The European Commission has approved tivozanib for the treatment of patients with advanced renal cell carcinoma.
Bernard Escudier, MD
The European Commission (EC) has approved tivozanib (Fotivda) for the treatment of patients with advanced renal cell carcinoma (RCC), according to AVEO, the manufacturer of the pan-inhibitor of VEGF receptors, and its partner EUSA Pharma.
The drug is specifically approved 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, which follows a positive recommendation from the European Medicines Agency’s Committee for Medicinal Products for Human Use, is based on the phase III TiVO-1 trial, in which tivozanib reduced the risk of disease progression or death by over 20% versus sorafenib (Nexavar) in patients with advanced RCC who received up to 1 prior line of therapy (excluding targeted agents).
“This is excellent news for patients with metastatic RCC,” Bernard Escudier, MD, member of the Genitourinary Tumour Board of Gustave Roussy, France, said in a press release. “Outcomes in this disease have greatly improved with the introduction of targeted therapies, meaning that patients are living for longer. However, we are still in need of effective and well-tolerated new treatments in metastatic RCC and thus, tivozanib is a welcomed addition.”
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).1
At the time of the overall survival (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.2 Median OS was 28.8 months in the tivozanib arm and 29.3 months in the sorafenib arm.
Patients assigned to tivozanib were more likely 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%).
Researchers at Institut Gustave Roussy are currently evaluating tivozanib in combination with nivolumab (Opdivo) for patients with advanced RCC in the phase I/II dose escalation/expansion TiNivo trial. Additionally, results are anticipated in 2018 for the pivotal TIVO-3 trial, a randomized, controlled, multicenter, open-label study comparing tivozanib to sorafenib in patients with refractory advanced RCC.
In June 2013, the FDA rejected tivozanib after concluding the TiVO-1 findings showed inconsistent PFS and OS results. The trial also had an imbalance in post-study 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.
In May of that year, the FDA’s Oncologic Drugs Advisory Committee voted 13-1 against tivozanib. The committee said that there are a number of drugs available to treat advanced RCC and tivozanib did not demonstrate superiority over the existing options.
EUSA holds exclusive commercialization rights from AVEO Oncology to tivozanib in RCC in Europe, South America, and South Africa.