According to topline findings from the phase III TIVO-3 trial, tivozanib (Fotivda) reduced the risk of disease progression or death by 26% compared with sorafenib (Nexavar) in patients with highly refractory advanced or metastatic renal cell carcinoma.
Brian Rini, MD
Brian Rini, MD
According to topline findings from the phase III TIVO-3 trial, tivozanib (Fotivda) reduced the risk of disease progression or death by 26% compared with sorafenib (Nexavar) in patients with highly refractory advanced or metastatic renal cell carcinoma (RCC).
The multicenter, open-label trial included 351 patients who had received ≥2 prior lines of therapy. Results showed the median progression-free survival among these patients was 5.6 months with tivozanib, compared with 3.9 months with sorafenib (HR, 0.74;P= .02). The overall response rates were 18% versus 8%, respectively (P= .02).1
Although overall survival (OS) data were not mature at the time of the final PFS analysis, the preliminary OS analysis did not show a statistically significant OS difference between the treatment arms (HR, 1.06;P= 0.69). AVEO Oncology, the manufacturer of tivozanib, plans to report additional TIVO-3 data at a future medical meeting. The company also intends to submit a new drug application to the FDA based on the TIVO-3 results, as well as data from the phase III TIVO-1 trial of tivozanib in frontline RCC.
“Tivozanib’s therapeutic profile is distinct among VEGF TKIs as a treatment for RCC, with the TIVO-3 trial demonstrating a significant PFS benefit and a favorable tolerability profile,” Brian Rini, MD, principal investigator of TIVO-3, professor of medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, director, Cleveland Clinic Genitourinary Cancer Program, said in a statement.
“In the advanced disease setting, these outcomes are particularly meaningful, providing the first large, pivotal dataset that shows sequencing of treatment following earlier TKI and immunotherapy treatment. This profile suggests an important place for tivozanib in the evolving treatment paradigm for RCC and, taken together with early combination data, the need to study tivozanib further in combination with immunotherapies,” added Rini.
The trial included patients with advanced or metastatic RCC who failed at least 2 prior lines of therapy, including a VEGFR-TKI. Patients were randomized 1:1 to tivozanib or sorafenib. Crossover between arms was not allowed. The primary endpoint was PFS. Twenty-six percent of patients had previously received an immune checkpoint inhibitor. There were no new safety signals with tivozanib. Though not common, there was a higher incidence of severe thrombotic events in the tivozanib arm. Hypertension was the most common adverse event among patients receiving tivozanib.
Tivozanib is approved in the European Union for the frontline treatment of adult patients with advanced RCC and for adults with advanced RCC who are VEGFR- and mTOR-inhibitor naïve following disease progression after 1 prior treatment with cytokine therapy. The approval was based on the phase III TIVO-1 trial, in which tivozanib reduced the risk of disease progression or death by over 20% versus sorafenib in patients with advanced RCC who received up to 1 prior line of therapy (excluding targeted agents).
TIVO-1 was first presented at the 2012 ASCO Annual Meeting, with follow-up results presented at the 2013 ASCO Genitourinary (GU) Cancers Symposium. Patients were randomly assigned to either 1.5 mg of tivozanib once daily for 3 weeks, followed by 1 week of rest (n = 260) or 400 mg twice daily sorafenib continuously in a 4-week cycle (n = 257). Patients were either treatment-naïve or had received no more than 1 prior systemic therapy for metastatic disease, and no patient in the study had received any prior VEGFR- or mTOR-targeted therapy.
According to the results presented in 2012, median PFS in the tivozanib arm was 11.9 months compared with 9.1 months in the sorafenib arm (HR, 0.797; 95% CI, 0.639-0.993;P= .042). Treatment-naïve patients who received tivozanib enjoyed a greater improvement in PFS. For those patients, median PFS was 12.7 months compared with 9.1 months in the sorafenib treatment-naïve arm (HR, 0.756; 95% CI, 0.580-0.985;P= .037).2
At the time of the OS analysis presented at the GU Symposium, mortality rates were 45.4% in the tivozanib group and 39.3% in the sorafenib group, corresponding with a stratified HR of 1.245 (95% CI, 0.954-1.624;P= .105) trending in favor of sorafenib.3Median OS was 28.8 months in the tivozanib arm and 29.3 months in the sorafenib arm.
Patients assigned to tivozanib were more likely to remain on full treatment dose (86% vs 57%;P= .001). Only 14% of patients in the experimental arm required dose reduction due to adverse events (AEs) compared with 43% in the sorafenib arm. Patients in the tivozanib group were also less likely to experience AEs usually associated with other VEGFR-TKIs including diarrhea (23% vs 33%) and hand-foot syndrome (14% vs 54%).
In June 2013, the FDA rejected an application for tivozanib in RCC after concluding the TIVO-1 findings showed inconsistent PFS and OS results. There was also an imbalance in poststudy treatments used, making its results and the efficacy of the drug compared with existing treatments difficult to interpret. Furthermore, the agency found the risk-benefit assessment inconclusive. The FDA’s decision followed the recommendation of the agency’s Oncologic Drugs Advisory Committee, which voted 13 to 1 against approving tivozanib.