No Progression-Free Survival Difference for Dovitinib vs Sorafenib in Third-Line Targeted Treatment of Metastatic Renal Cell Carcinoma
Fibroblast growth factor (FGF) pathway activation may be a mechanism of escape from vascular endothelial growth factor (VEGF)-targeted therapies. In a phase III trial reported in The Lancet Oncology, Motzer et al compared the VEGF and FGF receptor tyrosine kinase inhibitor dovitinib vs sorafenib (Nexavar) in third-line targeted treatment of metastatic renal cell carcinoma. There was no difference in progression-free survival between the two treatments. Biomarker analysis showed survival differences in both groups.
Study Details
In this open-label trial, 570 patients with metastatic renal cell carcinoma with clear cell or a component of clear cell histology who had received one previous VEGF-targeted therapy (eg, sunitinib [Sutent] or bevacizumab [Avastin]) and one previous mTOR inhibitor (eg, everolimus [Afinitor] or temsirolimus [Torisel]) were randomly assigned to receive dovitinib at 500 mg orally according to a 5-days-on/2-days-off schedule (n = 284) or sorafenib at 400 mg orally twice daily (n = 286). Randomization was stratified by risk group and region. The primary endpoint was progression-free survival on masked central review.
The dovitinib and sorafenib groups were generally balanced for age (median, 61 and 62 years, 34% and 42% ≥ 65 years), sex (75% and 77% male), ethnic origin (82% and 81% white), region (eg, 60% and 59% Europe and Middle East, America for 23% in both), Karnofsky performance score (100 in 29% and 26%, 90 in 33% and 35%), Memorial Sloan Kettering Cancer Center (MSKCC) risk group (intermediate in 58% and 57%, poor in 22% and 23%), metastatic sites (eg, lung in 79% and 76%, lymph nodes in 51% in both), previous treatment (nephrectomy in 96% and 91%, radiotherapy in 23% and 32%, cytokines in 7% and 8%), VEGF-target therapy (eg, sunitinib in 92% and 88%), mTOR inhibitor therapy (eg, everolimus in 87% and 86%), and number of prior treatments (two in 93% and 91%).
No Progression-Free Survival Difference
Median follow up was 11.3 months. Median progression-free survival was 3.7 months in the dovitinib group and 3.6 months in the sorafenib group (hazard ratio [HR] = 0.86, P = .063). No subgroup had a clinically significant progression-free survival benefit with dovitinib treatment in analyses by demographic and disease characteristics. Median progression-free survival according to favorable-, intermediate-, and poor-risk MSKCC status was 5.5 vs 3.7 months, 3.7 vs 3.7 months, and 3.6 vs 2.1 months.
Partial response was observed in 4% of patients in each group. Median overall survival was 11.1 vs 11.0 months (HR = 0.96, 95% confidence interval [CI] = 0.75–1.22), and median overall survival by favorable-, intermediate-, and poor-risk MSKCC status was not reached vs 19.3 months, 10.5 vs 11.2 months, and 5.1 vs 6.3 months.
Adverse Events
Common grade 3 or 4 adverse events included hypertriglyceridemia (14%), fatigue (10%), hypertension (8%), and diarrhea (7%) in the dovitinib group and hypertension (17%), fatigue (8%), dyspnea (7%), and palmar-plantar erythrodysesthesia (6%) in the sorafenib group. The most common serious adverse event was dyspnea (6% and 5%). Adverse events led to treatment discontinuation in 15% and 10% of patients and to dose change or interruption in 51% and 49%.
Survival Differences in Biomarker Analysis
Plasma samples for biomarker analysis were available from 281 dovitinib patients and 280 sorafenib patients. Analysis of overall survival by low (< median) and high (≥ median) biomarker levels at baseline showed improved median overall survival for: low vs high FGF2 (fibroblast growth factor 2) for dovitinib (13.4 vs 8.6 months, HR for high vs low = 1.56, P = .0085) and for sorafenib (13.3 vs 9.7 months, HR = 1.43, P = .0186); low vs high hepatocyte growth factor (HGF) for dovitinib (18.4 vs 6.7 months, HR = 3.89, P < .0001) and sorafenib (14.3 vs 7.0 months, HR = 2.30, P < .0001); low vs high placental growth factor (PLGF) for dovitinib (15.7 vs 8.1 months, HR = 1.86, P = .0014) and sorafenib (13.8 vs 7.4 months, HR = 1.59, P = .0050); and low vs high VEGFA for dovitinib (13.4 vs 8.1, HR = 1.77, P = .0043) and sorafenib (13.8 vs 7.0, HR = 2.00, P = .0001).
Similar trends were observed for progression-free survival but with higher P values for all markers except HGF. Significant increases from baseline in PLGF and VEGFA levels were observed after treatment with dovitinib and sorafenib. HGF and FGF2 levels increased after dovitinib treatment and decreased after sorafenib treatment.
The investigators concluded, “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.”
Robert J. Motzer, MD, of Memorial Sloan Kettering Cancer Center, is the corresponding author for The Lancet Oncology article.
The study was funded by Novartis Pharmaceuticals Corporation. For full disclosures of the study authors, visit www.thelancet.com.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
