Long-Term Survival in Patients With Relapsed/Refractory Advanced Renal Cell Carcinoma Treated With Tivozanib: Analysis of the Phase III TIVO-3 Trial

Abstract

Background: Tivozanib is an oral vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI) with efficacy in advanced renal cell carcinoma (RCC). Long-term exploratory analyses from the TIVO-3 trial in relapsed/refractory (R/R) RCC including patients (26%) with prior immuno-oncology (IO) therapy are reported.

Methods: Patients with R/R advanced RCC that progressed with 2 or 3 prior systemic therapies (≥1 VEGFR TKI) were randomized to tivozanib 1.5 mg QD or sorafenib 400 mg BID, stratified by IMDC risk and previous therapy. Safety, investigator-assessed long-term progression-free survival (LT-PFS), and serial overall survival (OS) were assessed.

Results: Mean time on treatment was 11.0 months with tivozanib (n = 175) and 6.3 months with sorafenib (n = 175). Fewer grade ≥3 treatment-related adverse events occurred with tivozanib (46%) than sorafenib (55%). Dose modification rates were lower with tivozanib than sorafenib across age/prior IO subgroups; prior IO therapy did not impact dose reductions or discontinuations in either arm. Landmark LT-PFS rates were higher with tivozanib (3 years: 12.3% vs 2.4%; 4 years: 7.6% vs 0%). After 22.8 months mean follow-up, the OS HR was 0.89 (95% CI, 0.70-1.14); when conditioned on 12-month landmark PFS, tivozanib showed significant OS improvement over sorafenib (HR, 0.45; 95% CI, 0.22-0.91; 2-sided P = .0221).

Conclusions: Tivozanib demonstrated a consistent safety profile and long-term survival benefit in patients with R/R advanced RCC who were alive and progression free at 12 months. These post hoc exploratory analyses of LT-PFS and conditional OS support a clinically meaningful improvement with tivozanib versus sorafenib in this advanced RCC population.

Keywords: carcinoma; long-term progression free survival; relapsed kidney cancer; renal cell; tivozanib; vascular endothelial growth factor.

Figure 1.

Dose modifications by age and prior IO therapy status. Dose interruption, dose reduction, and dose discontinuation for patients treated with tivozanib or sorafenib by age (<65, 65-74, and ≥75 years; A) and IO status (B). Data cutoff: May 2020. Abbreviation: IO, immuno-oncology.

Figure 2.

Grade ≥3 TRAEs attributed to VEGFR TKI class effects by age and prior IO therapy status. Grade ≥3 TRAEs for patients treated with tivozanib or sorafenib by age (<65, 65-74, and ≥75 years; A) and IO therapy status (B). Data cutoff: May 2020. TRAE grading was performed using the criteria from the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03). Overall grade ≥3 TRAEs and grade ≥3 TRAEs attributed to VEGFR TKI class effects were reported. Abbreviations: IO, immuno-oncology; PPE, palmar-plantar erythrodysesthesia; TKI, tyrosine kinase inhibitor; TRAE, treatment-related adverse event; VEGFR, vascular endothelial growth factor receptor.

Figure 3.

Landmark rates (95% CI) of LT-PFS in TIVO-3: tivozanib versus sorafenib. The INV-assessed PFS HR with extended follow-up was 0.624 (95% CI, 0.49-0.79) and favored tivozanib over sorafenib (2-sided, log-rank P < .0001). HR was obtained from a Cox hazards regression model, and P values were 2-sided log-rank tests. ^aPercentage (95% CI); ^bodds ratio not calculated at months 42 and 48 due to insufficient number at risk. Abbreviations: ∆, absolute difference; HR, hazard ratio; INV, investigator; LT-PFS, long-term progression-free survival; SOR, sorafenib; TIVO, tivozanib.

Figure 4.

Serial OS with extended follow-up. To evaluate for effects of maturation of OS, Cox proportional hazards and log-rank statistics were used to estimate HR (95% CI) for OS using prespecified (2 years after last patient in, August 2019; 251 events, May 2020) and exploratory (extended follow-up: 270 events, January 2021; database closure, May 24, 2021) ITT analyses. HR, hazard ratio; ITT, intention to treat; OS, overall survival.

Figure 5.

Kaplan-Meier survival curve of conditional OS in patients with 12-month PFS. The Kaplan-Meier survival curves for tivozanib and sorafenib groups conditioned on 12-month PFS. Conditional analyses of Cox proportional hazards models and stratified log-rank statistics, using data from patients achieving 12-month PFS in either group, were used to estimate the hazard ratio. Data cutoff: May 24, 2021. Abbreviations: HR, hazard ratio; OS, overall survival; PFS, progression-free survival; SOR, sorafenib; TIVO, tivozanib.