FGF Inhibitor No Better Than Sorafenib in Third-Line Metastatic RCC

Chemical structure of dovitinib

The fibroblast growth factor (FGF) inhibitor dovitinib failed to improve progression-free survival outcomes as a third-line treatment for patients with metastatic renal cell carcinoma compared with sorafenib, according to the results of a phase III study.

The study, funded by Novartis, was published online in Lancet Oncology.

“FGF pathway activation has been proposed as a mechanism of escape from VEGF-targeted therapies, and increased plasma FGF2 concentrations were reported in patients with renal cell carcinoma who had disease progression while receiving VEGF-targeted therapies, and in patients who previously received VEGF-targeted therapies,” wrote researchers led by Robert J. Motzer, MD, of Memorial Sloan-Kettering Cancer Center.

Therefore, Motzer and colleagues conducted this phase III study to compared outcomes of dovitinib to the VEGFR inhibitor sorafenib in the third-line setting. In this study, patients who had progressed on previous VEGF-targeted therapy and at least one mTOR inhibitor were randomly assigned to treatment with dovitinib (TKI258; n = 284) or to sorafenib (n = 286). The primary efficacy endpoint was progression-free survival.

At a median follow-up of 11.3 months, the median progression-free survival was 3.7 months for dovitinib compared with 3.6 months for sorafenib (P = .063). Similarly, no significant difference was seen between the two groups for overall survival. According to the researchers, these results challenge “the hypothesis that FGF activation is the fundamental mechanism of resistance to VEGF-targeted therapy.”

The most common grade 3 or 4 adverse events for dovitinib were hypertriglyceridemia, fatigue, hypertension, and diarrhea; in the sorafenib group they were hypertension, fatigue, dyspnea, and palmar plantar erythrodysaesthesia.

“The results of the current study support the use of a VEGFR tyrosine-kinase inhibitor (ie, sorafenib) in patients who have already received VEGF and mTOR inhibitors,” the researchers wrote.

In an editorial that accompanied the article, Manuela Schmidinger, MD, department of medicine at the Medical University of Vienna, Austria, questioned if FGF was the right target in this patient population.  

“Most patients in this trial (92%) had received the sequence VEGF inhibitor followed by an mTOR inhibitor before the study drug,” wrote Schmidinger. “The timing of FGF inhibitor treatment in Motzer and colleagues’ trial might have been wrong because the potential importance of FGF inhibition has been linked to the presence of VEGF-inhibitor resistance. It could be speculated that dovitinib might have had more effect in the second line, when resistance to VEGF inhibitors has occurred.”

However, Schmidinger added that since the trial sponsor already has an effective second-line treatment-everolimus-marketing considerations “might have influenced the trial design.”