Dovitinib versus sorafenib for third-line targeted treatment of patients with metastatic renal cell carcinoma: An open-label, randomised phase 3 trial Journal Article
| Authors: | Motzer, R. J.; Porta, C.; Vogelzang, N. J.; Sternberg, C. N.; Szczylik, C.; Zolnierek, J.; Kollmannsberger, C.; Rha, S. Y.; Bjarnason, G. A.; Melichar, B.; De Giorgi, U.; Grünwald, V.; Davis, I. D.; Lee, J. L.; Esteban, E.; Urbanowitz, G.; Cai, C.; Squires, M.; Marker, M.; Shi, M. M.; Escudier, B. |
| Article Title: | 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. © 2014 Elsevier Ltd. |
| Keywords: | vasculotropin; cancer chemotherapy; cancer survival; controlled study; treatment response; aged; major clinical study; constipation; fatigue; neutropenia; sorafenib; bevacizumab; sunitinib; diarrhea; drug dose reduction; drug efficacy; drug safety; hypertension; treatment duration; drug targeting; cancer patient; follow up; progression free survival; drug eruption; liver toxicity; anemia; leukopenia; nausea; randomized controlled trial; stomatitis; thrombocytopenia; myalgia; weight reduction; bone pain; kidney carcinoma; temsirolimus; abdominal pain; alanine aminotransferase blood level; arthralgia; aspartate aminotransferase blood level; asthenia; backache; coughing; dizziness; drug fever; dyspnea; gamma glutamyl transferase blood level; lymphocytopenia; pruritus; alanine aminotransferase; alkaline phosphatase; aspartate aminotransferase; bilirubin; chemotherapy induced emesis; drug induced headache; hyperkalemia; insomnia; survival time; cytokine; disease severity; cancer vaccine; multicenter study; pazopanib; muscle weakness; peripheral edema; xerostomia; erythema; limb pain; pleura effusion; open study; alkaline phosphatase blood level; metastasis potential; phase 3 clinical trial; drug blood level; hypothyroidism; axitinib; mammalian target of rapamycin inhibitor; gamma glutamyltransferase; dyspepsia; hand foot syndrome; triacylglycerol lipase blood level; muscle spasm; dry skin; alopecia; bilirubin blood level; everolimus; hypertriglyceridemia; dysgeusia; triacylglycerol lipase; decreased appetite; dysphonia; conjunctivitis; physical disease; upper abdominal pain; body weight disorder; lacrimation disorder; dovitinib; musculoskeletal chest pain; noncardiac chest pain; human; male; female; priority journal; article |
| Journal Title: | Lancet Oncology |
| Volume: | 15 |
| Issue: | 3 |
| ISSN: | 1470-2045 |
| Publisher: | Elsevier Science, Inc. |
| Date Published: | 2014-03-01 |
| Start Page: | 286 |
| End Page: | 296 |
| Language: | English |
| DOI: | 10.1016/s1470-2045(14)70030-0 |
| PROVIDER: | scopus |
| PUBMED: | 24556040 |
| PMCID: | PMC5719485 |
| DOI/URL: | |
| Notes: | Export Date: 1 May 2014 -- CODEN: LOANB -- Source: Scopus |
