Long-Term PFS From TIVO-3: Tivozanib (TIVO) Vs Sorafenib (SOR) in Relapsed/Refractory (R/R) Advanced RCC

Background

• Tivozanib (TIVO) is an oral vascular endothelial growth factor tyrosine kinase inhibitor that is approved by the US Food and Drug Administration (FDA) for treatment of patients with relapsed/refractory (R/R) renal cell carcinoma (RCC) following ≥2 prior systemic therapies1,2
• Long-term progression-free survival (LT-PFS) is a clinically meaningful outcome for evaluating efficacy in patients with R/R metastatic RCC (mRCC) who received ≥2 prior lines of therapy
• The TIVO-3 trial supported FDA approval of TIVO in R/R advanced RCC by demonstrating significantly improved efficacy outcomes over sorafenib (SOR), including:
  • Significantly longer independent review committee (IRC)–assessed PFS with TIVO vs SOR (unstratified hazard ratio [HR], 0.672; 95% CI, 0.52-0.87; stratified HR, 0.73; 95% CI, 0.56-0.95)
  • A higher overall response rate with TIVO compared with SOR as evaluated by IRC (18% vs 8%; P=.02)1
  • 1-year duration of response (DOR) was 71% (95% CI, 53%-88%) with TIVO and 46% (95% CI, 19%-73%) with SOR3
    • The median DOR by IRC was not reached (NR; 95% CI, 9.8-NR) with TIVO and was 5.7 months (95% CI, 5.6-NR) with SOR1
    • The median DOR by investigator (INV) assessment was 20.3 months (95% CI, 9.8-29.9) for TIVO and 9.0 months (95% CI, 3.7-16.6) with SOR4
• In this analysis, we assessed the proportion of TIVO-3 patients with R/R mRCC who achieved LT-PFS at regular intervals up to 4 years after initiation of TIVO or SOR

Methods

• TIVO-3 (NCT02627963) is a phase 3, global, open-label, parallel-arm study comparing TIVO with SOR in patients with R/R advanced mRCC.
• 350 patients were randomized 1:1 to receive TIVO (n=175) or SOR (n=175)
• Exploratory analysis of INV-assessed LT-PFS and long-term overall survival (OS) used a data cutoff of May 24, 2021. Unstratified PFS and OS HR for the intent-to-treat (ITT) population and prespecified subgroups (data not shown), as well as landmark values of LT-PFS at 6, 12, 24, 30, 36, 42, and 48 months are reported.
• Results include findings from the ITT population, with censoring for missing assessments and discontinuations without progressive disease
• Cox proportional hazards and log-rank statistics were used to estimate the HR and 95% CI for INV PFS and OS; odds ratios (ORs) are reported for landmark time points of LT-PFS up to 36 months
• Due to low patient numbers at the month 42 and 48 time points (data cutoff), no inferential statistical analyses were conducted. Data are presented descriptively
• LT-PFS rates across prespecified subgroups were analyzed descriptively and are presented at 1-year intervals, up to 4 years

Results

• The INV PFS HR analyzed with extended follow-up (data cutoff: May 24, 2021) favored TIVO compared with SOR (HR, 0.624; 95% CI, 0.49-0.79), which was comparable to the primary IRC PFS HR reported at the original October 2018 data cutoff (HR, 0.672; 95% CI, 0.52-0.87)
• Mature OS was also analyzed, and a nonsignificant trend favoring TIVO continued to emerge with accumulation of events (HR, 0.89; 95% CI, 0.70-1.14)
• Landmark INV LT-PFS rates up to 48 months were consistently higher with TIVO vs SOR: 12.3% vs 2.4% (36 months) and 7.6% vs 0% (48 months)
• Despite low numbers of patients at risk, subgroups with ≥15% INV LT-PFS at 3 years included International mRCCDatabase Consortium (IMDC) favorable risk, female sex, ECOG PS of 0, age ≥65 years, and geographic region of North America.
• Three-year INV LT-PFS rates ≥15% were only observed in the TIVO (and not SOR) arm

Conclusions

• INV PFS analyzed with extended follow-up was consistent with the primary IRC PFS
• OS continued to mature with longer follow-up, now demonstrating a nonsignificant trend in favor of TIVO
• Overall, the rates of INV LT-PFS were higher with TIVO compared with SOR at every time point evaluated
• The odds of experiencing LT-PFS at 36 months with TIVO were over 5 times higher than with SOR
• The higher LT-PFS rates with TIVO vs SOR were observed across subgroups, with clinically meaningful effects in the TIVO group (defined as ≥15% INV LT-PFS at 36 months) in patients with favorable risk status evaluated by IMDC, female sex, ECOG PS of 0, age ≥65 years, and North American residence
• A clinically relevant proportion of patients were alive and progression free at 3 and 4 years after initiating TIVO therapy compared with SOR, and this difference was consistent across all clinical and demographic subgroups evaluated

1. Atkins MB, Verzoni E, Escudier BJ, et al. Long-Term PFS From Tivo-3: Tivozanib (TIVO) Vs Sorafenib (SOR) in Relapsed/Refractory (R/R) Advanced RCC presented at: 2022 American Society of Clinical Oncology Genitourinary, February 17-19,2022; Abstract 362.