Lenvima (Lenvatinib) Approved in Combination with Everolimus for Patients with Advanced Renal-Cell Carcinoma

Loretta Fala

February 2017, Vol 7, No 2 - Drug Update

Approximately 394,336 Amer­icans were living with kidney cancer in 2013.1 In 2016 alone, an estimated 62,700 people were diagnosed with kidney cancer, and 14,240 people died from the disease.1 Renal-cell carcinoma (RCC), the most common type of kidney cancer, accounts for 85% to 90% of new cases of the disease.2,3 More than 70% of kidney cancers are clear-cell tumors—named for the clearness (or paleness) of the cells when viewed under a microscope.2,3

The treatment of patients with RCC may include 1 or more modalities, such as surgery; cryoablation; radiofrequency ablation; radiation therapy; and pharmacologic options, including immunotherapy and targeted therapies, and less frequently, chemotherapy.4,5 Patients with advanced RCC often receive multiple lines of drug therapy.5

The antiangiogenesis therapies, including tyrosine kinase inhibitors (TKIs) and mTOR inhibitors, are targeted therapies that are designed to slow the growth of tumors and cancer cells and shrink the size of the tumor.5 A new TKI was recently added to the treatment options of patients with advanced RCC.

Lenvima Approved for Renal-Cell Carcinoma

On May 13, 2016, the US Food and Drug Administration (FDA) approved lenvatinib (Lenvima; Eisai), an oral TKI, in combination with everolimus (Afinitor), for the treatment of patients with advanced RCC after 1 antiangiogenic therapy.6,7 Lenvatinib was initially approved by the FDA in February 2015 for the treatment of patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer.8

“Lenvatinib plus everolimus is the first and only FDA-approved regimen that successfully combines treatments that employ tyrosine kinase and mTOR inhibition, the primary targets of advanced RCC treatment for the past decade,” said Robert Motzer, MD, Memorial Sloan Kettering Cancer Center, New York, NY, and principal investigator of the pivotal study in patients with RCC.6 “This combination regimen led to enhanced efficacy and helped patients with advanced RCC live longer without disease progression or death than those treated with everolimus alone,” he added.6

Mechanism of Action

Lenvatinib is a receptor TKI that blocks the kinase activities of several vascular endothelial growth factor (VEGF) receptors (ie, receptors 1, 2, and 3). Lenvatinib also inhibits other receptor tyrosine kinases involved in angiogenesis, tumor growth, and cancer progression in addition to their normal cellular functions, including fibroblast growth factor receptors 1, 2, 3, and 4; KIT, RET, and the platelet-derived growth factor receptor–alpha. In preclinical studies, the combination of lenvatinib and everolimus demonstrated increased antiangiogenic and antitumor activity.7

Dosing and Administration

For patients with RCC, the recommended dosage is lenvatinib 18 mg plus everolimus 5 mg, once daily. For patients with RCC and severe renal or hepatic impairment, the recommended lenvatinib dosage is 10 mg. Lenvatinib is available as 4-mg and 10-mg oral capsules.7

Specialty Pharmacy Distribution

Lenvatinib is distributed through 2 specialty pharmacies—Accredo and Biologics.9

Pivotal Clinical Trial

The FDA approval of lenvatinib for RCC was based on a randomized, open-label, phase 2 study that was conducted between March 16, 2012, and June 19, 2013.7,10 The study included 153 patients with advanced or metastatic RCC who received antiangiogenic therapy.10

Of these 153 patients who were randomized to treatment, 95% had metastases and 5% had unresectable advanced disease. The patients were randomized to 1 of 3 treatment groups, including lenvatinib 18 mg plus everolimus 5 mg; lenvatinib 24-mg monotherapy; or everolimus 10-mg monotherapy. All study drugs were administered orally once daily.10 The primary efficacy end point was investigator-assessed progression-free survival (PFS), as evaluated according to the Response Evaluation Criteria in Solid Tumors version 1.1.7,10,11

