Tivozanib Outperforms Sorafenib as First-Line Treatment in Advanced Renal-Cell Carcinoma

Wayne Kuznar

July 2012, Vol 3, No 5 - ASCO Annual Meeting


Tivozanib, a potent investigational tyrosine kinase inhibitor with a long half-life, demonstrated significant improvement in progression-free survival (PFS) as first-line targeted therapy for metastatic renal-cell carcinoma (RCC), according to results from a phase 3 randomized, open-label trial.

The results suggest that “tivozanib should be considered a first-line treatment option for metastatic RCC,” said Robert Motzer, MD, an oncologist at Memorial Sloan-Kettering Cancer Center, New York, and the trial’s lead investigator.

Tivozanib targets all 3 vascular endothelial growth factor (VEGF) receptors and is designed to optimize blockade while minimizing off-target toxicities. The long half-life permits once-daily dosing.

Impressive phase 2 safety data for tivozanib warranted a phase 3 trial comparing tivozanib with sorafenib in patients with metastatic RCC as firstline, targeted therapy.

The study included 517 patients with clear-cell advanced RCC, prior nephrectomy, Response Evaluation Criteria In Solid Tumors–defined measurable disease, and Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomized to tivozanib once daily for 3 weeks (followed by 1 week of rest) or sorafenib twice daily continuously in a 4-week cycle. Patients were either treatment-naive or had received no more than 1 prior systemic therapy for metastatic disease. Treatment continued until either disease progression or intolerance.

Patients randomized to the sorafenib arm were eligible to cross over to tivozanib therapy under a separate protocol after radiographic confirmation of disease progression, and many of them did. No crossover protocol was available for patients randomized to the tivozanib arm.

In the overall study population, tivozanib demonstrated a statistically significant improvement in PFS compared with sorafenib (median, 11.9 months vs 9.1 months) when assessed by an independent panel, correspond – ing to a 21% improvement with tivozanib. When assessed by the investigators, the difference in PFS between the 2 groups was 14.7 months with tivozanib versus 9.6 months for sorafenib, for a 28% improvement. The efficacy advantage of tivozanib was consistent across all subgroups.

Among the 70% of treatment-naive patients, median PFS was 12.7 months with tivozanib versus 9.1 months with sorafenib, and the objective response rate was 33% versus 23%, respectively.

Tolerability of tivozanib was also more favorable than sorafenib’s, as evidenced by a low rate of dose interruptions (17% vs 35%, respectively) and reductions (12% vs 43%, respectively); the discontinuation rates were 4% and 5%, respectively.

Treatment-emergent adverse events were present in 90% of patients in both groups, although important differences were seen in the safety profile between the 2 drugs.

According to Dr Motzer, although hypertension is the predominant adverse event with tivozanib, the development of hypertension is associated with tivozanib’s greater efficacy and potency for the VEGF receptor. The hypertension was treatable, requiring dose reduction in only 2% and dose discontinuation in only 1% of the patients treated with tivozanib.

“I think there’s clear evidence that the phase 2 safety profile has indeed been confirmed in phase 3,” said coinvestigator Tim Eisen, MD, Professor of Medical Oncology, Cambridge Research Institute, United Kingdom. The data require more careful evaluation over the next several months to “exclude any hypertension-related complication risk,” he said.