Dovitinib versus sorafenib for third-line targeted treatment of patients with metastatic renal cell carcinoma

An open-label, randomised phase 3 trial

Robert J. Motzer, Camillo Porta, Nicholas J. Vogelzang, Cora N. Sternberg, Cezary Szczylik, Jakub Zolnierek, Christian Kollmannsberger, SunYoung Rha, Georg A. Bjarnason, Bohuslav Melichar, Ugo De Giorgi, Viktor Grünwald, Ian D. Davis, Jae Lyun Lee, Emilio Esteban, Gladys Urbanowitz, Can Cai, Matthew Squires, Mahtab Marker, Michael M. Shi & 1 others Bernard Escudier

Research output: Contribution to journalArticle

172 Citations (Scopus)

Abstract

Background: An unmet medical need exists for patients with metastatic renal cell carcinoma who have progressed on VEGF-targeted and mTOR-inhibitor therapies. Fibroblast growth factor (FGF) pathway activation has been proposed as a mechanism of escape from VEGF-targeted therapies. Dovitinib is an oral tyrosine-kinase inhibitor that inhibits VEGF and FGF receptors. We therefore compared dovitinib with sorafenib as third-line targeted therapies in patients with metastatic renal cell carcinoma. Methods: In this multicentre phase 3 study, patients with clear cell metastatic renal cell carcinoma who received one previous VEGF-targeted therapy and one previous mTOR inhibitor were randomly assigned through an interactive voice and web response system to receive open-label dovitinib (500 mg orally according to a 5-days-on and 2-days-off schedule) or sorafenib (400 mg orally twice daily) in a 1:1 ratio. Randomisation was stratified by risk group and region. The primary endpoint was progression-free survival (PFS) assessed by masked central review. Efficacy was assessed in all patients who were randomly assigned and safety was assessed in patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01223027. Findings: 284 patients were randomly assigned to the dovitinib group and 286 to the sorafenib group. Median follow-up was 11·3 months (IQR 7·9-14·6). Median PFS was 3·7 months (95% CI 3·5-3·9) in the dovitinib group and 3·6 months (3·5-3·7) in the sorafenib group (hazard ratio 0·86, 95% CI 0·72-1·04; one-sided p=0·063). 280 patients in the dovitinib group and 284 in the sorafenib group received at least one dose of study drug. Common grade 3 or 4 adverse events included hypertriglyceridaemia (38 [14%]), fatigue (28 [10%]), hypertension (22 [8%]), and diarrhoea (20 [7%]) in the dovitinib group, and hypertension (47 [17%]), fatigue (24 [8%]), dyspnoea (21 [7%]), and palmar-plantar erythrodysaesthesia (18 [6%]) in the sorafenib group. The most common serious adverse event was dyspnoea (16 [6%] and 15 [5%] in the dovitinib and sorafenib groups, respectively). Interpretation: Dovitinib showed activity, but this was no better than that of sorafenib in patients with renal cell carcinoma who had progressed on previous VEGF-targeted therapies and mTOR inhibitors. This trial provides reference outcome data for future studies of targeted inhibitors in the third-line setting. Funding: Novartis Pharmaceuticals Corporation.

Original languageEnglish
Pages (from-to)286-296
Number of pages11
JournalThe Lancet Oncology
Volume15
Issue number3
DOIs
Publication statusPublished - 2014 Jan 1

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Renal Cell Carcinoma
Vascular Endothelial Growth Factor A
Therapeutics
Dyspnea
Disease-Free Survival
Fatigue
Pharmaceutical Preparations
Hypertension
4-amino-5-fluoro-3-(5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl)quinolin-2(1H)-one
sorafenib
Fibroblast Growth Factor Receptors
Fibroblast Growth Factors
Hypertriglyceridemia
Random Allocation
Protein-Tyrosine Kinases
Diarrhea
Appointments and Schedules
Safety

