Therapies targeting vascular endothelial growth factor (VEGF) and mTOR signaling pathways are standard first-line and second-line treatment options for patients with metastatic renal-cell carcinoma. However, an unmet medical need exists for patients who had previously received VEGF-targeted and mTOR inhibitor therapies.
Fibroblast growth factor pathway activation may be a mechanism of escape from VEGF-targeted therapies. Dovitinib (TKI258) is an oral tyrosine kinase inhibitor that inhibits VEGF, fibroblast growth factor receptors, and platelet-derived growth factor receptors. Therefore, researchers from the Global Oncologic Learnings for Dovitinib (GOLD) trial sought to compare dovitinib versus sorafenib (Nexavar) as third-line targeted therapies in this patient population (Motzer RJ, et al. Lancet Oncol. 2014;15:286-296).
GOLD was a multicenter, open-label, randomized, phase 3 trial that included 570 patients with metastatic renal-cell carcinoma with clear-cell or a component of clear-cell histology, and who had received 1 previous VEGF-targeted therapy (eg, sunitinib [Sutent] or bevacizumab [Avastin]) and 1 previous mTOR inhibitor (eg, everolimus [Afinitor] or temsirolimus [Torisel]). In a 1:1 ratio, patients were randomly assigned to receive dovitinib 500 mg orally according to a 5-days-on and 2-days-off schedule (N = 284), or to sorafenib 400 mg twice daily (N = 286). Randomization was stratified by risk group and by region. Patient characteristics were well-balanced between both groups.
The primary end point was progression-free survival (PFS) on masked central review. Efficacy was assessed in all patients who were randomly assigned, and safety was assessed in patients who received at least 1 dose of the study drug.
The findings showed no difference in PFS between the 2 treatment groups. The median follow-up was 11.3 months. The median PFS times were 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 PFS benefit with dovitinib versus sorafenib treatment in analysis by patient demographics and disease characteristics. Partial response was noted in 4% of the patients in each group. In the dovitinib and sorafenib groups, the median overall survival times were 11.1 months and 11 months, respectively (HR, 0.96).
Common grade 3 and 4 adverse events included hypertriglyceridemia (14%), fatigue (10%), hypertension (8%), diarrhea (7%), dyspnea (6%), and anemia (5%) in the dovitinib group; and hypertension (17%), fatigue (8%), dyspnea (7%), palmar-plantar erythrodysesthesia (6%), and anemia (6%) in the sorafenib group. The most common serious adverse event in the dovitinib and sorafenib groups was dyspnea (6% and 5%, respectively). Adverse events led to dose change or interruption in 51% of the patients receiving dovitinib and in 49% of the patients receiving sorafenib.
Although dovitinib showed activity, the researchers concluded that dovitinib and sorafenib had similar efficacies when used as third-line targeted treatments for metastatic renal-cell carcinoma. The findings provide efficacy data for future design of clinical trials of third-line therapies. The 11-month median overall survival highlights the need for study and identification of novel agents in this setting.
