Another Tyrosine Kinase Inhibitor Joins the Lineup in Renal Cell Carcinoma

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The novel tyrosine kinase inhibitor tivozanib was superior to sorafenib (Nexavar) for the treatment of advanced renal cell carcinoma in the phase III TIVO-1 trial.1 Tivozanib is a potent, selective inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, with a long half-life that is designed to optimize blockade while minimizing off-target toxicities.

For first-line treatment, 517 patients were randomly assigned to receive tivozanib at 1.5 mg/d given 3 weeks on/1 week off or sorafenib at 400 mg twice daily given continuously. Median progression-free survival was 11.9 months with tivozanib vs 9.1 months with sorafenib (HR = 0.797; P = .042). In most subgroups, tivozanib was favored, and about one-third of patients had a measurable response on the drug.

Side effects mostly associated with tivozanib included hypertension, dysphonia, and back pain, while those most likely with sorafenib included diarrhea, hand-foot syndrome, and alopecia.

Many First-line Options

William K. Oh, MD, of Mount Sinai School of Medicine, New York, commented on the findings at Best of ASCO Boston. He said tivozanib joins an already “crowded space” as a first-line option. No fewer than seven drugs are acceptable by the National Comprehensive Cancer Network (NCCN).

Dr. Oh presented several concerns about the drug and the TIVO-1 trial, one being the choice of sorafenib as the reference standard. Sorafenib has a category 2A recommendation from the NCCN, whereas sunitinib (Sutent) has a category 1 rating, is used more often, and may have been a more reliable comparator, he suggested. “The FDA approved the design, but the investigators picked the wimpiest guy in the room to pick a fight with,” he commented.

Secondly, he noted that determining the best initial targeted therapy in metastatic renal cell carcinoma is a challenge for clinicians. Efficacy, toxicity, cost, and patient acceptance are all relevant factors; given equivalent efficacy, many choices will be made based on toxicity, he said.

Finally, he questioned whether tivozanib is much different from current first-line therapies. The results of an ongoing noninferiority study comparing pazopanib to sunitinib will be informative, he said.

Moving Forward

“What we really need in metastatic renal cell carcinoma is an understanding of tyrosine kinase inhibitor resistance,” Dr. Oh concluded. “No question, we are much better off than before we had the tyrosine kinase inhibitors, but the problem is that these agents are very similar to each other. We need better drugs that focus on new targets, as we have seen in tumors such as lung cancer, to move forward in renal cell carcinoma.” ■

Disclosure: Dr. Oh disclosed a relationship with Pfizer.


1. Motzer RJ, Nosov D, Eisen T, et al: Tivozanib versus sorafenib as initial targeted therapy for patients with advanced renal cell carcinomas: Results from a phase III randomized, open-label, multicenter trial. 2012 ASCO Annual Meeting. Abstract 4501. Presented June 2, 2012.