hepatotoxicity, proteinuria, renal failure and impairment, gastrointestinal perforation and fistula formation, QT-interval prolongation, hypocalcemia, reversible posterior leukoencephalopathy syndrome, hemorrhagic events, impairment of thyroid-stimulating hormone suppression, and embryofetal toxicity.

Patients must have blood pressure controlled prior to treatment and should have blood pressure, liver function tests, and proteinuria monitored prior to and regularly during treatment. Patients should be monitored for clinical symptoms or signs of cardiac decompensation.

Electrolytes should be monitored in all patients and abnormalities corrected. Blood calcium levels should be monitored at least monthly, with calcium replacement as necessary. Thyroid-stimulating hormone levels should be monitored monthly and thyroid replacement medication adjusted as needed. Patients should be advised regarding potential fetal risk and effective contraception. ■

References

1. U.S. Food and Drug Administration: Lenvatinib (Lenvima). Available at http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm434347.htm. Accessed February 19, 2015.

2. Lenvatinib (LenvimaTM) capsules prescribing information. Esai Inc, February 2015. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2015/206947s000lbl.pdf. Accessed February 19, 2015.

3. Schlumberger M, Tahara M, Wirth LJ, et al: Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med 372:621-630, 2015.

 



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