Tivozanib NDA for RCC Pushed Back Once Again

Following a meeting with the FDA, AVEO Oncology has decided to push back the planned New Drug Application submission for tivozanib to the first quarter of 2020 and to narrow for the proposed indication for tivozanib to the treatment of relapsed or refractory renal cell carcinoma, according to a press release from the company.

Following a meeting with the FDA, AVEO Oncology has decided to push back the planned New Drug Application (NDA) submission for tivozanib (Fotivda) to the first quarter of 2020 and to narrow for the proposed indication for tivozanib to the treatment of relapsed or refractory renal cell carcinoma (RCC), according to a press release from the company.1

The FDA offered concerns about the overall survival (OS) results from the phase III TIVO-3 trial comparing tivozanib with sorafenib (Nexavar) for the treatment of patients with highly refractory, metastatic RCC. The agency believed the OS results could worsen by the time of the final analysis, and so the agency suggested that the company should not submit an NDA at this time.

OS data from a prespecified second analysis of the TIVO-3 trial were released in September. The median OS in the tivozanib arm was 16.4 months (95% CI, 13.4-22.2) compared with 19.7 months (95% CI, 15.0-24.2) for sorafenib (HR, 0.99; 95% CI, 0.76-1.29;P= .95).2

However, the trial had previously met its primary end point of improved progression-free survival (PFS) as well as a secondary end point of improved overall response rate (ORR) in the tivozanib arm compared with the sorafenib arm. The median PFS was 5.6 months versus 3.9 months for tivozanib and sorafenib, respectively (HR, 0.73;P= .0165). The ORR was 18% with tivozanib and 8% with sorafenib (P= .02).3

AVEO now plans to submit an NDA to the FDA by the first quarter of 2020 and submit the final OS data from TIVO-3 to the agency by June 2020. They both agreed that should the final analysis yield a hazard ratio for OS above 1.00, then AVEO will withdraw its NDA application.1However, the FDA said that a discussion with the Oncologic Drug Advisory Committee will likely be required over a tivozanib NDA.

“During the meeting with the FDA, we believe that we established an appropriate path forward toward filing an NDA for tivozanib in the near term and a final analysis plan for OS,” Michael Bailey, president and CEO of AVEO, said in a press release. “The continued separation of the PFS curves and the positive trend in OS HR observed from the first to the second interim analysis, together with tenfold more patients remaining progression free and on tivozanib vs sorafenib therapy, make us believe that the final OS results will not worsen.”

The TIVO-3 trial (NCT02627963) is a randomized, controlled, multi-center, open-label study that has randomized 350 patients with highly refractory metastatic RCC who had failed ≥2 prior regimens, including previous VEGF tyrosine kinase inhibitor therapy, 1:1 to receive either oral tivozanib or sorafenib. Patients were allowed to have received prior checkpoint inhibitor therapy as well.

However, previous treatment with sorafenib or tivozanib was not allowed, nor were patients who had 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 those who had a second primary malignancy.

Patients in the trial were stratified by International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk category as well as prior therapies.

Additional secondary end points included duration of response, safety, and tolerability.

The company had previously pushed back an NDA submission for tivozanib after a discussion with the FDA earlier this year.4In addition, a complete response letter was issued to the company in June 2013 expressing the agency’s concerns regarding existing clinical data from the phase III TIVO-1 trial.

The TIVO-1 trial had explored the use of tivozanib versus sorafenib in a population of patients with RCC who had previously received 0 to 1 prior treatment regimens for RCC. The OS in this trial also favored the sorafenib arm with a median OS of 28.8 months (95% CI, 22.5-NA) in the tivozanib arm and 29.3 months (95% CI, 29.3-NA) in the sorafenib arm.5


  1. AVEO Oncology Announces Regulatory Update for Tivozanib in Renal Cell Carcinoma [press release]. Cambridge, MA: AVEO Oncology; November 4, 2019. https://bwnews.pr/32cLyIX. Accessed November 4, 2019.
  2. AVEO Oncology Announces Updated Overall Survival Hazard Ratio of 0.99 in Phase 3 TIVO-3 Trial of Tivozanib in Renal Cell Carcinoma. AVEO Oncology. Published September 10, 2019. https://bit.ly/2lOAlic. Accessed November 4, 2019.
  3. AVEO Oncology Announces Phase 3 TIVO-3 Trial Of Tivozanib In Renal Cell Carcinoma Meets Primary Endpoint. AVEO Oncology. Published November 5, 2018. https://bit.ly/2OrdaDy. Accessed November 4, 2019.
  4. AVEO Oncology Announces NDA Timing Update. Aveo Oncology. Published January 31, 2019. https://bit.ly/2WAkAtd. Accessed November 4, 2019.
  5. 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).