Dovitinib versus sorafenib for third-line targeted treatment of patients with metastatic renal cell carcinoma: an open-label, randomised phase 3 trial

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• 作者：Dr Prof Robert J Motzer ; MD^a ; ^{motzerr@mskcc.org" class="auth_mail} ; Camillo Porta ; MD^b ; Prof Nicholas J Vogelzang ; MD^c ; Cora N Sternberg ; MD^d ; Prof Cezary Szczylik ; MD^e ; Jakub Zolnierek ; MD^f ; Christian Kollmannsberger ; MD^g ; Sun Young Rha ; MD^h ; Georg A Bjarnason ; MDⁱ ; Prof Bohuslav Melichar ; MD^j ; Ugo De Giorgi ; MD^k ; Prof Viktor Gr&uuml ; nwald ; MD^l ; Ian D Davis ; MBBS^m ; Prof Jae-Lyun Lee ; MDⁿ ; Prof Emilio Esteban ; MD^o ; Gladys Urbanowitz ; MBA^p ; Can Cai ; PhD^p ; Matthew Squires ; PhD^q ; Mahtab Marker ; PhD^p ; Michael M Shi ; MD^p ; Prof Bernard Escudier ; MD^r
• 刊名：Lancet Oncology
• 出版年：March, 2014
• 年：2014
• 卷：15
• 期：3
• 页码：286-296
• 全文大小：435 K

文摘

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Summary

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 , number .

Findings

284 patients were randomly assigned to the dovitinib group and 286 to the sorafenib group. Median follow-up was 11路3 months (IQR 7路9-14路6). Median PFS was 3路7 months (95% CI 3路5-3路9) in the dovitinib group and 3路6 months (3路5-3路7) in the sorafenib group (hazard ratio 0路86, 95% CI 0路72-1路04; one-sided p=0路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.