The primary findings are listed in the Table. Patients who received lenvatinib plus everolimus had a significantly prolonged median PFS (9.1 months longer) than patients who received everolimus mono­therapy (hazard ratio [HR], 0.40; 95% confidence interval [CI], 0.24-0.68; P = .0005).7,10 The treatment effect with lenvatinib plus everolimus was further supported by a retrospective independent review of radiographs (HR, 0.43; 95% CI, 0.24-0.75) compared with everolimus monotherapy.7


An interim overall survival anal­ysis (cutoff date, July 31, 2015) showed that treatment with the combination of lenvatinib and everolimus was associated with a 10.1-month longer median overall survival versus treatment with everolimus monotherapy—25.5 months (95% CI, 16.4-32.1) versus 15.4 months (95% CI, 11.8-20.6), respectively (HR, 0.67; 95% CI, 0.42-1.08).7

Adverse Events

In RCC studies with lenvatinib, the most common (>30%) grade 1 to 4 adverse reactions in the combination arm compared with everolimus alone were diarrhea, fatigue, arthralgia or myalgia, decreased appetite, vomiting, nausea, stomatitis or oral inflammation, hypertension, peripheral edema, cough, abdominal pain, dyspnea, rash, weight decrease, hemorrhagic events, and proteinuria.7 Adverse reactions led to treatment discontinuation in 29% of patients taking the 2 drugs versus 12% with everolimus alone.7

Lenvatinib has no contraindications.

Warnings and Precautions

Before initiating lenvatinib, review the patient’s blood pressure, liver function, and check for proteinuria. During treatment, monitor for cardiac decompensation; liver function; proteinuria; diarrhea; electrolyte abnormalities; blood calcium levels; and thyroid-stimulating hormone.7

Lenvatinib treatment should be withheld if grade 3 hypertension is present despite antihypertensive treatment; grade 3 cardiac dysfunction, grade ≥3 liver impairment, ≥2 grams of proteinuria for 24 hours, grade 3 or 4 diarrhea, grade 3 or 4 renal failure or impairment; and corrected QT interval prolongation >500 msec, reversible posterior leukoencephalopathy, and grade 3 hemorrhage.7 Also stop treatment in patients with life-threatening hypertension, grade 4 cardiac dysfunction after an arterial thromboembolic event, hepatic failure, nephritic syndrome, grade 4 diarrhea, gastrointestinal perforation or life-threatening fistula, or grade 4 hemorrhage.7

Use in Specific Populations

Women should be advised to discontinue breast-feeding during lenvatinib therapy.7 Because of the risk for fetal harm with lenvatinib, women of reproductive potential should use effective contraception during treatment with lenvatinib and for at least 2 weeks after the completion of treatment.7


The FDA-approved expanded indication for lenvatinib, a receptor TKI, in combination with everoli­mus, marks the availability of an important second-line treatment option for patients with advanced RCC. Available as a convenient once-daily capsule, lenvatinib targets VEGF receptors and other pathways implicated in angiogenesis, tumor growth, and cancer progression. Patients who received lenvatinib plus everolimus had a 9.1-month longer PFS compared with everolimus alone. Moreover, the median overall survival was 10.1 months longer with the addition of lenvatinib to everolimus therapy.

Copyright © 2017 American Health & Drug Benefits. Used with permission.


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  4. Mayo Clinic staff. Diseases and conditions: kidney cancer: treatments and drugs. February 13, 2015. www.mayoclinic.org/diseases-conditions/kidney-cancer/basics/treatment/con-20024753. Accessed September 8, 2016.
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  8. US Food and Drug Administration. FDA approves Lenvima for a type of thyroid cancer. Press release. February 13, 2015. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm434288.htm. Accessed December 27, 2016.
  9. Eisai. Lenvima (lenvatinib) capsules: distribution and financial assistance information. September 2016. www.lenvima.com/pdfs/access-reimbursement-brochure.pdf. Accessed September 8, 2016.
  10. Motzer RJ, Hutson TE, Glen H, et al. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol. 2015;16:1473-1482.
  11. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228-247.