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.
Bibliographical noteFunding Information:
RJM has received research funding from Novartis, Pfizer, and GlaxoSmithKline, has consulted for Bayer and Pfizer, and has provided paid expert testimony for Pfizer. CP has acted as a speaker or consultant for Novartis, GlaxoSmithKline, Bayer Schering, Astellas, AVEO, and Boehringer Ingelheim and has received research grants from Novartis and Bayer Schering. NJV has consulted for Novartis and Bayer. CNS has received honoraria from Novartis, Pfizer, and GlaxoSmithKline. CS has been an advisory board member for GlaxoSmithKline, Astellas, Pfizer, and Novartis. CK has received honoraria for presentations from and has consulted and been an advisory board member for Novartis. GAB has received honoraria for continuing medical education lectures on renal cell carcinoma and funding for travel to cancer meetings from Novartis. BM has received honoraria for speeches and advisory board meetings from Novartis, Bayer, Pfizer, Roche, and Astellas. UDG has received honoraria as a speaker or consultant for GlaxoSmithKline, Pfizer, Bayer, and Novartis. VG has received honoraria from Novartis, Pfizer, Astellas, Bayer, Roche, and GlaxoSmithKline and has consulted for Novartis, Pfizer, Astellas, Bayer, and GlaxoSmithKline. IDD has chaired advisory boards for GlaxoSmithKline, Janssen, and Bayer Asia-Pacific, and has been an advisory board member for Pfizer, Novartis, Medivation, Bristol-Myers Squibb, Sanofi, Astellas, and Ipsen. IDD received no remuneration for any of this activity; all payments and honoraria were invoiced by and paid to ANZUP Cancer Trials Group. J-LL has received research funding from Bayer and has consulted for Pfizer, Novartis, Bayer, Sanofi-Aventis, and Astellas. EE has been an advisory board member for GlaxoSmithKline, Pfizer, and Novartis with all honoraria directly donated to Fundeso (Fundacion for Cancer Research). GU, CC, MS, MM, and MMS are employees of Novartis Pharmaceuticals Corporation. BE has received honoraria for advisory board meetings from Bayer, Pfizer, Novartis, GlaxoSmithKline, and AVEO. JZ and SYR other authors declare that they have no competing interests.
The study was sponsored by Novartis Pharmaceuticals Corporation. The authors thank the patients, families, and research teams for their involvement with the study. Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals Corporation. We thank Peter J Simon for medical editorial assistance with this manuscript.
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