Tivozanib Improves PFS Versus Sorafenib in Patients With Renal Cell Carcinoma

Robert J. Motzer, MD

Tivozanib increased progression-free survival (PFS) and objective response rate (ORR) in patients with renal cell carcinoma compared with sorafenib (Nexavar), according to the results of a phase III trial presented at ASCO 2012. The targeted therapy tivozanib inhibits VEGF receptors 1, 2, and 3, which have been known to promote angiogenesis and tumor progression.

“This study demonstrated that a more potent selective VEGF-R inhibitor with a long half-life achieved superior efficacy combined with decreased off-target toxicities,” Robert J. Motzer, MD, attending physician, Genitourinary Oncology Service, Memorial Sloan-Kettering Cancer Center in New York City and professor of Medicine, Weill Medical College at Cornell University, said in a presentation at ASCO. “Tivozanib should be considered as a first-line treatment option for metastatic renal cell carcinoma,” he added.

In the phase III tivozanib trial, 517 patients with advanced renal cell carcinoma were randomized to receive either 1.5 mg of tivozanib once daily for 3 weeks, followed by 1 week of rest (n = 260), or 400 mg of sorafenib twice daily continuously in a 4-week cycle (n = 257). Patients were either treatment-naïve or received no more than one prior systemic therapy for metastatic disease. No patients in the study received any prior VEGF- or mTOR-targeted therapy. The primary endpoint for the study was PFS.

According to the results, which were verified through blinded, independent radiological review, the median PFS in the tivozanib arm was 11.9 months compared with 9.1 months in the sorafenib arm (hazard ratio [HR] = 0.797; 95% CI, 0.639-0.993; P = .042). Further analysis of patients who were treatment-naïve, which accounted for approximately 70% of the patients enrolled in each arm, showed that median PFS in the treatment-naïve tivozanib arm was 12.7 months versus 9.1 months in the sorafenib treatment-naïve arm (HR = 0.756; 95% CI, 0.580-0.985; P = .037).

The toxicity profiles for the arms varied in some areas. Patients receiving tivozanib experienced higher overall rates of hypertension (44% vs 34%), dysphonia (21% vs 5%), and back pain (14% vs 7%), as compared with the sorafenib arm. Although hypertension was the most common adverse event associated with tivozanib, “This study and others suggest that the development of hypertension is associated with increased efficacy [of tivozanib],” Motzer said.

Patients receiving sorafenib had higher overall rates of diarrhea (32% vs 22%), hand-foot syndrome (54% vs 13%), and alopecia (21% vs 2%), compared with the tivozanib arm.

Other common side effects, including fatigue, weight loss, asthenia, nausea, dyspnea, and decreased appetite, were roughly equivalent across both study arms.

There were more dose interruptions and reductions in the sorafenib arm than in the tivozanib arm. In the tivozanib arm, 18% of patients had dose interruptions, 12% had dose reductions, and 4% discontinued the use of the drug, compared with 35%, 43%, and 5%, respectively, in the sorafenib arm.

Motzer RJ, Nosov D, Eisen T, et al. Tivozanib versus sorafenib as initial targeted therapy for patients with advanced renal cell carcinoma: Results from a phase III randomized, openlabel, multicenter trial. J Clin Oncol. 2012;30(suppl; abstr 4501).