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AVEO Oncology (NASDAQ: AVEO) today announced that previously reported data from its Phase 3 TIVO-3 study were published in The Lancet Oncology. 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 renal cell carcinoma (RCC). The article, titled “Tivozanib versus sorafenib in patients with advanced renal cell carcinoma (TIVO-3): a phase 3, multicentre, randomised, controlled, open-label study”, is available online first via this link.
“TIVO-3 represents the first study to demonstrate a superior progression free survival (PFS) benefit versus an active comparator in patients with advanced or metastatic RCC who have failed at least two prior lines of therapy, including a VEGFR-TKI, and the first Phase 3 study to investigate a predefined subpopulation of patients who received prior immunotherapy, the emerging standard of care for earlier lines of therapy,” said Brian Rini, MD, Chief of Clinical Trials at Vanderbilt Ingram Cancer Center, principal investigator of the TIVO-3 trial, and lead author of the publication. “Data from this study reinforce that tivozanib has the potential to serve as an effective, tolerable therapy in the evolving RCC treatment landscape.”
“With durable improvements observed in this highly refractory RCC patient population, TIVO-3 offers valuable insight into the potential sequencing of therapy following earlier TKI and immunotherapy treatment,” said Michael Bailey, president and chief executive officer of AVEO. “We are committed to maximizing the full potential of tivozanib both as a monotherapy and in the immunotherapy combination setting. We remain hopeful that the overall survival hazard ratio will continue to improve ahead of the final readout, expected in June 2020.”
“This agent has shown in clinical trials to be effective in delaying cancer growth beyond established standards for patients who have returning kidney cancer,” said Sumanta Pal, MD, a medical oncologist at City of Hope and co-lead author of the new study. “Although there are many options for patients with kidney cancer today, most are intended for first- and second-line therapy. We need a treatment that works for kidney cancer patients who have failed several lines of therapy.”
AVEO recently provided 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. The Company has submitted an update to the TIVO-3 statistical analysis plan to the FDA allowing for the final OS analysis to be conducted, intends to submit a New Drug Application (NDA) in the first quarter of 2020, and expects to report results from the final OS analysis 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. 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 overall response rate (18% vs. 8%; p=0.02).
As of the October 4, 2018 topline data analysis, in patients who received prior checkpoint inhibitor and VEGF TKI therapies, 29 PFS events occurred in the tivozanib group and 27 in the sorafenib group. Median PFS was 7.3 months with tivozanib and 5.1 months with sorafenib (HR 0.55, 95% CI 0.32–0.94). In this subpopulation, PFS at one year was 37% (95% CI 0.22–0.51) with tivozanib and 5% (0–0.14) with sorafenib. Two-year PFS was 28% (0.12–0.44) with tivozanib. No patients in the sorafenib subgroup were progression free at two years as of the October 4, 2018 data cutoff. In patients who had previously received two prior VEGF TKI therapies, 56 PFS events occurred in the tivozanib group and 61 occurred in the sorafenib group. Median PFS was 5.5 months tivozanib and 3.7 with sorafenib (HR 0.58, 95% CI 0.4–0.8).
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 hazard ratio (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 intent to treat population at the second analysis, an improvement from an HR of 1.12 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.
AVEO Pharmaceuticals is a biopharmaceutical company seeking to advance targeted medicines for oncology and other unmet medical needs. The Company’s lead candidate is tivozanib, a potent, selective, long half-life inhibitor of vascular endothelial growth factor 1, 2 and, 3 receptors, which AVEO is seeking to develop and commercialize in North America as a treatment for renal cell carcinoma (RCC), hepatocellular carcinoma (HCC) and other cancers. Tivozanib (FOTIVDA®) is approved by the European Commission for the treatment of adult patients with advanced RCC in the European Union plus Norway, New Zealand and Iceland. AVEO is leveraging or seeks to leverage partnerships to develop and commercialize its pipeline of products and product candidates, including tivozanib in oncology and other indications in various geographies, and ficlatuzumab (HGF MAb) in head and neck cancer, pancreatic cancer and acute myeloid leukemia. AVEO’s earlier-stage pipeline includes AV-203 (anti-ErbB3 MAb), AV-380 (GDF15 MAb) and AV-353 (Notch 3 MAb) drug candidates being developed for various oncology indications.
