Dmitry Nosov

354 Background: Tivozanib hydrochloride (T) is a potent, selective, tyrosine kinase inhibitor of all 3 VEGF receptors with a long half-life. T has shown tolerability and has extended progression-free survival (PFS) compared with sorafenib (S; median 11.9 months vs. 9.1 months; p =0.042) in a phase III trial (TIVO-1) as initial targeted therapy for pts with mRCC. We report results of PFS subgroup analyses from TIVO-1. Methods: Pts with clear-cell mRCC, prior nephrectomy, and ≤1 prior treatment for mRCC were randomized to T (n=260) or S (n=257). Cox proportional hazards model was used to evaluate PFS. Results: Significant improvement in PFS by T vs. S was observed for the following prespecified subgroups: white, Eastern Cooperative Oncology Group (ECOG) performance status 0, ≥1 year since diagnosis, no prior treatment, ≥2 metastatic sites, North America/Western Europe, baseline systolic blood pressure (SBP) ≤140 mm Hg, and baseline diastolic BP (DBP) ≤90 mm Hg. Exploratory subgroup analysis showed a similar significant improvement by T vs. S in Memorial Sloan-Kettering Cancer Center (MSKCC) favorable prognostic group, and pts who developed hypertension on study had significantly longer PFS than pts with normal BP. The improvement in PFS by T vs S was more marked for the subgroups that developed hypertension (selected subgroups shown in the table). Conclusions: PFS subgroup analyses showed a consistent advantage with T vs. S for mRCC. Clinical trial information: NCT01030783. [Table: see text]

364 Background: Tivozanib hydrochloride (tivozanib) is a potent, selective, tyrosine kinase inhibitor of all three vascular endothelial growth factor receptors, with a long half-life and has shown superior efficacy, measured as progression-free survival (PFS), as first-line, targeted therapy vs. sorafenib in a phase III trial (TIVO-1) in patients with advanced renal cell carcinoma (J Clin Oncol2012;30[suppl]:Abstract 4501). Patients who progressed (PD) on sorafenib could receive tivozanib in an open-label, prospective multicenter extension study of TIVO-1. We report preliminary efficacy and safety data for patients who had PD on sorafenib and subsequently received tivozanib in this extension study. Methods: Patients with PD on sorafenib, per RECIST version 1.0, were eligible to receive tivozanib dosed at 1.5 mg/day PO for 3 weeks followed by a 1-week rest, in repeated 4-week cycles, until PD or unacceptable toxicity. Patients were to have been no more than 4 weeks from last dose of sorafenib until initiation of tivozanib, and have an ECOG performance status of ≤2. Dose adjustments were performed as previously reported. Objectives included assessing objective response rate (ORR), duration of response, PFS for tivozanib following PD on sorafenib, and overall survival. Results: As of January 20, 2012, 127 patients (72.4% male) were evaluable for response. Median age was 59.0 years (range: 23–85 years). ORR was 7.9% (95% CI 3.8–14.0%; partial response [PR]=7.9%; stable disease [SD]=65.4%; PD=18.9%), and 71.3% of patients showed tumor shrinkage. Median duration of PR was 11.1 months (95% CI ≥7.5 months). Median duration of SD was 12.7 months (95% CI ≥7.4 months). Median PFS was 5.6 months (95% CI 5.4–9.1 months). Median OS was not yet reached. Most commonly reported treatment-emergent adverse events (all grades/Grade ≥3) were hypertension (22.4%/10.2%), asthenia (11.0%/3.1%), fatigue (11.0%/3.9%), palmar-plantar erythrodysesthesia (11.0%/1.6%), and diarrhea (10.2%/1.6%). Conclusions: Tivozanib has anti-tumor activity after PD on sorafenib. The adverse-event profile of tivozanib after sorafenib is similar to that observed in TIVO-1. Clinical trial information: NCT01076010.

Purpose: The antitumor activity and safety of tivozanib, which is a potent and selective vascular endothelial growth factor receptor-1, -2, and -3 inhibitor, was assessed in patients with advanced/metastatic renal cell carcinoma (RCC). Patients and Methods: In this phase II, randomized discontinuation trial, 272 patients received open-label tivozanib 1.5 mg/d (one cycle equaled three treatment weeks followed by a 1-week break) orally for 16 weeks. Thereafter, 78 patients who demonstrated ≥ 25% tumor shrinkage continued to take tivozanib, and 118 patients with less than 25% tumor change were randomly assigned to receive tivozanib or a placebo in a double-blind manner; patients with ≥ 25% tumor growth were discontinued. Primary end points included safety, the objective response rate (ORR) at 16 weeks, and the percentage of randomly assigned patients who remained progression free after 12 weeks of double-blind treatment; secondary end points included progression-free survival (PFS). Results: Of 272 patients enrolled onto the study, 83% of patients had clear-cell histology, 73% of patients had undergone nephrectomy, and 54% of patients were treatment naive. The ORR after 16 weeks of tivozanib treatment was 18% (95% CI, 14% to 23%). Of the 118 randomized patients, significantly more patients who were randomly assigned to receive double-blind tivozanib remained progression free after 12 weeks versus patients who received the placebo (49% v 21%; P = .001). Throughout the study, the ORR was 24% (95% CI, 19% to 30%), and the median PFS was 11.7 months (95% CI, 8.3 to 14.3 months) in the overall study population. The most common grade 3 and 4 treatment-related adverse event was hypertension (12%). Conclusion: Tivozanib was active and well tolerated in patients with advanced RCC. These data support additional development of tivozanib in advanced RCC.