On May 13, 2016, the U. S. Food and Drug Administration approved lenvatinib capsules (Lenvima, Eisai, Inc.), in combination with everolimus, for the treatment of advanced renal cell carcinoma following one prior anti-angiogenic therapy. Lenvatinib was first approved in 2015 for the treatment of locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer.
The current approval was based on a randomized, multicenter study in patients with advanced or metastatic renal cell carcinoma who previously received anti-angiogenic therapy. The major efficacy outcome measure was investigator-assessed progression-free survival (PFS) evaluated according to RECIST v1.1.
The trial randomized 153 patients 1:1:1 to lenvatinib 18 mg plus everolimus 5 mg (N=51), lenvatinib 24 mg monotherapy (N=52), or everolimus 10 mg monotherapy (N=50). All medications were administered orally once daily. Metastases were present in 95% of patients. Memorial Sloan Kettering Cancer Center favorable, intermediate, and poor risk prognostic categories were seen, respectively, in 24%, 37%, and 39% of patients receiving lenvatinib plus everolimus and were well balanced between arms.
The hazard ratio for the comparison of investigator-assessed PFS between lenvatinib plus everolimus and everolimus was 0.37 (95% CI: 0.22, 0.62). The median PFS was 14.6 (95% CI: 5.9, 20.1) months for the lenvatinib plus everolimus arm versus 5.5 (95% CI: 3.5, 7.1) months for patients on the everolimus arm. This treatment effect was supported by a retrospective independent review of radiographs in these two arms with an observed hazard ratio of0.43 (95% CI: 0.24, 0.75). The hazard ratio for a post-hoc, updated comparison of overall survival between the lenvatinib plus everolimus and everolimus arms was 0.67 (95% CI: 0.42, 1.08).
Comparison of investigator-assessed PFS between lenvatinib monotherapy and everolimus monotherapy supported the activity of lenvatinib in renal cell cancer. The combination of lenvatinib plus everolimus demonstrated numerically superior PFS, objective response rate, and overall survival, compared to lenvatinib monotherapy. There was no pre-specified plan for multiple comparisons.
The most common adverse reactions (greater than 30%) with lenvatinib in combination with everolimus were diarrhea, fatigue, arthralgia/myalgia, decreased appetite, vomiting, nausea, stomatitis/oral inflammation, hypertension, peripheral edema, cough, abdominal pain, dyspnea, rash, decreased weight, bleeding events, and proteinuria. Diarrhea was increased with the combination of lenvatinib plus everolimus, 19 % grade 3-4, and was added to the package insert as a new safety Warning.
The recommended dose and schedule is lenvatinib 18 mg plus everolimus 5 mg taken by mouth once daily.
This application was approved before the Prescription Drug User Fee Act (PDUFA) goal date of May 16, 2016. Lenvatinib in combination with everolimus received Breakthrough Therapy Designation for the treatment of advanced renal cell cancer following one prior anti-angiogenic therapy and the application was granted Priority Review. A description of these expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics, available at: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf.
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).