FDA Approval Sought for Tivozanib in Relapsed/Refractory Renal Cell Carcinoma

A new drug application has been submitted to the FDA for tivozanib for the treatment of patients with relapsed/refractory renal cell carcinoma, according to Aveo Oncology, the company developing the VEGFR TKI.

Michael Bailey

A new drug application (NDA) has been submitted to the FDA for tivozanib (Fotivda) for the treatment of patients with relapsed/refractory renal cell carcinoma (RCC), according to Aveo Oncology, the company developing the VEGFR TKI.1

The NDA is based on data from the phase III TIVO-3 trial, in which the median overall survival (OS) was 16.4 months (95% CI, 13.4-22.2) for tivozanib and 19.7 months (95% CI, 15.0-24.2) for sorafenib (Nexavar; HR, 0.99; 95% CI, 0.76-1.29; P = .95).2 Regarding progression-free survival (PFS), at a median duration on study of 32.5 months, 20 patients remained progression free on the tivozanib arm compared with 2 patients on the sorafenib arm. The application is also supported by data from the phase III TIVO-1 trial and the phase II Study 902 and Study 201 trials.

In January 2019, the FDA recommended that Aveo should not submit an NDA for tivozanib with the preliminary OS data from the phase III TIVO-3 trial. The agency indicated that the initial data did not alleviate their concerns regarding a potential detriment in OS, which were outlined in a complete response letter issued in June 2013. The preliminary OS analysis showed a hazard ratio >1.

Accordingly, the FDA and Aveo made an agreement based on the final OS data from the trial, which are expected by June 2020. Aveo agreed to withdraw its NDA if the HR for OS at the final analysis is greater than 1.00.

"NDA submission is a distinguishing milestone for any development stage biotechnology company, and our tivozanib NDA is an important step in our goal of providing an effective and more tolerable therapeutic option to patients with relapsed or refractory RCC," Michael Bailey, president and chief executive officer, Aveo, said in a press release.

"The TIVO-3 study provides valuable insight into the potential sequencing of therapy following earlier TKI and immunotherapy treatment, an area of significant need for kidney cancer patients whose disease has relapsed or become refractory to multiple lines of therapy. All of us at Aveo offer our continued gratitude to the patients, caregivers, and investigators who participated in our clinical trials. We look forward to working closely with the FDA during their review process and remain hopeful that the study’s overall survival hazard ratio will continue to favor tivozanib at the time of the final readout, expected by June 2020,” added Bailey.

In the randomized, controlled, multicenter, open-label, phase III TIVO-3 study, investigators randomized 350 patients with highly refractory metastatic RCC who had failed ≥2 prior regimens, including VEGF-TKI treatment, 1:1 to receive either oral tivozanib or sorafenib. No cross over was permitted between arms.

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 criteria; an ECOG performance status of 0 or 1; and a life expectancy of ≥3 months. Eligibility criteria also included patients who received checkpoint inhibitor therapy in earlier lines of therapy.

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 primary endpoint was PFS; secondary endpoints were OS, objective response rate (ORR), and safety and tolerability.

For the second prespecified analysis, the data cutoff date was August 15, 2019, which was 2 years from the last patient enrolled and approximately 10 months from the data cutoff date for the first prespecified analysis. Between the two dates, 16 additional OS events were reported on the tivozanib arm and 28 on the sorafenib arm, which led to 114 OS events for tivozanib and 113 for sorafenib.

In November 2018, final results for the primary endpoint showed that the median PFS was 5.6 months and 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

The safety data that were also reported at this time showed that tivozanib was found to be generally well tolerated; grade ≥3 adverse events were consistent with previously observed findings in studies of the VEGF TKI. Thrombotic events were higher in the tivozanib arm, which was also similar to previously reported data. Additionally, the most common adverse event in the tivozanib arm was hypertension.

In August 2017, 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. 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.4


  1. AVEO Oncology Announces Submission of New Drug Application to U.S. FDA for Tivozanib in Patients with Relapsed or Refractory Renal Cell Carcinoma. Published March 31, 2020. https://yhoo.it/3bIA70K Accessed March 31, 2020.
  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 September 10, 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 September 10, 2019.
  4. 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