Lenvatinib, everolimus, and the combination in patients with
metastatic renal cell carcinoma: a randomised, phase 2,
open-label, multicentre trial

J 2015

Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial

MOTZER, Robert J.; Thomas E. HUTSON; Hilary GLEN; M. Dror MICHAELSON; Ana MOLINA et. al.

Basic information

Original name

Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial

Authors

MOTZER, Robert J. (840 United States of America); Thomas E. HUTSON (840 United States of America); Hilary GLEN (826 United Kingdom of Great Britain and Northern Ireland); M. Dror MICHAELSON (840 United States of America); Ana MOLINA (840 United States of America); Timothy EISEN (826 United Kingdom of Great Britain and Northern Ireland); Jacek JASSEM (616 Poland); Jakub ZOLNIEREK (616 Poland); Jose Pablo MAROTO (724 Spain); Begoña MELLADO (724 Spain); Bohuslav MELICHAR (203 Czech Republic); Jiří TOMÁŠEK (203 Czech Republic, guarantor, belonging to the institution); Alton KREMER (840 United States of America); Han-Joo KIM (840 United States of America); Karen WOOD (826 United Kingdom of Great Britain and Northern Ireland); Corina DUTCUS (840 United States of America) and James LARKIN (826 United Kingdom of Great Britain and Northern Ireland)

Edition

Lancet Oncology, New York, Elsevier Science INC, 2015, 1470-2045

Other information

Language

English

Type of outcome

Article in a journal

Field of Study

30200 3.2 Clinical medicine

Country of publisher

United States of America

Confidentiality degree

is not subject to a state or trade secret

Impact factor

Impact factor: 26.509

RIV identification code

RIV/00216224:14110/15:00086819

Organization unit

Faculty of Medicine

DOI

http://dx.doi.org/10.1016/S1470-2045(15)00290-9

UT WoS

000364470900030

EID Scopus

2-s2.0-84955253186

Keywords in English

ANTITUMOR ACTIVITIES; INTERFERON-ALPHA; III TRIAL; BEVACIZUMAB; INHIBITOR; GROWTH; E7080; TEMSIROLIMUS; SORAFENIB; TARGETS

Abstract

In the original language

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. Findings 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. Interpretation 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.

Cite

MOTZER, Robert J.; Thomas E. HUTSON; Hilary GLEN; M. Dror MICHAELSON; Ana MOLINA; Timothy EISEN; Jacek JASSEM; Jakub ZOLNIEREK; Jose Pablo MAROTO; Begoña MELLADO; Bohuslav MELICHAR; Jiří TOMÁŠEK; Alton KREMER; Han-Joo KIM; Karen WOOD; Corina DUTCUS and James LARKIN. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncology. New York: Elsevier Science INC, 2015, vol. 16, No 15, p. 1473-1482. ISSN 1470-2045. Available from: https://dx.doi.org/10.1016/S1470-2045(15)00290-9.

@article{1337419,
   author = {Motzer, Robert J. and Hutson, Thomas E. and Glen, Hilary and Michaelson, M. Dror and Molina, Ana and Eisen, Timothy and Jassem, Jacek and Zolnierek, Jakub and Maroto, Jose Pablo and Mellado, Begoña and Melichar, Bohuslav and Tomášek, Jiří and Kremer, Alton and Kim, HanandJoo and Wood, Karen and Dutcus, Corina and Larkin, James},
   article_location = {New York},
   article_number = {15},
   doi = {http://dx.doi.org/10.1016/S1470-2045(15)00290-9},
   keywords = {ANTITUMOR ACTIVITIES; INTERFERON-ALPHA; III TRIAL; BEVACIZUMAB; INHIBITOR; GROWTH; E7080; TEMSIROLIMUS; SORAFENIB; TARGETS},
   language = {eng},
   issn = {1470-2045},
   journal = {Lancet Oncology},
   title = {Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial},
   volume = {16},
   year = {2015}
}

TY  - JOUR
ID  - 1337419
AU  - Motzer, Robert J. - Hutson, Thomas E. - Glen, Hilary - Michaelson, M. Dror - Molina, Ana - Eisen, Timothy - Jassem, Jacek - Zolnierek, Jakub - Maroto, Jose Pablo - Mellado, Begoña - Melichar, Bohuslav - Tomášek, Jiří - Kremer, Alton - Kim, Han-Joo - Wood, Karen - Dutcus, Corina - Larkin, James
PY  - 2015
TI  - Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial
JF  - Lancet Oncology
VL  - 16
IS  - 15
SP  - 1473-1482
EP  - 1473-1482
PB  - Elsevier Science INC
SN  - 14702045
KW  - ANTITUMOR ACTIVITIES
KW  - INTERFERON-ALPHA
KW  - III TRIAL
KW  - BEVACIZUMAB
KW  - INHIBITOR
KW  - GROWTH
KW  - E7080
KW  - TEMSIROLIMUS
KW  - SORAFENIB
KW  - TARGETS
N2  - 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. Findings 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. Interpretation 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.
ER  -

MOTZER, Robert J.; Thomas E. HUTSON; Hilary GLEN; M. Dror MICHAELSON; Ana MOLINA; Timothy EISEN; Jacek JASSEM; Jakub ZOLNIEREK; Jose Pablo MAROTO; Begoña MELLADO; Bohuslav MELICHAR; Jiří TOMÁŠEK; Alton KREMER; Han-Joo KIM; Karen WOOD; Corina DUTCUS and James LARKIN. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. \textit{Lancet Oncology}. New York: Elsevier Science INC, 2015, vol.~16, No~15, p.~1473-1482. ISSN~1470-2045. Available from: https://dx.doi.org/10.1016/S1470-2045(15)00290-9.

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