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

Abstract

Summary Background An unmet medical need exists for patients with metastatic renal cell carcinoma (RCC) who have progressed on a vascular endothelial growth factor (VEGF)–targeted therapy plus a mammalian target of rapamycin (mTOR) inhibitor. 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. This open-label, multicenter phase 3 study compared dovitinib with sorafenib as a third-line targeted therapy in metastatic RCC. Methods Patients (N = 570) with clear cell metastatic RCC who received one prior VEGF-targeted therapy and one prior mTOR inhibitor were randomized 1:1 to receive dovitinib (500 mg orally on a 5-days-on/2-days-off schedule) or sorafenib (400 mg orally twice daily). Randomization was stratified by risk group and region. The primary endpoint was progression-free survival (PFS) by central review. Secondary endpoints included overall survival (OS) and safety. Biomarker studies were an exploratory endpoint. Findings The median PFS was 3·7 months for dovitinib (n = 284) and 3·6 months for sorafenib (n = 286) (hazard ratio [HR], 0·86; 95% CI, 0·72-1·04; one-sided P = 0·063). Median OS was 11·1 months for dovitinib and 11·0 months for sorafenib (HR, 0·96; 95% CI, 0·75-1·22). Diarrhea, nausea, and vomiting were more common with dovitinib, whereas palmar-plantar erythrodysesthesia, hypertension, and alopecia were more common with sorafenib. In both arms, prolonged OS was observed in patients with low baseline plasma levels of FGF2, hepatocyte growth factor, and VEGFA. Interpretation Dovitinib demonstrated activity but not superior efficacy compared with sorafenib in patients who progressed on prior VEGF-targeted therapies and mTOR inhibitors. This trial provides landmark outcome data for future studies in this third-line setting. Funding Novartis Pharmaceuticals Corporation

Treatment patterns in metastatic renal cell carcinoma: a retrospective review of medical records from US community oncology practices

“…In the INTORSECT trial, comparing the effectiveness of sorafenib versus temsirolimus in the second-line treatment setting, no significant difference was noted between temsirolimus and sorafenib on progression-free survival but an overall survival advantage was reported for sorafenib in the second-line setting 12 . In a parallel trial, no statistically significant difference was found between sorafenib and dovitinib in a third-line treatment setting 13 . However, outcomes of second-line mTOR and TKI treated patients in the community setting have not been extensively explored.…”

Treatment options in advanced renal cell carcinoma after first-line treatment with vascular endothelial growth factor receptor tyrosine kinase inhibitors

“…Despite positive phase 2 data with this drug, 15 the GOLD study failed to show any improvement in outcomes with dovitinib. 16 Other data from phase 3 trials suggest the potential use of approved second-line agents in the third-line setting. In the RECORD-1 trial, 26% of patients had undergone treatment with two prior anti-VEGFR-TKIs and demonstrated a similar PFS benefit with everolimus to the overall population.…”

Targeting fibroblast growth factor receptor (FGFR) pathway in renal cell carcinoma

“…Dovitinib, a TKI that targets FGFR, PDGRF and VEGFR, [17] failed in demonstrating a progression-free survival (PFS) and overall survival advantage over sorafenib in the third-line setting after progression to VEGFR and mTOR inhibitors, not corroborating the strong preclinical rational of targeting the FGF pathway critical for antiangiogenic escape. [18] The main criticism of this phase 3 study (the GOLD trial) lies in the inappropriate timing of FGF inhibition (immediately after failure of an mTOR inhibitor). [19] During mTOR inhibition treatment, in fact, cancer cells could restore a VEGF-driven angiogenesis (rather than FGF), given the temporary effects of VEGF-inhibitor resistance.…”