MILAN – Tivozanib, an investigational agent, is not only active in the treatment of renal cell carcinoma, but is also associated with minimal “off target” toxicity, according to phase II study findings.
The tyrosine kinase inhibitor (TKI), which targets all three vascular epithelial growth factor (VEGF) receptors, was associated with an overall median progression-free survival of 11.8 months in a difficult-to-treat patient population; 17% of 272 patients had nonclear cell histology, 27% did not have prior nephrectomy, and 46% had received at least one prior treatment.
Median progression-free survival was slightly longer, at 14.8 months, in patients with clear cell histology who had also undergone nephrectomy, which is the population of patients that is most commonly studied to gain drug approval in renal cell carcinoma.
“Patients randomized to continue tivozanib had a significantly higher disease control rate and median progression-free survival compared with those randomized to placebo,” said Dr. Dimitry Nosov of the N.N. Blokhin Russian Cancer Research Center in Moscow, who presented preliminary results of the randomized discontinuation trial at the annual congress of the European Society for Medical Oncology.
The trial involved a 16-week, open-label phase during which all patients received treatment with tivozanib, at a dosage of 1.5 mg/day for 3 weeks of a 4-week cycle. In all, 76 patients with progressive disease then stopped treatment, 78 of those with partial or complete responses continued open-label treatment, and 111 patients with stable disease were randomized to receive tivozanib or placebo for a further 12 weeks.
Dr. Nosov noted that the percentage of patients who remained progression free at 12 weeks following randomization to either tivozanib or placebo doubled with the active treatment (48% vs. 21%; P = .003).
The drug is reported to have greater potency for VEGF receptors 1, 2, and 3 than do other available agents, including Pfizer Inc.’s investigational agent axitinib, which may account for its low rate of “off-target” adverse events such as mucositis, stomatitis, fatigue, neutropenia, and hand-foot syndrome as seen in the trial. The most common side effects (all grades) reported for at least 10% of patients were hypertension (50%), dysphonia (22%), asthenia (approximately 13%), and diarrhea (12%).
“What’s extremely encouraging is the very good tolerability of this agent,” Dr. Tim Eisen, a professor at the University of Cambridge (England).
Dr. Eisen noted that although the number of patients who discontinued treatment was high at the end of the open-label treatment phase, it was also encouraging that progression-free survival was almost as good in patients who had stable disease and continued treatment with tivozanib as it was in those who had achieved a partial or complete response and received continued open-label treatment. “This might influence how we use the agent,” in clinical practice, he suggested.
The study was sponsored by AVEO Pharmaceuticals Inc. Dr. Nosov had no potential conflicts of interest, but several of his coauthors were employees of AVEO. The discussant, Dr. Eisen, has acted in advisory capacity for AVEO and GlaxoSmithKline, and has received research support and acted as an advisor to Bayer, Pfizer, and Roche.