AVEO Oncology warns of "regulatory action" by EMA if overall survival results for Fotivda come up short

AVEO Oncology disclosed in a filing with the US Securities and Exchange Commission that the European Medicines Agency will consider "regulatory action" if an interim overall survival (OS) analysis from the TIVO-3 trial confirms a negative trend for Fotivda (tivozanib). The study is comparing Fotivda to Bayer's Nexavar (sorafenib) in patients with highly refractory advanced or metastatic renal cell carcinoma (RCC), with an interim OS analysis planned for August.

The European Commission approved Fotivda in 2017 for the first-line treatment of adults with advanced RCC and for adults who are VEGF receptor and mTOR pathway inhibitor-naïve following disease progression after one prior treatment with cytokine therapy for advanced RCC. Clearance was based on results from the TIVO-1 () trial, which showed that patients given Fotivda had superior progression-free survival (PFS) to Nexavar.

However, as part of post-marketing procedures the EMA requested top-line data from TIVO-3, as well as data analyses to explain the discordance between the final PFS results and the preliminary OS results. In the study, the results of which were disclosed last November, Fotivda was demonstrated to improve median PFS by 44 percent versus Nexavar, while no statistically significant difference in OS was observed at the time of the preliminary analysis (for related analysis, see ViewPoints: Tivozanib clears bar in TIVO-3 – but was it set too low?)

Meanwhile, the company presented topline data from the study at the American Society of Clinical Oncology (ASCO) Genitourinary (GU) Cancers Symposium in February, noting that the secondary endpoint of OS rate for patients receiving tivozanib was 18 percent compared to 8 percent for patients receiving sorafenib, adding that the OS analysis was not mature at the time of the final PFS analysis, and "currently reflects approximately 50 percent of potential OS events."

The company indicated that the regulator determined that the analyses of various factors that may have impacted the preliminary OS data do not fully explain the discordance, and is thus seeking more mature OS data.

In 2013, the FDA issued a complete response letter to AVEO for its submission of Fotivda and suggested the need for an additional clinical study in response to inconsistencies in PFS and OS data in the TIVO-1 study.  

More recently, AVEO announced that it agreed with the FDA's recommendation to not re-submit Fotivda for approval based on preliminary results from the TIVO-3 study. The drugmaker indicated at the time that it will make a decision concerning a US filing for the treatment after more mature OS data are available.

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