AVEO Oncology recently announced that it has submitted to the US Food and Drug Administration (FDA) a new drug application (NDA) targeting the anticancer drug Fotivda (tivozanib), a vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR-TKI), used to treat relapsed or refractory renal cell carcinoma (RCC).
The NDA submission was based on the key phase III clinical study TIVO-3, and the application was supported by three other studies, including phase III study TIVO-1 (compare Fotivda and sorafenib first-line treatment RCC), and two phase II Research (Study 902, Study 201). TIVO-3 is a randomized, positive-controlled, multi-center, open-label study conducted in 351 patients with highly refractory advanced or metastatic RCC and evaluated Fotivda relative to Bayer targeted anticancer drug Nexavar Common name: sorafenib, sorafenib) efficacy and safety. The patients enrolled in the study had previously failed at least 2 regimens, and approximately 26% of patients had already received immune checkpoint inhibitor therapy during early treatment.
It is worth mentioning that the TIVO-3 study is also the first phase III study with positive results in third- and fourth-line RCC. The results of the study were published in November 2018, and the data showed that the study reached the primary endpoint: the median progression-free survival (PFS) was increased by 44% (5.6 months vs 3.9 months in the Fotivda treatment group compared to the Nexavar treatment group ), The risk of disease progression or death is reduced by 26% (HR = 0.74, p = 0.02). In patients who received and did not receive immune checkpoint inhibitor treatment, PFS of Fotivda was longer than that of Nexavar. In terms of overall response rate, it was 18% in the Fotivda treatment group and 8% in the Nexavar treatment group (p = 0.02). At the time of the final PFS analysis, the overall survival (OS) data was not yet mature, and only 46% of potential OS events were reported. During the preliminary OS analysis, it was observed that OS was not statistically significantly different (HR = 1.06, p = 0.69).
Since the research data deadline is May 1, 2020, the final OS analysis will be conducted in the second quarter of 2020. AVEO is expected to report the final OS analysis results by June 2020. The company has reached an agreement with the FDA, if during the review period, the final analysis of the OS hazard ratio (HR) is higher than 1.00, AVEO will withdraw the new drug application (NDA).
In terms of safety, Fotivda was well tolerated in this study, and adverse reactions of grade 3 or higher were consistent with those observed in previous studies. The fewer but serious adverse events reported by the Fotivda treatment group were thrombotic events, similar to those observed in previous studies. The most common adverse event in the Fotivda treatment group was hypertension, which is known to reflect an effective inhibition of the VEGF pathway.
tivozanib molecular structure formula (Image source: Wikipedia)
Professor Brian Rini, the principal investigator of the TIVO-3 study and the director of the Cleveland Clinic Urogenital Oncology Program, previously said: "Among the VEGF TKI drugs for RCC, the treatment characteristics of tivozanib are very unique. The drug has significant PFS benefits and good tolerability. These results are particularly meaningful in the advanced RCC population, the study provides the first large, key data showing the treatment sequence after early TKI and immunotherapy, highlighting Tivozanib's important position in the evolving RCC treatment model. "
Michael Bailey, President and CEO of AVEO Oncology, said: "The submission of tivozanib NDA is an important step for us to provide effective and more tolerant treatment options for patients with relapsed or refractory kidney cancer. The TIVO-3 study follows early TKI and immunotherapy The treatment sequence provides valuable insights. Among relapsed or refractory patients who have failed multiple treatments, there are significant unmet medical needs. We look forward to working closely with the FDA during the review process and hope that The HR data from the final OS analysis obtained in June this year can continue to benefit tivozanib. "
Tivozanib is an oral, once-daily vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI), which was discovered by the Japanese Pharmaceutical Enterprise Association and Kyowa Kirin. Approved for adult patients with advanced RCC. Tivozanib is a potent, selective, long-acting inhibitor that inhibits all three VEFG receptors, while minimizing off-target toxicity, potentially bringing improved efficacy and minimized dose adjustment. In preclinical models, when combined with immunomodulatory therapy, tivozanib can significantly reduce the production of regulatory T cells and potentially enhance activity. In the RCC Phase II study, the combination of tivozanib and Bristol-Myers Squibb's anti-PD-1 therapy Opdivo (Odivo, nivolumab, nivolumab) showed a synergistic effect. Currently, tivozanib is being investigated for the treatment of various types of tumors, including renal cell carcinoma, hepatocellular carcinoma, colorectal cancer, ovarian cancer and breast cancer. (Bioon.com)