Tivozanib versus sorafenib as initial targeted therapy for patients with advanced renal cell carcinoma: Results from a phase III randomized, open-label, multicenter trial.

Abstract

4501 Background: Tivozanib, a potent, selective, long half-life tyrosine kinase inhibitor targeting all three VEGF receptors, showed activity and tolerability in a Phase II trial (JCO 2011;29[18S]:4550). Methods: Patients (pts) with clear cell advanced renal cell carcinoma (RCC), prior nephrectomy, RECIST-defined measurable disease, and Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 were randomized 1:1 to tivozanib (T) 1.5 mg once daily for 3 weeks (wks) followed by 1 wk rest, or sorafenib (S) 400 mg twice daily continuously in a 4-wk cycle. Pts were treatment naïve or received no more than 1 prior systemic therapy for metastatic disease; pts receiving prior VEGF- or mTOR-targeted therapy were excluded. The primary endpoint was progression-free survival (PFS) per blinded, independent radiological review. 500 pts were to be enrolled to observe 310 events, yielding 90% power to detect medians of 9.7 and 6.7 months (m) with 5% type I error (2-sided). Results: A total of 517 pts were randomized to T (n=260) or S (n=257). Demographics were well balanced between the 2 groups, except ECOG 0 (T: 45% vs S: 54%, p=0.035). Median PFS was 11.9 m for T vs 9.1 m for S (HR=0.797, 95% CI 0.639–0.993; p=0.042). In the treatment-naïve stratum (70% of pts enrolled in each arm), the median PFS was 12.7 m for T vs 9.1 m for S (HR 0.756, 95% CI 0.580–0.985; p=0.037). In all pts, objective response rate (ORR) for T was 33% vs 23% for S (p=0.014). The most common adverse event (AE; all grades/≥grade 3) for T was hypertension (T: 46%/26% vs S: 36%/18%) and for S was hand-foot syndrome (T: 13%/2% vs S: 54%/17%). Other important AEs included diarrhea (T: 22%/2% vs S: 32%/6%), fatigue (T: 18%/5% vs S: 16%/4%), and neutropenia (T: 10%/2% vs S: 9%/2%). Patient-reported outcome data are being analyzed. Overall survival data are not mature. Conclusions: Tivozanib demonstrated significant improvement in PFS and ORR compared with sorafenib as initial targeted treatment for advanced RCC. The safety profile of tivozanib is favorable, and includes a low incidence of fatigue, diarrhea, myelosuppression, and hand-foot syndrome.

Targeting PI3K and mTORC2 in metastatic renal cell carcinoma: New strategies for overcoming resistance to VEGFR and mTORC1 inhibitors

“…In patients with RCC who were treatment-na€ ıve or who had received no more than one prior systemic therapy (excluding VEGFR-or mTOR-targeted therapies), tivozanib showed significant improvement in PFS and ORR compared with sorafenib [PFS (11.9 vs. 9.1 mo), ORR (33 vs. 23%)], suggesting that tivozanib may become another option for first-line therapy for mRCC. 25 In addition, the anti-VEGF monoclonal antibody bevacizumab (Avastin), in combination with IFN-a, was approved for use in patients with mRCC after demonstrating improved PFS and response in comparison with IFN-a plus placebo [PFS (10.2 vs. 5.4 mo), ORR (30 vs. 12%)]. 26,27 Molecular Mechanisms of mTORC1-Targeted mRCC Therapies Another mechanism to prevent HIF/VEGF-mediated angiogenesis is to inhibit mTORC1, one of the two mTOR complexes that couples environmental growth signals to the cellular growth machinery.…”

Effects of ketoconazole or rifampin on the pharmacokinetics of tivozanib hydrochloride, a vascular endothelial growth factor receptor tyrosine kinase inhibitor

“…10 In a recent phase III trial (TIVO-1 NCT01030783) in patients with metastatic RCC, tivozanib was well tolerated and demonstrated longer progression-free survival relative to sorafenib. 11,12 Tivozanib is an investigational drug that has not been approved for use in any country; it has been studied in RCC, triple-negative breast cancer, and colorectal cancer. Data from in vitro studies indicate that a portion of tivozanib metabolism is mediated by cytochrome P450 (CYP) isoforms, specifically CYP3A4 and CYP1A1 (extrahepatic).…”

The effect of food on the pharmacokinetics of tivozanib hydrochloride

“…1 Tivozanib has demonstrated anti-tumor activity and was well tolerated in Phase II and Phase III studies in patients with renal cell carcinoma. 2,3 In a Phase III study, tivozanib significantly improved progression-free survival (PFS) compared with sorafenib (median PFS, 11.9 vs. 9.1 months, respectively; P ¼ .042) in the overall study population. 3 Tivozanib also was well tolerated; the most commonly reported adverse event (AE) was hypertension, a common, reversible, ontarget effect of VEGFR inhibition.…”