CHICAGO – The investigational targeted agent tivozanib was associated with significantly more clinical responses and greater progression-free survival than was sorafenib in a head-to-head comparison among patients with metastatic renal cell carcinoma.
Median progression-free survival for 260 patients randomized to tivozanib was 11.9 months in an independent reviewer analysis, compared with 9.1 months for 257 patients randomized to sorafenib (Nexavar) in an open-label, multicenter phase III clinical trial (P = .042), Dr. Robert Motzer reported at the annual meeting of the American Society of Clinical Oncology.
Dr. Robert Motzer
Dr. Motzer, from the genitourinary oncology service at Memorial Sloan-Kettering Cancer Center in New York City, said data on overall survival, a secondary end point of the trial, would be presented at a later date.
Like sorafenib (Nexavar), tivozanib is a selective tyrosine kinase inhibitor (TKI) with affinity for vascular endothelial growth factor receptors (VEGFR) 1, 2, and 3.
"This study demonstrated that a more potent, selective VEGFR inhibitor with a long half-life achieved superior efficacy, combined with decreased off-target toxicity. Tivozanib should be considered a first-line treatment option for metastatic renal cell carcinoma," Dr. Motzer said.
The invited discussant, Dr. Tim Eisen, a professor of oncology at the University of Cambridge, England, was a coauthor of the study, but he took a more cautious approach. He noted that tivozanib may have looked better than it really is, because the trial pitted a brash young up and comer against a paunchy, aging fighter.
"There are still doubts in my view about the choice of sorafenib, and I would very much like to see comparative data with sunitinib [Sutent] or pazopanib [Votrient] before fully adopting [tivozanib] as a first-line option," he said.
The best responses seen in the study for sorafenib were a 1% complete response rate and 23% partial response, and the progression-free survival values observed were about as good as it gets with sorafenib compared with other studies, Dr. Eisen said, but they stood in contrast to those of the newer agent.
"I think we also need quality of life data, because although the side effect profile is very good as measured in the studies with tivozanib, we don\'t yet know whether that translates into patient preference," he added.
In the TIVO-1 phase III trial, patients with advanced renal cell carcinoma (RCC) with clear cell histology, prior nephrectomy, good performance status (ECOG 0-1), not more than one prior line of therapy, and no prior VEGF or mTOR (mammalian target of rapamycin) inhibitor therapy were assigned to either tivozanib 1.5 mg/day orally for 3 weeks of a 4-week cycle or sorafenib 400 mg orally twice daily continuously. Patients were stratified by geographic region, prior therapies, and number of metastatic lesions.
Independent reviewers determined that tivozanib was associated with a significantly lower risk for disease progress (hazard ratio, 0.797). The investigators were a bit more generous, however, reporting median progression-free survival reached 14.7 months with tivozanib vs. 9.6 months with sorafenib (HR, 0.722; P = .003).
The objective response rates by independent review were 33% and 23%, respectively (P = .014).
There were fewer dose interruptions (18% vs. 35%), dose reductions (12% vs. 43%), and discontinuations (4% vs. 5%) with tivozanib.
Patients on tivozanib had less treatment-emergent grade 3 or 4 diarrhea (2% vs. 6%), palmar plantar erythrodysesthesia (2% vs. 17%), and grade 1-2 alopecia (2% vs. 21%).
In contrast, patients who received the experimental agent had more hypertension (all grade, 44% vs. 34%; grades 3/4, 2% vs. less than 1%), dysphonia (21% vs. 5%), and back pain (14% vs. 7%).
Dr. Motzer noted that the hypertension seen with tivozanib appears to be related to the treatment effect, as higher levels correlated with longer median progression-free survival. Patients with a diastolic blood pressure (BP) reading above 90 mmHg had a median progression-free survival of 18.3 months, compared with 9.1 months for those with a diastolic BP of 90 mmHg or less (HR, 0.553, P =.001). Similarly, patients with systolic BP above 140 mmHg had a median progression-free survival of 16.7 months, compared with 9.0 months for those with normal systolic BP (HR, 0.543, P less than .001).
The study was supported by AVEO Oncology and Astellas Oncology. Dr. Motzer reported receiving research funding from AVEO. Dr. Eisen is a coauthor of the study and has received honoraria and serves in a consulting or advisory role to Astellas and AVEO.