FDA Recommends No NDA for Tivozanib in RCC


The FDA has recommended that Aveo Oncology should not submit a new drug application for tivozanib with the preliminary overall survival data from the phase III TIVO-3 trial of patients with highly refractory, advanced or metastatic renal cell carcinoma.

Michael Bailey

Michael Bailey, associate professor of oncology and urology at Johns Hopkins Medicine

Michael Bailey

The FDA has recommended that Aveo Oncology should not submit a new drug application (NDA) for tivozanib (Fotivda) with the preliminary overall survival (OS) data from the phase III TIVO-3 trial of patients with highly refractory, advanced or metastatic renal cell carcinoma (RCC).1

The agency indicated that the preliminary findings do not alleviate their concerns regarding a potential detriment in OS, which were outlined in a complete response letter issued in June 2013. Aveo Oncology, the manufacturer of the VEGF inhibitor, stated in a press release that it plans to make an NDA filing decision following the availability of additional mature OS findings.

In the international, multicenter, open-label, controlled TIVO-3 trial, 322 patients with refractory advanced RCC were randomized to receive tivozanib hydrochloride or sorafenib (Nexavar). The primary endpoint was progression-free survival (PFS); secondary endpoints were OS, objective response rate, and duration of response.

Results showed that the median PFS was 5.6 months with tivozanib compared with 3.9 months with sorafenib (HR, 0.74; P = .02), and the overall response rates were 18% versus 8%, respectively (P = .02).2

In the preliminary analysis of the OS endpoint, results showed a hazard ratio >1. Aveo Oncology had planned to conduct a final OS analysis in August 2019. However, due to the unexpected OS in both arms and the regulatory discussions, the company will designate the next OS analysis as an interim analysis.

Since the preliminary OS analysis in October 2018, a survival status of a subset of patients that were previously lost to follow-up, had been identified. This updated the prior hazard ratio, 1.06, to 1.12. No additional OS analyses beyond the October 4, 2018 cutoff date have been performed. The full findings of the TIVO-3 trial are slated to be presented at the 2019 Genitourinary Cancers Symposium.

“We are hopeful that the positive PFS outcome will translate into an improved hazard ratio when we evaluate a more mature interim OS outcome in the fourth quarter of 2019,” said Michael Bailey, president and chief executive officer of AVEO, the manufacturer of tivozanib. “We look forward to continuing to work with the FDA to determine tivozanib’s benefit-risk profile as a single agent in RCC patients.”

To be eligible for enrollment on TIVO-3, patients with metastatic RCC must have failed 2 or 3 prior systemic therapies, one of which includes a VEGF TKI other than sorafenib or tivozanib; histologically or cytologically confirmed clear-cell RCC; measurable disease as assessed by RECIST v1.1; an ECOG performance status of 0 or 1; and a life expectancy of ≥3 months.

Those who received prior therapy with sorafenib or tivozanib; received more than 3 prior regimens for their metastatic disease; had central nervous system metastases, significant hematologic, gastrointestinal, thromboembolic, vascular, bleeding, or coagulation disorders; significant cardiovascular disease or serum chemistry abnormalities; inadequate recovery from any prior surgical procedure or a major surgery within 4 weeks prior to administration of the study drug; or a currently active second primary malignancy were excluded.

The European Commission approved tivozanib for the frontline treatment of adult patients with advanced RCC and for those with advanced RCC who are VEGFR- and mTOR-inhibitor naïve following disease progression after 1 prior treatment with cytokine therapy in August 2017. The decision was based on findings from the phase III TiVO-1 trial, in which tivozanib reduced the risk of disease progression or death by over 20% compared with sorafenib in patients with advanced RCC who received up to 1 prior line of therapy, excluding targeted agents.3,4

However, in June 2013, the FDA rejected an application for tivozanib in RCC after concluding that the TIVO-1 findings demonstrated inconsistent PFS and OS data, adding that there was also an imbalance in poststudy treatments used; this made the findings and the efficacy of tivozanib compared with existing therapies difficult to interpret. Additionally, the FDA found the risk-benefit assessment inconclusive. This rejection followed the FDA’s Oncology Drugs Advisory Committee recommendation, which voted 13 to 1 against approving tivozanib.


  1. AVEO Oncology Announces NDA Timing Update. Aveo Oncology. Published January 31, 2019. Accessed January 31, 2019.
  2. AVEO Oncology Announces Phase 3 TIVO-3 Trial of Tivozanib in Renal Cell Carcinoma Meets Primary Endpoint. Posted November 6, 2018. Accessed November 6, 2018.
  3. 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. 2012;31(suppl; abstr 4501). doi: 10.1200/jco.2012.30.15_suppl.4501.
  4. 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. 2013;31(suppl 6; abstr 350). doi: 10.1200/jco.2013.31.6_suppl.350.
Related Videos
Rohan Garje, MD
Manmeet Ahluwalia, MD, MBA, FASCO
Petros Grivas, MD, PhD; and Chandler Park, MD, MSc, FACP
Viktor Grünwald, MD, PhD
David A. Braun, MD, PhD, assistant professor, medicine (medical oncology), Louis Goodman and Alfred Gilman Yale Scholar, member, Center of Molecular and Cellular Oncology, Yale Cancer Center
Sumanta Kumar Pal, MD, FASCO,
Kohei Shitara, MD
Kian-Huat Lim, MD, PhD
Benjamin Garmezy, MD
Kathryn Beckermann, MD, PhD