Tivozanib NDA Submitted to FDA for Relapsed or Refractory Renal Cell Carcinoma

A New Drug Application (NDA) has been submitted to the FDA for the vascular endothelial growth factor (VEGFR) tyrosine kinase inhibitor (TKI) tivozanib (Fotivda) for the treatment of patients with relapsed or refractory renal cell carcinoma (RCC), according to a press release from AVEO Oncology.¹

The NDA is based on data from the pivotal phase III TIVO-3 clinical trial, in which tivozanib is compared with sorafenib (Nexavar) as treatment of patients with RCC in the third- and fourth-line setting. The submission is also supported by data from the phase III TIVO-1 trial and 2 other phase II clinical trials, Study 902 and Study 201, which explored the use of tivozanib in earlier settings.

“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. 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,” said Michael Bailey, president and CEO, AVEO Oncology, in a statement.

In the international, multicenter, open-label trial, TIVO-3 enrolled 322 patients with relapsed/refractory advanced RCC and randomized them to receive either tivozanib or sorafenib. The primary end point is progression-free survival (PFS), and secondary end points include overall survival (OS), objective response rate (ORR), and duration of response (DOR).

The hazard ratio (HR) for OS was 0.99 (95% CI, 0.76-1.29;P= .95) for tivozanib versus sorafenib, according to findings from the second prespecified analysis of TIVO-3. The median OS was 16.4 months for tivozanib (95% CI, 13.4-22.2) compared with 19.7 months (95% CI, 15.0-24.2) in the sorafenib arm.²

Previously AVEO Oncology had considered not submitting an NDA based ona recommendation from the FDA due to unsatisfactory preliminary OS findings.³Additionally, in 2013, the FDA rejected an NDA for tivozanib for the treatment of patients with advanced RCC after the Oncologic Drugs Advisory Committee voted against the approval for the agent based off results from the TIVO-1 trial.

A final OS analysis is planned in the second quarter of 2020 with a data cutoff date of May 1, 2020. The company expects to have final OS data by June 2020. Should the final analysis yield an OS HR above 1.00, the company will withdraw its NDA submission.¹

According to the final results for the primary end point, the median PFS was 5.6 months with tivozanib versus 3.9 months with sorafenib (HR, 0.73;P= .165). The ORR was 18% with tivozanib versus 8% in the control arm (P= .02).⁴

Tivozanib was found to be generally well tolerated, and grade 3 or greater adverse events (AEs) observed similar to findings reported in previous trials. The tivozanib arm experienced more thrombotic events, and the most common AE was hypertension.

Tivozanib is a potent oral once-daily VEGFR TKI and has been approved for the treatment of adults with advanced RCC in the European Union and the United Kingdom, as well as in Norway, New Zealand, and Iceland. It is a selective inhibitor of all 3 VEGF receptors with a long half-life and it optimizes the VEGF blockade, minimizing off-target AEs to result in improved efficacy and minimal dose modifications.¹

This agent has demonstrated synergy in combination with anti—PD-1 nivolumab (Opdivo) in a phase II clinical trial for patients with RCC and is also under investigation in several tumor types, including hepatocellular carcinoma, colorectal cancer, ovarian cancer, and breast cancer.

“All of us at AVEO offer our continued gratitude to the patients, caregivers, and investigators who participated in our clinical trials,” said Bailey. “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."

References:

1. AVEO Oncology Announces Submission of New Drug Application to US FDA for Tivozanib in Patients with Relapsed or Refractory Renal Cell Carcinoma [news release]. Cambridge, MA: AVEO Oncology; March 31, 2020. https://bit.ly/2UTAOhe. Accessed April 1, 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 [news release]. Cambridge, MA: AVEO Oncology; September 10, 2019. https://bit.ly/2lOAlic. Accessed April 1, 2020.
3. AVEO Oncology Announces NDA Timing Update [news release]. Cambridge, MA: AVEO Oncology; January 31, 2019.https://bit.ly/2R4Vp0P. Accessed April 1, 2020.
4. AVEO Oncology Announces Phase 3 TIVO-3 Trial Of Tivozanib In Renal Cell Carcinoma Meets Primary Endpoint [news release]. Cambridge, MA: AVEO Oncology; November 5, 2018. https://bit.ly/2OrdaDy. Accessed April 1, 2020.