All Science Journal Classification (ASJC) codes

  • Oncology

Cite this

Motzer, Robert J. ; Porta, Camillo ; Vogelzang, Nicholas J. ; Sternberg, Cora N. ; Szczylik, Cezary ; Zolnierek, Jakub ; Kollmannsberger, Christian ; Rha, SunYoung ; Bjarnason, Georg A. ; Melichar, Bohuslav ; De Giorgi, Ugo ; Grünwald, Viktor ; Davis, Ian D. ; Lee, Jae Lyun ; Esteban, Emilio ; Urbanowitz, Gladys ; Cai, Can ; Squires, Matthew ; Marker, Mahtab ; Shi, Michael M. ; Escudier, Bernard. / Dovitinib versus sorafenib for third-line targeted treatment of patients with metastatic renal cell carcinoma : An open-label, randomised phase 3 trial. In: The Lancet Oncology. 2014 ; Vol. 15, No. 3. pp. 286-296.
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abstract = "Background: An unmet medical need exists for patients with metastatic renal cell carcinoma who have progressed on VEGF-targeted and mTOR-inhibitor therapies. Fibroblast growth factor (FGF) pathway activation has been proposed as a mechanism of escape from VEGF-targeted therapies. Dovitinib is an oral tyrosine-kinase inhibitor that inhibits VEGF and FGF receptors. We therefore compared dovitinib with sorafenib as third-line targeted therapies in patients with metastatic renal cell carcinoma. Methods: In this multicentre phase 3 study, patients with clear cell metastatic renal cell carcinoma who received one previous VEGF-targeted therapy and one previous mTOR inhibitor were randomly assigned through an interactive voice and web response system to receive open-label dovitinib (500 mg orally according to a 5-days-on and 2-days-off schedule) or sorafenib (400 mg orally twice daily) in a 1:1 ratio. Randomisation was stratified by risk group and region. The primary endpoint was progression-free survival (PFS) assessed by masked central review. Efficacy was assessed in all patients who were randomly assigned and safety was assessed in patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01223027. Findings: 284 patients were randomly assigned to the dovitinib group and 286 to the sorafenib group. Median follow-up was 11·3 months (IQR 7·9-14·6). Median PFS was 3·7 months (95{\%} CI 3·5-3·9) in the dovitinib group and 3·6 months (3·5-3·7) in the sorafenib group (hazard ratio 0·86, 95{\%} CI 0·72-1·04; one-sided p=0·063). 280 patients in the dovitinib group and 284 in the sorafenib group received at least one dose of study drug. Common grade 3 or 4 adverse events included hypertriglyceridaemia (38 [14{\%}]), fatigue (28 [10{\%}]), hypertension (22 [8{\%}]), and diarrhoea (20 [7{\%}]) in the dovitinib group, and hypertension (47 [17{\%}]), fatigue (24 [8{\%}]), dyspnoea (21 [7{\%}]), and palmar-plantar erythrodysaesthesia (18 [6{\%}]) in the sorafenib group. The most common serious adverse event was dyspnoea (16 [6{\%}] and 15 [5{\%}] in the dovitinib and sorafenib groups, respectively). Interpretation: Dovitinib showed activity, but this was no better than that of sorafenib in patients with renal cell carcinoma who had progressed on previous VEGF-targeted therapies and mTOR inhibitors. This trial provides reference outcome data for future studies of targeted inhibitors in the third-line setting. Funding: Novartis Pharmaceuticals Corporation.",
author = "Motzer, {Robert J.} and Camillo Porta and Vogelzang, {Nicholas J.} and Sternberg, {Cora N.} and Cezary Szczylik and Jakub Zolnierek and Christian Kollmannsberger and SunYoung Rha and Bjarnason, {Georg A.} and Bohuslav Melichar and {De Giorgi}, Ugo and Viktor Gr{\"u}nwald and Davis, {Ian D.} and Lee, {Jae Lyun} and Emilio Esteban and Gladys Urbanowitz and Can Cai and Matthew Squires and Mahtab Marker and Shi, {Michael M.} and Bernard Escudier",
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Motzer, RJ, Porta, C, Vogelzang, NJ, Sternberg, CN, Szczylik, C, Zolnierek, J, Kollmannsberger, C, Rha, S, Bjarnason, GA, Melichar, B, De Giorgi, U, Grünwald, V, Davis, ID, Lee, JL, Esteban, E, Urbanowitz, G, Cai, C, Squires, M, Marker, M, Shi, MM & Escudier, B 2014, 'Dovitinib versus sorafenib for third-line targeted treatment of patients with metastatic renal cell carcinoma: An open-label, randomised phase 3 trial', The Lancet Oncology, vol. 15, no. 3, pp. 286-296. https://doi.org/10.1016/S1470-2045(14)70030-0

Dovitinib versus sorafenib for third-line targeted treatment of patients with metastatic renal cell carcinoma : An open-label, randomised phase 3 trial. / Motzer, Robert J.; Porta, Camillo; Vogelzang, Nicholas J.; Sternberg, Cora N.; Szczylik, Cezary; Zolnierek, Jakub; Kollmannsberger, Christian; Rha, SunYoung; Bjarnason, Georg A.; Melichar, Bohuslav; De Giorgi, Ugo; Grünwald, Viktor; Davis, Ian D.; Lee, Jae Lyun; Esteban, Emilio; Urbanowitz, Gladys; Cai, Can; Squires, Matthew; Marker, Mahtab; Shi, Michael M.; Escudier, Bernard.

In: The Lancet Oncology, Vol. 15, No. 3, 01.01.2014, p. 286-296.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Dovitinib versus sorafenib for third-line targeted treatment of patients with metastatic renal cell carcinoma

T2 - An open-label, randomised phase 3 trial

AU - Motzer, Robert J.

AU - Porta, Camillo

AU - Vogelzang, Nicholas J.

AU - Sternberg, Cora N.

AU - Szczylik, Cezary

AU - Zolnierek, Jakub

AU - Kollmannsberger, Christian

AU - Rha, SunYoung

AU - Bjarnason, Georg A.

AU - Melichar, Bohuslav

AU - De Giorgi, Ugo

AU - Grünwald, Viktor

AU - Davis, Ian D.

