CHICAGO -- An investigational drug targeting all three forms of the vascular endothelial growth factor (VEGF) receptor was more effective against advanced renal cell carcinoma than a current standard agent, researchers found.
Results from a head-to-head phase III trial comparing the new drug, tivozanib, with sorafenib (Nexavar) in 517 patients showed significantly longer progression-free survival (11.9 months versus 9.1 months, P=0.042), according to Robert J. Motzer, MD, of Memorial Sloan-Kettering Cancer Center in New York City, and colleagues.
Action Points
- Note that this study was published as an abstract and will be presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.
- Note that in this study, tivozanib, a potent, selective, long half-life tyrosine kinase inhibitor targeting all three VEGF receptors demonstrated significant improvement in progression-free survival and objective response rate compared with sorafenib as initial targeted treatment for advanced renal cell carcinoma.
In an abstract published ahead of the annual meeting of the American Society of Clinical Oncology here, the researchers also reported an objective response rate of 33% with tivozanib versus 23% for sorafenib (P=0.014).
As has been the case with other angiogenesis inhibitors, the most common side effect with tivozanib was hypertension, seen at all levels of severity in 46% of patients and at grade 3 or 4 in 26%. The incidence with tivozanib was somewhat higher than in patients receiving sorafenib, of whom 36% had any degree of hypertension and 18% developed it at grade 3 or 4.
Tivozanib not only blocks VEGF receptor subtypes 1, 2, and 3, but also platelet-derived growth factor-beta and a third cancer promoter known as cKIT.
The phase III results were generally similar to those seen in earlier trials involving advanced renal cell carcinoma. For example, in a 272-patient, placebo-controlled study reported at the 2009 ASCO meeting, it produced an objective response rate of 25.4%.
In the current trial, Motzer and colleagues studied the drug in patients with clear cell, advanced renal cell carcinoma who had already undergone nephrectomy and who had Eastern Cooperative Oncology Group performance status of 0 or 1.
They had received no more than one prior systemic therapy for metastatic disease and some had not received drug treatment. Patients who had previously received VEGF inhibitors or mTOR-targeted drugs were excluded.
Patients were randomized equally to tivozanib (1.5 mg daily for three weeks followed by one week off therapy) or sorafenib (400 mg twice daily every day) in 4-week cycles.
The study's primary endpoint was median progression-free survival, evaluated by blinded, independent radiological reviewers. Overall survival rates were not reported in the abstract.
The two treatment groups were similar except that the tivozanib group had fewer patients with an ECOG performance status of 0 (45% versus 54%, P=0.035).
Tivozanib appeared to be especially effective in drug-naive patients. Median progression-free survival in this subgroup (70% of patients in both arms) was 12.7 months with the new agent compared with 9.1 months for sorafenib (P=0.037).
Although hypertension was somewhat more common with tivozanib, some other adverse effects appeared less frequent. These included the following:
- Hand-foot syndrome, all grades: tivozanib 13%, sorafenib 54%
- Hand-foot syndrome, grade 3+: tivozanib 2%, sorafenib 17%
- Diarrhea, all grades: tivozanib 22%, sorafenib 32%
- Diarrhea, grade 3+: tivozanib 2%, sorafenib 6%
Fatigue and neutropenia were seen in about equal numbers with both treatments and severe cases were rare. Mild to moderate fatigue was recorded for some 12% of patients and the incidence of grade 1 to 2 neutropenia was less than 10%.
Earlier this year, tivozanib's commercial backers indicated plans to apply for U.S. and European marketing approvals later this year.
Disclosures
The study was supported by Aveo Pharmaceuticals.
Motzer reported relationships with Aveo, Pfizer, GlaxoSmithKline, and Novartis. Several co-authors were Aveo employees.
Primary Source
American Society of Clinical Oncology
Motzer R, et al "Tivozanib versus sorafenib as initial targeted therapy for patients with advanced renal cell carcinoma: results from a phase III randomized, open-label, multicenter trial" ASCO 2012; Abstract 4501.