For more information, please visit the Company’s website at www.aveooncology.com.
Cautionary Note Regarding Forward-Looking Statements
This press release contains forward-looking statements of AVEO within the meaning of the Private Securities Litigation Reform Act of 1995 that involve substantial risks and uncertainties. All statements, other than statements of historical fact, contained in this press release are forward-looking statements. The words “anticipate,” “believe,” “expect,” “intend,” “may,” “plan,” “potential,” “could,” “should,” “would,” “seek,” “look forward,” “advance,” “goal,” “strategy,” or the negative of these terms or other similar expressions, are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. These forward-looking statements include, among others, statements about: the potential for tivozanib as a treatment option for patients with relapsed/refractory or advanced RCC; the potential efficacy, safety, and tolerability of tivozanib, both as a stand-alone drug candidate and in combination with other therapies in several indications; the potential for the TIVO-3 OS HR to improve in the final OS analysis; AVEO’s plans and strategies for commercialization of tivozanib in the United States and Europe; and AVEO’s strategy, prospects, plans and objectives for its product candidates and for the Company generally. AVEO has based its expectations and estimates on assumptions that may prove to be incorrect. As a result, readers are cautioned not to place undue reliance on these expectations and estimates. Actual results or events could differ materially from the plans, intentions and expectations disclosed in the forward-looking statements that AVEO makes due to a number of important factors, including risks relating to: AVEO’s ability, and the ability of its licensees, to demonstrate to the satisfaction of applicable regulatory agencies such as the FDA the safety, efficacy and clinically meaningful benefit of AVEO’s product candidates, including, in particular, tivozanib and ficlatuzumab; AVEO’s ability to successfully file an NDA for tivozanib; and AVEO’s ability to enter into and maintain its third party collaboration and license agreements, and its ability, and the ability of its strategic partners, to achieve development and commercialization objectives under these arrangements. AVEO faces other risks relating to its business as well, including risks relating to the timing and costs of seeking and obtaining regulatory approval; AVEO’s and its collaborators’ ability to successfully enroll and complete clinical trials; AVEO’s ability to maintain compliance with regulatory requirements applicable to its product candidates; AVEO’s ability to obtain and maintain adequate protection for intellectual property rights relating to its product candidates; AVEO’s ability to successfully implement its strategic plans; AVEO’s ability to raise the substantial additional funds required to achieve its goals, including those goals pertaining to the development and commercialization of tivozanib; unplanned capital requirements; adverse general economic and industry conditions; competitive factors; and those risks discussed in the sections titled “Risk Factors” and “Management’s Discussion and Analysis of Financial Condition and Results of Operations—Liquidity and Capital Resources” included in AVEO’s quarterly and annual reports on file with the Securities and Exchange Commission (SEC) and in other filings that AVEO makes with the SEC. The forward-looking statements in this press release represent AVEO’s views as of the date of this press release, and subsequent events and developments may cause its views to change. While AVEO may elect to update these forward-looking statements at some point in the future, it specifically disclaims any obligation to do so. You should, therefore, not rely on these forward-looking statements as representing AVEO's views as of any date other than the date of this press release.
1. Fotivda (Tivozanib) SmPC August 2017
2. Motzer RJ, Nosov D, Eisen T, et al. J Clin Oncol 2013; 31(30): 3791-9.
3. Pawlowski N et al. AACR 2013. Poster 3971.
4. Barthelemy et al. ESMO 2018. Poster 878P
David Pitts, Argot Partners
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