On November 18, 2019 AVEO Oncology (NASDAQ: AVEO) reported the presentation of updated data from the Phase 3 TIVO-3 trial (Press release, AVEO, NOV 18, 2019, View Source [SID1234551433]). The data were presented on Saturday, November 16, 2019, at the 18th International Kidney Cancer Symposium in Miami, in an oral presentation titled "TIVO-3: A Phase 3 Study to Compare Tivozanib to Sorafenib in Subjects with Refractory Advanced Renal Cell Carcinoma (RCC) Overall Survival 2-Year Update" by Sumanta (Monty) Kumar Pal, M.D., Associate Clinical Professor, Department of Medical Oncology and Therapeutics Research, and Co-director, Kidney Cancer Program, at City of Hope Comprehensive Cancer Center. TIVO-3 is the Company’s Phase 3 randomized, controlled, multi-center, open-label study to compare tivozanib (FOTIVDA), the Company’s vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR-TKI), to sorafenib in 350 subjects with highly refractory metastatic RCC.
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As previously presented, results for the intent to treat (ITT) population showed that tivozanib significantly improved progression free survival (PFS), the study’s primary endpoint, and overall response rate (ORR) compared to sorafenib, with responses to tivozanib more durable than sorafenib. Newly presented data include the recently announced interim overall survival (OS) hazard ratio (HR) of 0.99 within the ITT population, as well as results from two prespecified subgroup analyses of patients previously treated with a checkpoint inhibitor and a VEGF-TKI, or two VEGFR-TKIs. Superior PFS and ORR, as well as OS HRs below 1, favoring tivozanib, were observed in the prespecified subgroups. Tivozanib was shown to have lower overall rates of adverse events and fewer dose interruptions and reductions versus sorafenib, indicating better patient tolerability. A copy of the presentation is available in the Publications & Presentations section of AVEO’s website.
"Until the TIVO-3 trial results, limited prospective data existed to inform sequencing of treatment after checkpoint inhibitor therapy, the emergent standard of care in earlier-line treatment," said Dr. Pal. "Tivozanib’s outcomes within this population, as well as in those receiving two prior VEGF-TKIs, suggest an important potential role for tivozanib in the evolving refractory advanced RCC setting. Furthermore, tivozanib’s unique tolerability profile is potentially well suited to an advanced setting, where many are reluctant to accept higher rates of adverse events following multiple courses of therapy."
"Tivozanib is the first RCC treatment to show superior outcomes over another active therapy in a Phase 3 study in the third/fourth line setting, a high unmet need population that is growing due to longer survival in earlier lines of therapy," said Michael Bailey, president and chief executive officer of AVEO. "We look forward to completing a final OS analysis of TIVO-3 in June 2020 after our planned submission of a new drug application (NDA) to the U.S. Food and Drug Administration (FDA) in the first quarter of 2020. The continued separation of the PFS curves and the positive trend in OS HR observed from the first to the second interim analyses of TIVO-3, together with tenfold more patients remaining progression free and on tivozanib vs. sorafenib therapy, make us believe that the final OS HR could continue to improve."
AVEO recently provided a regulatory update following a meeting with the FDA to discuss results from the August 2019 OS analysis of the TIVO-3 trial. The Company intends to submit an update to the TIVO-3 statistical analysis plan to the FDA allowing for the final OS analysis to be conducted, followed by an NDA submission in the first quarter of 2020, and expects to report results from a final OS analysis of the TIVO-3 trial in June 2020. The FDA and the Company agreed that if, during the review, the final analysis yields an OS HR above 1.00, the Company will withdraw its NDA application. The FDA informed the Company that an Oncologic Drugs Advisory Committee panel would likely be convened to review the final tivozanib data package.
Results in Detail
Patients enrolled in the TIVO-3 trial (n=350) were randomized and stratified for prior regimen and IMDC prognostic score. Prior treatment regimens included prior checkpoint inhibitor and VEGF TKI therapies (n=91), two prior VEGF TKI therapies (n=159) and prior VEGF TKI and other therapies (n=100). Statistically significant improvements favoring tivozanib were reported for the primary endpoint of PFS (HR=0.73; p=0.0165) and secondary endpoint of ORR (18% vs. 8%; p=0.02). Improvements were also observed in patients receiving prior checkpoint inhibitor and VEGF TKI therapies and two prior VEGF TKI therapies:
Prior Checkpoint Inhibitor + VEGFR TKI
For the secondary endpoint of OS, two prespecified analyses have been conducted, the first at a data cutoff date of October 4, 2018, and the second at August 15, 2019. The OS HR, which assesses the relative risk of death for the entirety of the data set, was 0.99 (95% CI: 0.76-1.29; p=0.95) for the ITT population at the second analysis, and improvement from an HR of 1.12 observed at the first analysis. At the second analysis, OS HR for patients receiving prior checkpoint inhibitor and VEGF TKI therapies was 0.88, and 0.98 for patients treated with two prior VEGF TKI therapies. Both hazard ratios were improved from hazard ratios of 1.14 and 1.05, respectively, observed at the first analysis.
As of the August 15, 2019 data cutoff date, median OS, a point in time value of the OS when half of the patients within each arm are still alive, was 16.4 months for tivozanib (95% CI: 13.4-22.2) and 19.7 months for sorafenib (95% CI: 15.0-24.2). As of the second data cutoff date, twenty patients remained progression free on the tivozanib arm and two on the sorafenib arm, with a median duration on study of 32.5 months.
Grade 3 or higher adverse events were consistent with those observed in previous tivozanib trials. Infrequent but severe adverse events reported in greater number in the tivozanib arm were thrombotic events similar to those observed in previous tivozanib studies. The most common adverse event in patients receiving tivozanib was hypertension, an adverse event known to reflect effective VEGF pathway inhibition.
About Tivozanib (FOTIVDA)
Tivozanib (FOTIVDA) is an oral, once-daily, vascular endothelial growth factor receptor (VEGFR) 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 is being studied in the TIVO-3 trial, which is intended to support a regulatory submission of tivozanib in the U.S. as a treatment for relapsed/refractory RCC. 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.