AU - Lee, Jae Lyun

AU - Esteban, Emilio

AU - Urbanowitz, Gladys

AU - Cai, Can

AU - Squires, Matthew

AU - Marker, Mahtab

AU - Shi, Michael M.

AU - Escudier, Bernard

PY - 2014/1/1

Y1 - 2014/1/1

N2 - Background: An unmet medical need exists for patients with metastatic renal cell carcinoma who have progressed on VEGF-targeted and mTOR-inhibitor therapies. Fibroblast growth factor (FGF) pathway activation has been proposed as a mechanism of escape from VEGF-targeted therapies. Dovitinib is an oral tyrosine-kinase inhibitor that inhibits VEGF and FGF receptors. We therefore compared dovitinib with sorafenib as third-line targeted therapies in patients with metastatic renal cell carcinoma. Methods: In this multicentre phase 3 study, patients with clear cell metastatic renal cell carcinoma who received one previous VEGF-targeted therapy and one previous mTOR inhibitor were randomly assigned through an interactive voice and web response system to receive open-label dovitinib (500 mg orally according to a 5-days-on and 2-days-off schedule) or sorafenib (400 mg orally twice daily) in a 1:1 ratio. Randomisation was stratified by risk group and region. The primary endpoint was progression-free survival (PFS) assessed by masked central review. Efficacy was assessed in all patients who were randomly assigned and safety was assessed in patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01223027. Findings: 284 patients were randomly assigned to the dovitinib group and 286 to the sorafenib group. Median follow-up was 11·3 months (IQR 7·9-14·6). Median PFS was 3·7 months (95% CI 3·5-3·9) in the dovitinib group and 3·6 months (3·5-3·7) in the sorafenib group (hazard ratio 0·86, 95% CI 0·72-1·04; one-sided p=0·063). 280 patients in the dovitinib group and 284 in the sorafenib group received at least one dose of study drug. Common grade 3 or 4 adverse events included hypertriglyceridaemia (38 [14%]), fatigue (28 [10%]), hypertension (22 [8%]), and diarrhoea (20 [7%]) in the dovitinib group, and hypertension (47 [17%]), fatigue (24 [8%]), dyspnoea (21 [7%]), and palmar-plantar erythrodysaesthesia (18 [6%]) in the sorafenib group. The most common serious adverse event was dyspnoea (16 [6%] and 15 [5%] in the dovitinib and sorafenib groups, respectively). Interpretation: Dovitinib showed activity, but this was no better than that of sorafenib in patients with renal cell carcinoma who had progressed on previous VEGF-targeted therapies and mTOR inhibitors. This trial provides reference outcome data for future studies of targeted inhibitors in the third-line setting. Funding: Novartis Pharmaceuticals Corporation.

AB - Background: An unmet medical need exists for patients with metastatic renal cell carcinoma who have progressed on VEGF-targeted and mTOR-inhibitor therapies. Fibroblast growth factor (FGF) pathway activation has been proposed as a mechanism of escape from VEGF-targeted therapies. Dovitinib is an oral tyrosine-kinase inhibitor that inhibits VEGF and FGF receptors. We therefore compared dovitinib with sorafenib as third-line targeted therapies in patients with metastatic renal cell carcinoma. Methods: In this multicentre phase 3 study, patients with clear cell metastatic renal cell carcinoma who received one previous VEGF-targeted therapy and one previous mTOR inhibitor were randomly assigned through an interactive voice and web response system to receive open-label dovitinib (500 mg orally according to a 5-days-on and 2-days-off schedule) or sorafenib (400 mg orally twice daily) in a 1:1 ratio. Randomisation was stratified by risk group and region. The primary endpoint was progression-free survival (PFS) assessed by masked central review. Efficacy was assessed in all patients who were randomly assigned and safety was assessed in patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01223027. Findings: 284 patients were randomly assigned to the dovitinib group and 286 to the sorafenib group. Median follow-up was 11·3 months (IQR 7·9-14·6). Median PFS was 3·7 months (95% CI 3·5-3·9) in the dovitinib group and 3·6 months (3·5-3·7) in the sorafenib group (hazard ratio 0·86, 95% CI 0·72-1·04; one-sided p=0·063). 280 patients in the dovitinib group and 284 in the sorafenib group received at least one dose of study drug. Common grade 3 or 4 adverse events included hypertriglyceridaemia (38 [14%]), fatigue (28 [10%]), hypertension (22 [8%]), and diarrhoea (20 [7%]) in the dovitinib group, and hypertension (47 [17%]), fatigue (24 [8%]), dyspnoea (21 [7%]), and palmar-plantar erythrodysaesthesia (18 [6%]) in the sorafenib group. The most common serious adverse event was dyspnoea (16 [6%] and 15 [5%] in the dovitinib and sorafenib groups, respectively). Interpretation: Dovitinib showed activity, but this was no better than that of sorafenib in patients with renal cell carcinoma who had progressed on previous VEGF-targeted therapies and mTOR inhibitors. This trial provides reference outcome data for future studies of targeted inhibitors in the third-line setting. Funding: Novartis Pharmaceuticals Corporation.

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