Tivozanib Recommended for EU Approval for RCC

The Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion recommending marketing authorization of tivozanib (Fotivda) for adult patients with advanced renal cell carcinoma (RCC).

The committee is an arm of the European Medicines Agency’s (EMA). Should the full committee accept the positive opinion, tivozanib would be approved for use in the 28 European Union member states plus Norway and Iceland to treat adults with advanced RCC who are VEGFR and mTOR pathway inhibitor-naïve and are either untreated or have failed prior therapy with interferon-alpha or interleukin-2.

EUSA Pharma announced the decision in a press release. EUSA holds exclusive commercialization rights from AVEO Oncology to tivozanib in RCC in Europe, South America, and South Africa.

“Today’s opinion by the CHMP to recommend marketing authorization of tivozanib in the EU is an important step in expanding treatment options for patients with advanced renal cell carcinoma, where, despite advancements in therapy, survival rates in advanced disease remain low and existing treatments can be associated with therapy-limiting toxicities,” Jon Morgan, MBBS, medical director, EUSA Pharma, said in a release. “The opinion is supported by robust and consistent results from the TiVO-1 pivotal study which demonstrated compelling efficacy of tivozanib as a first-line treatment, and importantly for this class of agents, a highly favorable and advantageous tolerability profile.”

CHMP based its opinion on results from the phase III TiVO-1 trial, which evaluated the efficacy and tolerability of tivozanib compared with sorafenib (Nexavar). TiVO-1 was first presented at the 2012 ASCO Annual Meeting. Follow-up results with were presented at the 2013 ASCO Genitourinary 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 one 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 Genitourinary 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. Median OS was 28.8 months in the tivozanib arm and 29.3 months in the sorafenib arm.²

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%).

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.

References

1. Motzer RJ, Nosov D, Eisen T, et al. Tivozanib versus sorafenib as initial targeted therapy for patients with advanced renal cell carcinoma: Results from a phase III randomized, open label, multicenter trial. J Clin Oncol. 31, 2012 (suppl; abstr 4501).
2. Motzer RJ, Eisen T, Hutson TE, et al. Overall survival in patients from a phase III study of tivozanib hydrochloride versus sorafenib in patients with renal cell carcinoma. J Clin Oncol. 31, 2013 (suppl 6; abstr 350).