Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial.
BACKGROUND
Currently, metastatic renal cell carcinoma is treated with sequential single agents targeting VEGF or mTOR. Here, we aimed to assess lenvatinib, everolimus, or their combination as second-line treatment in patients with metastatic renal cell carcinoma.


METHODS
We did a randomised, phase 2, open-label, multicentre trial at 37 centres in five countries and enrolled patients with advanced or metastatic, clear-cell, renal cell carcinoma. We included patients who had received treatment with a VEGF-targeted therapy and progressed on or within 9 months of stopping that agent. Patients were randomised via an interactive voice response system in a 1:1:1 ratio to either lenvatinib (24 mg/day), everolimus (10 mg/day), or lenvatinib plus everolimus (18 mg/day and 5 mg/day, respectively) administered orally in continuous 28-day cycles until disease progression or unacceptable toxic effects. The randomisation procedure dynamically minimised imbalances between treatment groups for the stratification factors haemoglobin and corrected serum calcium. The primary objective was progression-free survival in the intention-to-treat population. This study is closed to enrolment but patients' treatment and follow-up is ongoing. This study is registered with ClinicalTrials.gov, number NCT01136733.


RESULTS
Between March 16, 2012, and June 19, 2013, 153 patients were randomly allocated to receive either the combination of lenvatinib plus everolimus (n=51), single-agent lenvatinib (n=52), or single-agent everolimus (n=50). Lenvatinib plus everolimus significantly prolonged progression-free survival compared with everolimus alone (median 14·6 months [95% CI 5·9-20·1] vs 5·5 months [3·5-7·1]; hazard ratio [HR] 0·40, 95% CI 0·24-0·68; p=0·0005), but not compared with lenvatinib alone (7·4 months [95% CI 5·6-10·2]; HR 0·66, 95% CI 0·30-1·10; p=0·12). Single-agent lenvatinib significantly prolonged progression-free survival compared with everolimus alone (HR 0·61, 95% CI 0·38-0·98; p=0·048). Grade 3 and 4 events occurred in fewer patients allocated single-agent everolimus (25 [50%]) compared with those assigned lenvatinib alone (41 [79%]) or lenvatinib plus everolimus (36 [71%]). The most common grade 3 or 4 treatment-emergent adverse event in patients allocated lenvatinib plus everolimus was diarrhoea (ten [20%]), in those assigned single-agent lenvatinib it was proteinuria (ten [19%]), and in those assigned single-agent everolimus it was anaemia (six [12%]). Two deaths were deemed related to study drug, one cerebral haemorrhage in the lenvatinib plus everolimus group and one myocardial infarction with single-agent lenvatinib.


CONCLUSIONS
Lenvatinib plus everolimus and lenvatinib alone resulted in a progression-free survival benefit for patients with metastatic renal cell carcinoma who have progressed after one previous VEGF-targeted therapy. Further study of lenvatinib is warranted in patients with metastatic renal cell carcinoma.


BACKGROUND
Eisai Inc.
Memorial Sloan-Kettering Cancer Center, New York, NY, USA. Electronic address: motzerr@mskcc.org.
Robert J
RJ
Motzer
Texas Oncology, Dallas, TX, USA.
Thomas E
TE
Hutson
Beatson West of Scotland Cancer Centre, Glasgow, UK.
Hilary
H
Glen
Massachusetts General Hospital Cancer Center, Boston, MA, USA.
M Dror
MD
Michaelson
Weill Cornell Medical College, New York Presbyterian Hospital, New York, NY, USA.
Ana
A
Molina
Addenbrooke's Hospital, Cambridge Biomedical Research Centre, Cambridge, UK.
Timothy
T
Eisen
Medical University of Gdańsk, Gdańsk, Poland.
Jacek
J
Jassem
Centrum Onkologii, Instytut w Warszawie, Warsaw, Poland.
Jakub
J
Zolnierek
Departamento de Oncología Médica, Barcelona, Spain.
Jose Pablo
JP
Maroto
Medical Oncology Department, Translational Genomics and Targeted Therapeutics in Solid Tumors Group, IDIBAPS, Hospital Clinic de Barcelona, Barcelona, Spain.
Begoña
B
Mellado
Onkologicka klinika, Lekarska fakulta Univerzity Palackeho a Fakultni nemocnice, Olomouc, Czech Republic.
Bohuslav
B
Melichar
Masaryk Memorial Cancer Institute, Masaryk University, Brno, Czech Republic.
Jiri
J
Tomasek
Eisai Inc, Woodcliff Lake, NJ, USA.
Alton
A
Kremer
Eisai Inc, Woodcliff Lake, NJ, USA.
Han-Joo
HJ
Kim
Eisai Ltd, Hatfield, UK.
Karen
K
Wood
Eisai Inc, Woodcliff Lake, NJ, USA.
Corina
C
Dutcus
Royal Marsden Hospital NHS Foundation Trust, London, UK.
James
J
Larkin
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000556:secondary*; D000068338:Everolimus / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D010671:Phenylurea Compounds / Q000008:administration & dosage*; D011804:Quinolines / Q000008:administration & dosage*
D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D011804:Quinolines; D000068338:Everolimus; C531958:lenvatinib