No Survival Advantage for Tivozanib Over Sorafenib in TIVO-1 Study

Robert J. Motzer, MD

The selective tyrosine kinase inhibitor (TKI) tivozanib did not show a significant difference in overall survival (OS) when compared with sorafenib in patients with renal cell carcinoma who received up to one prior line of therapy excluding targeted agents, according to the final results of a phase III trial. However, certain aspects of the design of the study could have affected these results.

The updated analysis was presented at the 2013 Genitourinary Cancers Symposium, held in Orlando, Florida, from February 14 — 16, 2013.

The study was designed to compare tivozanib, a second generation targeted therapy with increased specificity and potency for the vascular endothelial growth factor (VEGF) receptor, to sorafenib, which is approved by the FDA for the treatment of advanced renal cell carcinoma.

No difference in OS between the two treatments emerged despite superior progression-free survival (PFS), the primary endpoint, with tivozanib, which targets all three VEGF receptors.

However, 70% of patients assigned to sorafenib advanced to next-line VEGF therapy, including tivozanib, following disease progression, which confounded OS comparison, according to Robert J. Motzer, MD, attending physician in the Genitourinary Oncology Service at Memorial Sloan-Kettering Cancer Center in New York City and professor of medicine at Weill Medical College at Cornell University, and lead author of the study. Only 10% of patients in the tivozanib arm received next-line VEGF therapy.

The design of the study called for an extension phase in which patients who progressed on sorafenib based on investigator assessment were eligible to receive tivozanib, and patients who progressed while on tivozanib received subsequent treatment according to regional standards of care. It was this allowance for next-line therapy that hindered the ability to detect a difference in survival between the treatment groups.

“Tivozanib was developed as a highly selective and potent VEGF receptor inhibitor,” Motzer said. “It has fewer of the off-target effects [than sorafenib]. It’s felt that inhibition of the VEGF receptor is the most important part of response to treatment and so a drug that inhibits the receptor more strongly is believed to be potentially more effective. Also, since it’s more selective it has a better safety profile, and that’s what we see in the trial.”

In the phase III TIVO-1 trial, 517 patients with advanced renal cell carcinoma were randomized in a 1:1 ratio to receive either 1.5 mg of tivozanib once daily for 3 weeks, followed by 1 week off the drug (n=260), or 400 mg of sorafenib twice daily continuously in a 4-week cycle (n=257).

The study achieved its primary endpoint, but the difference in PFS with tivozanib relative to sorafenib was relatively modest (11.9 vs. 9.1 months; hazard ratio [HR] = 0.797; 95% CI, 0.639-0.993; P =.042). In a pre-specified subgroup analysis of patients who were treatment-naïve for metastatic disease, the PFS benefit of tivozanib was 12.7 months versus 9.1 months with sorafenib (HR = 0.756; 95% CI, 0.580-0.985; P = .037).

At the time of the final overall survival analysis, the mortality rates were 45.4% in the tovazinib group and 39.3% in the sorafenib group, corresponding to a stratified hazard ratio of 1.245 (95% CI, 0.954—1.624; P = .105) trending in favor of sorafenib. Median overall survival was 28.8 months for tivozanib and 29.3 months for sorafenib.

“The anti-tumor activity of tivozanib may be contributing to the overall survival of patients randomized to sorafenib in TIVO-1,” Motzer said. Median PFS was 8.4 months after switching from sorafenib to tivozanib, he noted, and tumor shrinkage occurred in 74% after the switch.

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Dr. Robert Motzer Analyzes Overall Survival in the TIVO-1 Study

At final analysis, 27% of patients were alive and had not discontinued tivozanib versus 12% of patients alive and without discontinuation of sorafenib.

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.

“The one side effect that occurs most commonly with tivozanib is hypertension,” Motzer said. “It’s believed that hypertension relates to the ability to inhibit the VEGF receptor. It’s actually an on-target effect. The hypertension is something we can generally manage with antihypertensives.” Hypertension on next-line tivozanib was about half as common as it was in TIVO-1—24% versus 44%.

Motzer RJ, Eisen T, Hutson TE, et al. Overall survival in patients from a phase III study of tivozanib hydrochloride versus sorafenib in patients with renal cell carcinoma. J Clin Oncol. 2013;31(suppl 6; abstr 350).

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