SILVER SPRING, Md.—The Oncologic Drugs Advisory Committee voted not to recommend approval of tivozanib, an investigational oral tyrosine kinase inhibitor (TKI) for treatment of patients with metastatic renal cell carcinoma. The FDA does not have to take the advice of its advisory committees, but often does.
The only ODAC member voting for approval of tivozanib was Dan Lumley, EdD, of Kansas City, Mo., the committee's temporary patient representative; he said the relatively favorable data on side effects were persuasive to him. Tivozanib inhibits angiogenesis by targeting all three VEGF receptors.
“I'm concerned about the conduct of this study,” said ODAC Chair Mikkael Sekeres, MD, MS, Director of the Leukemia Program at the Cleveland Clinic Taussig Cancer Institute, Chair of the Hematology/Oncology Pharmacy & Therapeutics Committee, and OT's Clinical Advisory Editor for Hematology/Oncology.
The key issue in the data from the single randomized trial presented at the ODAC meeting was that although the trial met its endpoint of a 20 percent improvement in progression-free survival compared against sorafenib, the analysis of overall survival data showed a potential 25 percent increase in death with tivozanib compared with sorafenib.
Sekeres said that as a physician, he could not picture himself sitting down in a room with a patient and talking about a drug that might cause that patient “possibly to die faster,” especially when other approved TKIs are available for RCC.
Agreeing with Sekeres were ODAC members Louis F. Diehl, MD, Professor of Medicine at Duke University Medical Center; and David Steensma, MD, Associate Professor of Medicine at Harvard Medical School.
“We have discussed this application for months and months,” said Richard Pazdur, MD, Director of FDA's Office of Hematology & Oncology Products. He said he was very concerned about the uncertainty over the potential 25 percent increased risk of death, and cited his fear about compromising the physician's duty to “first do no harm.”
He said that while patients want new cancer drugs, “wild enthusiasm with no data” benefits no one. He emphasized that the FDA does accept progression-free survival (PFS) as an endpoint (although the preference is for overall survival [OS]) and will accept a single clinical trial (although it prefers at least two) for new drug approval if the data are truly compelling.
“Obviously OS is a much more important endpoint than PFS,” Pazdur commented. He said he was “extremely disappointed” with the proposed labeling of tivozanib, which does not mention overall survival data. Before prescribing the drug, he noted, a physician “would need to have a meaningful conversation with a patient about overall survival.” Like Sekeres, Pazdur cited the fact that there are other approved TKIs available for the treatment of RCC.
“Progression-free survival is primarily a radiological endpoint” and thus has limitations, said Jonathan Jarow, MD, a medical officer in FDA's Division of Oncology Products, who served on the agency's review team for tivozanib. In contrast, he said, “Overall survival ensures that both safety and efficacy are critical for the risk-benefit analysis and is an important endpoint for patients.”
Like Sekeres and other ODAC members, Jarow questioned how a physician would explain the 25 percent increase in risk of death to a patient. Added Amna Ibrahim, MD, Deputy Director of FDA's Division of Oncology Products, “The inconsistent PFS and OS results and imbalance in post-study treatments makes the trial results inconclusive when making a risk-benefit assessment necessary for approval of a drug.”
Post-ODAC Telephone Briefing by Aveo CEO
The new drug application for tivozanib may not be dead. In a post-ODAC telephone briefing, Tuan Ha-Ngoc, President and CEO of Aveo Oncology, the company that is sponsoring tivozanib along with Astellas Pharma Global Development, Inc., said that although the company is “very disappointed” with the outcome of the ODAC meeting and “strongly disagrees” with the basis of the vote, “there remains a need for new treatment options for patients with kidney cancer.”
Therefore, he said, Aveo is evaluating the New Drug Application for tivozanib in light of the comments made at the ODAC meeting. He said the company is confident in “the efficacy, safety and tolerability of tivozanib,” and believes it will be of real benefit to RCC patients. In a post-ODAC news release, he stated, “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.”
The Aveo CEO did not take questions during the call.
Daniel George and Robert Motzer Spoke in Favor of Tivozanib
Non-ODAC members speaking in favor of tivozanib at the meeting included Daniel George, MD, Associate Professor of Medicine and Surgery in the Division of Medical Oncology and Division of Urology and Director of Genitourinary Oncology at Duke Cancer Institute; and Robert Motzer, MD, Attending Physician at Memorial Sloan-Kettering Cancer Center and Professor of Medicine at Cornell University's Weill College of Medicine.
Motzer, principal investigator of the Phase III tivozanib trial, stressed that TKIs with activity against VEGF receptors are standard of care for advanced RCC, and that physicians need “access to therapies with different toxicities to allow individualization.” He said tivozanib's once-daily dosing is attractive to patients, and noted that another plus is that this drug has no interaction with CYP3A4 inhibitors.
During the open public-hearing portion of the ODAC meeting, several patients spoke eloquently in favor of tivozanib, including Jim Kaya, who has been on the drug for 15 months. “It's all about quality of life,” said Kaya, a Boy Scout leader. He said his main side effects—high blood pressure and slight diarrhea—are manageable, and his voice hoarseness is “acceptable.”
Problems with the Trial's Design
In addition to concerns about the troubling data on overall survival, ODAC members had questions about the study design. In this trial of 517 randomized patients with advanced RCC, 88 percent of patients came from Central and Eastern Europe, raising questions about the generalizability of the data to patients in the U.S.
“Why was this trial done mainly in Europe?” asked Pazdur. William Schlichenmyer, MD, ScM, Chief Medical Officer at Aveo Oncology, responded that at the time of trial recruitment there was great competition for study subjects, and recruiting the majority of trial subjects in Europe allowed Aveo to complete accrual faster.
Sekeres said he questioned the ethics of having so many trial subjects recruited from countries where multiple TKIs are not readily available, as they are in the United States. Also of concern to ODAC members was that patients on sorafenib who had progression were allowed to cross over to tivozanib, a single crossover that members felt was a confounder. So did Pazdur: “It's very, very, very confounded.”
“This is a classic case of why we recommend against crossover,” said Lori Dodd, PhD, a temporary ODAC voting member who is a mathematical statistician in the Division of Clinical Research, Biostatistics, in the Research Branch of the National Institute of Allergy and Infectious Diseases. Dodd said she found listening to patient testimonies during the public hearing “very moving,” and said she was “angry” that the trial on tivozanib had “severe limitations.” While listening to the patients, said Dodd, “I wished that we were not in the gray zone here.”
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