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

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.

Figure 1

Trial profile. OS, overall survival; PFS, progression-free survival.

Figure 2

Kaplan-Meier estimates of progression-free survival (by central analysis).

Figure 3

Best percentage change from baseline. Excludes one dovitinib patient who had 170% increase from baseline and 48 dovitinib and 60 sorafenib patients who had percentage changes in target lesions that were contradicted by overall lesion response of disease progression.

Figure 4

Kaplan-Meier estimates of overall survival.

Figure 5

Kaplan-Meier estimates of overall survival by treatment and baseline plasma biomarker groups and model-adjusted average fold-change from baseline ± 1 standard error. FGF2, fibroblast growth factor 2; HGF, hepatocyte growth factor; HR, hazard ratio; PLGF, placental growth factor; VEGFA, vascular endothelial growth factor A. Low biomarker is defined as < median, and high biomarker is defined as ≥ median. P values are adjusted for the false discovery rate. *0.05 ≥ P > 0.01. **P ≤ 0.01 (change from baseline). #P ≤ 0.05 (dovitinib to sorafenib).