Lenvatinib (Lenvima) Wins FDA Nod for Treatment of Renal Cell Carcinoma

Drug previously approved for patients with thyroid cancer

The FDA has approved lenvatinib (Lenvima, Eisia, Inc.), a multiple receptor tyrosine kinase (RTK) inhibitor, in combination with everolimus for the treatment of patients with advanced renal cell carcinoma (RCC) who were previously treated with an antiangiogenic therapy. The agency’s decision was based on positive results from a phase 2 registration study in which the once-daily combination of lenvatinib 18 mg and everolimus 5 mg demonstrated a substantial improvement in progression-free survival (PFS), in the objective response rate (ORR), and in overall survival (OS) compared with everolimus alone––a standard of care for patients with advanced RCC who have received prior antiangiogenic therapy.

Lenvatinib was granted a breakthrough therapy designation for this indication and the application received priority review, which is assigned to drugs that the FDA believes have the potential to provide a significant improvement in the treatment of a serious condition.

Lenvatinib was first approved in the U.S. in February 2015 for patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory, differentiated thyroid cancer.

Lenvatinib is an RTK inhibitor that inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR 1–3. Lenvatinib also inhibits other RTKs that have been implicated in pathogenic angiogenesis, tumor growth, and cancer progression in addition to their normal cellular functions, including fibroblast growth factor (FGF) receptors FGFR 1–4, platelet-derived growth factor receptor alpha (PDGFR-alpha), KIT, and RET. The combination of lenvatinib and everolimus showed increased antiangiogenic and antitumor activity, as demonstrated by decreased human endothelial cell proliferation, tube formation, and VEGF signaling in vitro and tumor volume in mouse xenograft models of human RCC compared with each drug alone.

A pivotal, randomized phase 2 study evaluated lenvatinib in 153 patients with unresectable advanced or metastatic RCC who were previously treated with an antiangiogenic therapy. The patients were randomly assigned to receive a combination of lenvatinib 18 mg plus everolimus 5 mg once daily, lenvatinib only (24 mg once daily), or everolimus only (10 mg once daily) administered orally in continuous 28-day cycles until disease progression or unacceptable toxicity occurred. The study’s primary efficacy endpoint was investigator-assessed PFS. Other endpoints included ORR, OS, and safety.

In this study, treatment with lenvatinib plus everolimus resulted in median PFS (the length of time from randomization until disease progression or death) that was nearly three times that of everolimus alone. The median PFS in 51 patients treated with the combination was 14.6 months compared with 5.5 months in 50 patients treated with everolimus alone (hazard ratio [HR], 0.37). Thus, the combination regimen resulted in a 63% reduction in the risk of disease progression or death compared with everolimus alone.

The ORR was 37% in the patients treated with the combination regimen (35% partial response plus 2% complete response) compared with 6% (all partial responses) in patients treated with everolimus alone.

The patients who received lenvatinib plus everolimus experienced a 10.1-month increase in median OS compared with those who received everolimus monotherapy (25.5 months versus 15.4 months, respectively; HR, 0.67). This OS analysis was conducted when 63% of deaths had occurred in the combination arm and 74% of deaths had occurred in the everolimus arm.

Serious risks from treatment with the combination of lenvatinib and everolimus can include hypertension, cardiac dysfunction, arterial thromboembolic events, hepatotoxicity, proteinuria, diarrhea, 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/thyroid dysfunction, and embryofetal toxicity.

In the pivotal phase 2 study, the most common adverse events observed with the combination treatment included diarrhea, fatigue, arthralgia/myalgia, decreased appetite, vomiting, nausea, stomatitis/oral inflammation, hypertension, peripheral edema, cough, abdominal pain, dyspnea, rash, weight decrease, hemorrhagic events, and proteinuria.

The most common serious adverse events included renal failure (11%), dehydration (10%), anemia (6%), thrombocytopenia (5%), diarrhea (5%), vomiting (5%), and dyspnea (5%). Adverse events led to dose reductions or interruptions in 89% of patients receiving lenvatinib plus everolimus and in 54% in patients receiving everolimus alone.

Source: Eisai, Inc.; May 16, 2016.