Tivozanib (Fotivda®; AVEO Pharmaceuticals) is an oral vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor approved in the United States for treating relapsed or refractory renal cell carcinoma (RCC) following two or more previous systemic therapies.[1]

The TIVO-3 study showed that tivozanib treatment improved progression-free survival compared with sorafenib (Nexavar®; Bayer), with a stratified hazard ratio of 0.73 (95% CI, 0.56-0.95). Long-term follow-up revealed that PFS at 3 years was higher in TIVO-treated patients in those receiving sorafenib (12% vs 2%).[1]

Significantly longer progression-free survival
The utility of survival data in assessing the clinical effectiveness of cancer treatments depends on both prescribed study endpoints and their timeframes. The TIVO-3 study met the primary endpoint of significantly longer progression-free survival for tivozanib, a finding on which, in part, the U.S. Food and Drug Administration (FDA) based its approval of this drug. Despite noting a greater than five-fold improvement in progression-free survival for tivozanib at three-year follow-up, however, the data did not support a significant benefit for the drug in overall survival.

This study reports on the contributions of event accumulation and data maturation to the stability of Kaplan-Meier survival, leading to a re-evaluation of overall survival benefits for the two treatments.

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To quantify the effects of overall survival maturation, investigators used Cox proportional hazards and log-rank statistics to estimate hazards ratio at a 95% CI) for overall survival using prespecified (two years after last-patient in) and exploratory intent-to-treat analyses. To estimate the hazards ratio (95% confidence interval) for overall survival, researchers used conditional analysis of Cox proportional hazards and stratified log-rank statistics from patients experiencing progression-free survival at 12 and 18 months. Survival was noted until death, patient withdrawal, or loss to follow-up

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Consistent benefit
Serial overall survival analyses using Kaplan-Meier estimates are affected by increased curve reliability with decreased censoring and limited residual patients at risk for death. As events accumulated over the follow-up period, the hazard ratio for overall survival fell from 0.99 to 0.89 in favor of tivozumab. Conditional analysis suggests that improved overall survival for tivozumab-treated patients, compared with those receiving sorafenib, persisted at one year.

This finding suggests that the early, consistent progression-free survival benefit of tivozumab compared with sorafenib are associated with an overall survival advantage as more events accumulate.

Clinical trial
A Study to Compare Tivozanib Hydrochloride to Sorafenib in Subjects With Refractory Advanced RCC (TIVO-3) – NCT02627963
An Extension Treatment Protocol for Subjects Who Have Participated in a Study of Tivozanib Versus Sorafenib in Kidney Carcinoma (Protocol AV-951-09-301) – NCT01076010
A Study to Compare Tivozanib (AV-951) to Sorafenib in Subjects With Advanced Renal Cell Carcinoma (TIVO-1) – NCT01030783

Highlights of prescribing information
Tivozanib (Fotivda®; AVEO Pharmaceuticals) [Prescribing information]
Sorafenib (Nexavar®; Bayer) [Prescribing Information]

References
Rini BI, Pal SK, Escudier B, Atkins MB, McDermott DF, Verzoni E, Porta C, Kasturi V, Hutson TE. Maturation of overall survival (OS) in TIVO-3 with long-term follow-up. DOI: 10.1200/JCO.2022.40.16_suppl.4557 Journal of Clinical Oncology 40, no. 16_suppl (June 01, 2022) 4557-4557.

Featured image: Kidneys. Photo by Julien Tromeur on Unsplash. Used with permission

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