On November 4, 2019 AVEO Oncology (NASDAQ: AVEO) reported a regulatory update following a meeting with the U.S. Food and Drug Administration (FDA) to discuss results from the August 2019 overall survival (OS) analysis of the TIVO-3 trial and the Company’s proposal to proceed with a New Drug Application (NDA) for tivozanib (Press release, AVEO, NOV 4, 2019, View Source [SID1234550264]).
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TIVO-3 is the Company’s Phase 3 randomized, controlled, multi-center, open-label study to compare tivozanib, the Company’s vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR-TKI), to sorafenib in 350 subjects with highly refractory metastatic renal cell carcinoma (RCC). The TIVO-3 trial was designed to address the FDA’s concerns regarding the OS trend in the TIVO-1 trial. In the TIVO-1 trial, the Company’s initial RCC pivotal trial, the FDA found that the inconsistent progression free survival (PFS) and OS results and imbalance in post study treatments made the trial results uninterpretable and inconclusive when making a risk-benefit assessment necessary for drug approval.
The Company previously announced that the TIVO-3 trial met its primary endpoint of demonstrating a significant improvement in PFS. The study also demonstrated a significant improvement in the secondary endpoint of overall response rate. The August 2019 analysis of the secondary endpoint of OS was the second prespecified interim OS analysis of the TIVO-3 trial, and showed an updated OS hazard ratio (HR) of 0.99 at two years from the last patient enrolled in the study.
In the FDA’s preliminary feedback, based on its assessment of the totality of evidence presented to date, the FDA recommended that the Company not submit an NDA at this time. The FDA stated that it remained concerned about the results of TIVO-3 in the context of the overall development of tivozanib. The FDA noted that the Company’s current interim OS results do not abrogate the FDA’s concerns over detriment and that those results may worsen with final analysis at 263 events, and that the median OS for tivozanib is worse than that of sorafenib.
In view of the changing first-line treatment landscape as well as the FDA’s continued concerns, the Company informed the FDA that it intends to narrow its proposed indication to relapsed/refractory RCC. At the meeting, the FDA acknowledged AVEO’s responses and reiterated its concerns about the survival information and the totality of data. The FDA noted that the choice to submit the data is the Company’s, and that a discussion with the Oncologic Drug Advisory Committee will likely be required. The FDA said that if AVEO wishes to proceed with a revised OS analysis in June 2020, AVEO should submit an updated statistical analysis plan (SAP) with a planned OS update based on the projected number of events at that time.
AVEO intends to submit to the FDA an update to the SAP for the final OS analysis consistent with these discussions, followed by an NDA submission in the first quarter of 2020. AVEO expects to report the final OS analysis in June 2020 based on a May 1, 2020 cutoff, at which point the Company estimates that the study will have reached approximately 263 OS events, as discussed with the FDA. The FDA and the Company agreed that if the final analysis yields an OS HR above 1.00, the Company will withdraw its NDA application.
"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," said Michael Bailey, president and chief executive officer of AVEO. "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."
About TIVO-3
The TIVO-3 trial was designed to enroll patients with RCC who have failed at least two prior regimens, including VEGFR-TKI therapy. Eligible patients may also have received checkpoint inhibitor therapy in earlier lines of treatment. Patients were randomized 1:1 to receive either tivozanib or sorafenib, with no crossover between arms. The primary endpoint of the study is progression free survival (PFS). Secondary endpoints include overall survival (OS), overall response rate (ORR), and safety and tolerability. TIVO-3, together with the previously completed TIVO-1 trial of tivozanib in the first line treatment of RCC, is designed to support a regulatory submission of tivozanib in the U.S. as a treatment for RCC in multiple lines of therapy. TIVO-3 patients were exclusively enrolled in North America, Western Europe, and Central Europe.
About Tivozanib
Tivozanib (FOTIVDA) is an oral vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) discovered by Kyowa Kirin and approved for the treatment of adult patients with advanced renal cell carcinoma (RCC) in the European Union plus Norway, New Zealand and Iceland. It is a potent, selective and long half-life inhibitor of all three VEGF receptors and is designed to optimize VEGF blockade while minimizing off-target toxicities, potentially resulting in improved efficacy and minimal dose modifications.1,2 Tivozanib has been shown to significantly reduce regulatory T-cell production in preclinical models3 and has demonstrated synergy in combination with nivolumab (anti PD-1) in a Phase 2 study in RCC4. Tivozanib has been investigated in several tumor types, including renal cell, hepatocellular, colorectal, ovarian and breast cancers.