Novel VEGF inhibitor may play role in advanced renal cell carcinoma

Orlando, FL-Use of tivozanib, an experimental tyrosine kinase inhibitor (TKI) with increased specificity and potency for the vascular endothelial growth factor (VEGF) receptor, as initial targeted therapy for patients with advanced renal cell carcinoma did not translate into improved overall survival compared with sorafenib (Nexavar) in a phase III clinical trial.

However, allowance for use of next-line cancer therapies hindered the overall survival comparison, said first author Robert J. Motzer, MD.

In TIVO-1, final overall survival results showed no significant difference between tivozanib and the first-generation TKI sorafenib in patients with renal cell carcinoma who received up to one prior line of therapy, excluding targeted agents, said Dr. Motzer, attending physician in the genitourinary oncology service at Memorial Sloan-Kettering Cancer Center, New York.

As part of the design of the extension phase of TIVO-1, patients who experienced disease progression 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. Of the 257 patients on sorafenib, 70% advanced to next-line VEGF therapy, including 155 who started next-line tivozanib at the time of the final analysis. Only 10% of patients in the tivozanib arm received next-line VEGF therapy.

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

“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,” said Dr. Motzer.

“Also, since it’s more selective it has a better safety profile, and that’s what we see in the trial,” added Dr. Motzer, who presented the findings at the Genitourinary Cancers Symposium in Orlando, FL.

In TIVO-1, 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 off drug, or 400 mg of sorafenib twice daily continuously in a 4-week cycle. Although the study achieved its primary endpoint, the difference in PFS with tivozanib relative to sorafenib was relatively modest (11.9 vs. 9.1 months, p=.042). In a pre-specified subgroup analysis of patients who were treatment-naïve, which accounted for approximately 70% of patients in each treatment arm, the PFS benefit of tivozanib was 12.7 months versus 9.1 months with sorafenib (hazard ratio=0.756; p=.037).

Little difference in overall survival

Median overall survival was 28.8 months for tivozanib and 29.3 months for sorafenib.

At final analysis, 27% of patients were alive and had not discontinued tivozanib versus 12% of patients who were alive and had not discontinued sorafenib.

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

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. It’s believed that hypertension relates to the ability to inhibit the VEGF receptor. It’s actually an on-target effect,” Dr. Motzer said. “The hypertension is something we can generally manage with antihypertensives.”

Clinical trials in kidney cancer to date have used PFS as the primary endpoint, for two reasons, Dr. Motzer told Urology Times. “Survival is improving, so PFS gives you an answer faster,” he said. “Also, with multiple therapies that have become available in the last 5 years, it’s hard to control what therapies the patients are going to get after they are on the study,” confounding overall survival comparisons.

Tivozanib “should be an option for patients,” he continued. “What I really would like to see is a head-to-head comparison between tivozinab and one of the drugs we commonly use as first-line in the United States, such as pazopanib [Votrient].”

Dr. Motzer is a consultant/adviser for Pfizer, and has received research funding from AVEO, GlaxoSmithKline, and Pfizer. Several of his co-authors are consultant/advisers; have employment/leadership positions in; and/or own stock in AVEO.UT