Poor trial design costs AVEO’s Tivopath at ODAC meeting.
Tivopath has suffered a major setback as ODAC recommends additional clinical trials in renal cell cancer
By Aine Slowey, Lead Analyst
7 May 2013
I am the Lead Analyst for cardiovascular and metabolic diseases at Datamonitor Healthcare. I have a DPhil in Organic Che...
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The FDA’s Oncologic Drugs Advisory Committee (ODAC) has voted 13 to one against AVEO’s Tivopath (tivozanib) in renal cell cancer (RCC). The committee decided that tivozanib did not demonstrate a favorable benefit-to-risk ratio in an adequate and well-controlled trial, and recommended that another clinical trial should be undertaken before Tivopath can be considered for US approval.
The committee’s main concerns surrounded the overall survival (OS) benefit demonstrated by Tivopath in its Phase III TIVO-1 trial. Interim analysis of the trial data showed that at one year, 77% of patients receiving Tivopath were still alive compared to 81% of patients receiving the active comparator Nexavar (sorafenib; Bayer Schering/Onyx). Patients receiving Tivopath demonstrated a median OS of 28.8 months, compared to 29.3 months for patients in the Nexavar arm.
AVEO maintained that the unfavorable survival trend for Tivopath was due to the movement of patients from the Nexavar arm to the Tivopath arm of the trial. A one-sided crossover for patients randomized to Nexavar was offered to trial participants upon disease progression, with 61% of Nexavar patients receiving subsequent treatment with Tivopath. AVEO claimed that improved clinical outcomes have been observed in RCC patients receiving more than one line of therapy, which may have artificially improved the OS benefit demonstrated by patients in the Nexavar arm.
However, ODAC did not feel that the results of the TIVO-1 trial adequately proved this hypothesis. The committee felt that the flawed trial design did not address concerns that Tivopath’s survival trend was a result of delayed adverse reactions to the drug or the superiority of the active comparator.
ODAC’s recommendation will now be submitted to the FDA during its review of Tivopath’s New Drug Application. While the regulator is not bound by the committee’s guidance, it is very unlikely that the FDA will approve Tivopath after such a one-sided vote. AVEO may now be forced to initiate an additional clinical trial to better illustrate the drug’s efficacy and safety profile in advanced RCC.
ODAC’s decision highlights the importance of adequate clinical trial design. In its TIVO-1 trial, Tivopath met its primary endpoint, demonstrating a progression-free survival advantage of 2.8 months over Nexavar. However, the confusion caused by the crossover of patients and associated OS benefit has prevented Tivopath from entering the RCC market for at least another year. As such, pharmaceutical companies wishing to enter the RCC market will pay close attention to ODAC’s assessment of Tivopath and may reconsider the design of future clinical trials.