Shares in AVEO Oncology were down as much as 30% on Monday after it said the FDA has recommended that the company should not submit a regulatory filing for Fotivda (tivozanib) in renal cell carcinoma (RCC) "at this time." This latest recommendation follows another given by the FDA about a year ago against seeking marketing approval for Fotivda based on preliminary overall survival (OS) results from the Phase III TIVO-3 trial, which had met its primary endpoint, improving progression-free survival (PFS) by 44% over Bayer and Onyx Pharmaceuticals' Nexavar (sorafenib), but showed no significant difference in OS during a preliminary analysis.
At the time, the FDA said the preliminary OS data "do not allay...concerns about the potential detriment in OS" outlined in a complete response letter issued for Fotivda in 2013, in which the agency called for an additional study to clarify PFS and OS inconsistencies seen in the earlier TIVO-1 trial comparing the VEGF receptor tyrosine kinase inhibitor to Nexavar. AVEO indicated in January this year that it planned to submit Fotivda for US approval following the availability of more mature OS results.
This time around, AVEO says it met with the FDA in August to discuss results from the second interim OS analysis of the TIVO-3 trial, which enrolled 351 patients with highly refractory advanced or metastatic RCC and was designed to address the agency's concerns regarding the OS trend seen in TIVO-1. According to AVEO, this latest analysis showed an updated OS hazard ratio (HR) of 0.99 at two years from the last patient enrolled in the study.
However, the FDA still remains concerned about the TIVO-3 results "in the context of the overall development" for Fotivda, AVEO said. The FDA noted that the new findings do not "abrogate...concerns over detriment and that those results may worsen with final analysis at 263 events, and that the median OS for Fotivda is worse than that of Nexavar."
AVEO stated Monday that "in view of the changing first-line treatment landscape, as well as the FDA's continued concerns, the company...intends to narrow its proposed indication to relapsed/refractory RCC." The drugmaker added that it plans to submit Fotivda for approval in the first quarter of 2020, as well as report the final OS analysis in June next year based on a May 1 cutoff, at which point it is believed the study will have reached roughly 263 OS events. However, if the final analysis yields an OS HR above 1.00, AVEO said it will withdraw its US marketing application.
CEO Michael Bailey remarked "we believe that we established an appropriate path forward toward filing a [new drug application] for Fotivda in the near term and a final analysis plan for OS." He suggested that 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 ten-fold more patients remaining progression free and on Fotivda versus Nexavar, make us believe that the final OS results will not worsen."
Regulators in Europe approved Fotivda in 2017 for patients with advanced RCC. In April, AVEO warned of possible regulatory action by the European Medicines Agency if the more mature OS analysis from TIVO-3 confirmed a negative trend for Fotivda.
For related analysis, read ViewPoints: Aveo’s never-ending Fotivda struggle not done yet – according to it anyway.
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