Elsevier

The Lancet Oncology

Volume 15, Issue 3, March 2014, Pages 286-296
The Lancet Oncology

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

https://doi.org/10.1016/S1470-2045(14)70030-0Get rights and content

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 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.

Introduction

Renal cell carcinoma is characterised by high vascularity and is dependent on angiogenesis for growth and survival.1, 2 Therapies targeting VEGF and mTOR signalling pathways represent standard first-line and second-line treatment options for patients with metastatic renal cell carcinoma.3, 4 Nearly all patients who initially respond to these treatments acquire resistance, and there is an unmet medical need for new agents targeting angiogenesis and tumour growth in patients with renal cell carcinoma that was previously treated with VEGF-targeted therapies and mTOR inhibitors.

Fibroblast growth factor (FGF) signalling drives angiogenesis at both the early invasive phase (eg, migration and proliferation) and the late vascular maturation phase (eg, morphogenesis and vessel maturation).5, 6, 7 FGF pathway activation has been proposed as a mechanism of escape from VEGF-targeted therapies,8 and increased plasma FGF2 concentrations were reported in patients with renal cell carcinoma who had disease progression while receiving VEGF-targeted therapies,9 and in patients who previously received VEGF-targeted therapies.10, 11 Additionally, increased FGF2 concentrations are reported to be prognostic for metastasis and survival.12, 13, 14, 15 Therefore, targeting antiangiogenic escape with FGF pathway inhibition is one potential strategy in patients with renal cell carcinoma who progress on anti-VEGF therapy.16

Dovitinib (TKI258) is an oral tyrosine-kinase inhibitor that inhibits FGF receptor (FGFR), VEGFR, and platelet-derived growth factor receptor (PDGFR).17 Results of studies in renal cell carcinoma xenograft models have suggested dovitinib causes greater tumour reduction than do sunitinib and sorafenib.10, 18 Phase 1 results indicated antitumour activity of dovitinib at the maximum tolerated dose of 500 mg on a 5-days-on and 2-days-off schedule in pretreated patients with renal cell carcinoma.10 Results of a phase 2 study have shown patients previously treated with VEGF and mTOR inhibitors had a median progression-free survival (PFS) of 5·5 months and overall survival of 11·8 months.11 In phase 2 studies of second-line or third-line sorafenib, the median PFS of 3·4 months to 4 months19, 20, 21, 22, 23 lent support to a comparison of dovitinib with sorafenib for third-line targeted treatment in patients who progressed on therapies targeting VEGF and mTOR. We therefore undertook this open-label, randomised phase 3 trial (GOLD; Global Oncologic Learnings for Dovitinib in renal cell carcinoma) for the comparison of dovitinib with sorafenib in patients with metastatic renal cell carcinoma.

Section snippets

Patients

In this multicentre (appendix), open-label, randomised phase 3 trial, eligible patients had metastatic renal cell carcinoma with clear cell or a component of clear cell histology and had received one previous VEGF-targeted therapy (eg, sunitinib or bevacizumab) plus one previous mTOR inhibitor (eg, everolimus or temsirolimus) in either sequence. Patients (aged ≥18 years) must have had disease progression on or within 6 months of last therapy (VEGF-targeted agent or mTOR inhibitor therapy).

Results

764 patients were assessed for eligibility. 169 (87%) of 194 patients who were not enrolled were judged to be screening failures. The most common reason for screening failure was the presence of brain metastases (n=70). Between March 4, 2011, and Sept 12, 2012, 570 patients were randomly assigned at 199 sites to receive dovitinib (n=284) or sorafenib (n=286) and were included in the efficacy analyses (figure 1). The safety analysis included all patients who received at least one dose of

Discussion

In this study, no differences in efficacy outcomes were noted between patients who received dovitinib and those who received sorafenib as third-line targeted treatment for metastatic renal cell carcinoma. To the best of our knowledge, this study is the first phase 3 trial in which two tyrosine-kinase inhibitors have been compared in the third-line setting after both VEGF-inhibitor and mTOR-inhibitor drugs (panel). Nearly all patients treated with these drugs in first-line and second-line

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