A single clinical trial was deemed insufficient to support approval of tivozanib for the treatment of patients with advanced renal cell carcinoma, according to a 13-1 vote by the FDA's Oncologic Drugs Advisory Committee.
President and CEO of Aveo
A single clinical trial was deemed insufficient to support approval of tivozanib for the treatment of patients with advanced renal cell carcinoma (RCC), according to a 13-1 vote by the FDA’s Oncologic Drugs Advisory Committee (ODAC).
The clinical trial in question was the phase III TIVO-1 trial in which patients with advanced RCC were randomized to receive tivozanib or sorafenib, the latter of which is already approved for the treatment of advanced RCC.
In the trial, 517 patients with advanced RCC were randomized to receive either 1.5 mg of tivozanib once daily for 3 weeks, followed by 1 week of rest (n = 260), or 400 mg of sorafenib twice daily continuously in a 4-week cycle (n = 257). Patients were either treatment-naïve or received no more than one prior systemic therapy for metastatic disease, and no patients in the study received any prior VEGF- or mTOR-targeted therapy.
In results from the study that were presented at last year’s American Society of Clinical Oncology (ASCO) Annual Meeting, patients with advanced RCC who received tivozanib had a significant improvement in the primary endpoint of progression-free survival (PFS) when compared to sorafenib. However, when overall survival (OS) results were presented at the 2013 Genitourinary Cancers Symposium earlier this year, patients who received tivozanib had a slightly lower median OS than patients in the sorafenib arm.
The median PFS in the tivozanib arm was 11.9 months compared with 9.1 months in the sorafenib arm (hazard ratio [HR] = 0.797; 95% CI, 0.639-0.993; P = .042). Additionally, the study found an even more marked improvement in treatment-naïve patients who received tivozanib. Those patients experienced a median PFS of 12.7 months compared with 9.1 months in the sorafenib treatment-naïve arm (HR = 0.756; 95% CI, 0.580-0.985; P = .037).1
At the time of the OS analysis, the mortality rates were 45.4% in the tivozanib group and 39.3% in the sorafenib group, corresponding to a stratified hazard ratio of 1.245 (95% CI, 0.954—1.624; P = .105) trending in favor of sorafenib. Median overall survival was 28.8 months in the tivozanib arm and 29.3 months for the sorafenib arm.2
The ODAC meeting was convened to provide advice regarding questions from the FDA concerning the OS data and whether another trial was warranted before the federal agency could make a decision regarding the approval of tivozanib. In the meeting, members of ODAC and other experts criticized the design of the trial and the ability of the crossover to confound the results, ultimately voting that the trial did not provide sufficient evidence.
When the OS analysis was initially presented, lead investigator Robert J. Motzer, MD, addressed the crossover event. He argued that the OS comparison was confounded because 70% of patients assigned to sorafenib advanced to next-line VEGF therapy, including tivozanib, following disease progression.
“Tivozanib was developed as a highly selective and potent VEGF receptor inhibitor,” said Motzer, who is an attending physician in the Genitourinary Oncology Service at Memorial Sloan-Kettering Cancer Center in New York City and professor of medicine at Weill Medical College at Cornell University. “It has fewer of the off-target effects [than sorafenib]. It’s felt that inhibition of the VEGF receptor is the most important part of response to treatment and so a drug that inhibits the receptor more strongly is believed to be potentially more effective. Also, since it’s more selective it has a better safety profile, and that’s what we see in the trial.”
Several patients who had been enrolled on the trial told ODAC that the drug had improved their health and quality of life, during the public comments section of the meeting. However, the panelists were concerned by tivozanib’s lack of an improvement over an existing therapy, especially given that multiple drugs have already been approved by the FDA for the treatment of advanced renal cell carcinoma, including sorafenib, sunitinib, everolimus, and several others.
“While we are disappointed with the outcome of the ODAC vote, we remain confident in the efficacy, safety and tolerability of tivozanib in RCC patients,” said Tuan Ha-Ngoc, president and chief executive officer of Aveo Pharmaceuticals Inc., the company that developed tivozanib, in a statement. “We are committed to the RCC patient community and will work closely with the FDA to address the issues discussed by the panel today as the Agency continues its ongoing review of the New Drug Application for tivozanib.”
A Prescription Drug User Free Act (PDUFA) date of July 28, 2013, has been set for tivozanib. The FDA will decide whether to approve the drug on or before that date. The FDA is not required to follow the advice of ODAC, but historically, the federal agency tends to uphold decisions made by the advisory panel.