FDA Panel Gives Thumbs Down to AML Drug



SILVER SPRING, Md. -- An FDA advisory committee recommended against approval of tyrosine kinase inhibitor (TKI) quizartinib for patients with relapsed/refractory acute myeloid leukemia (AML) associated with FLT3-ITD mutations.

By an 8-3 vote, the Oncology Drugs Advisory Committee (ODAC) decided that the available data did not make a case for approval. In a pivotal clinical trial, treatment with the second-generation class III TKI resulted in a 6.5-week improvement in median overall survival (OS) versus chemotherapy. An inconsistency between OS and event-free survival (EFS), as well as concerns about cardiac risk -- including evidence of an increased risk in women versus men -- appeared to sway the committee's decision.

Even so, some members of the ODAC panel expressed ambivalence about the vote, given the lack of treatment options for patients with advanced AML.

"The overall survival benefit and the magnitude of benefit, I think it's been articulated," said ODAC chair Brian Rini, MD, of the Cleveland Clinic in Ohio, who voted in favor of approval. "There's uncertainty about the other clinical endpoints, like the increased transplant rate and CRi [complete response with incomplete hematologic recovery] rate that would complement the OS benefit if there is one."

Michael Lincoff, MD, of Case Western University in Cleveland, who also voted in favor of approval, said he was less concerned abut the risk. "I do think, on the balance, that there is benefit, within the constraints of being able to estimate precisely."

Anthony Sung, MD, of Duke University Medical Center in Durham, North Carolina, voted against approval but objected to the wording of the principal question presented to the panel: Do the benefits outweigh the safety risks in the population of patients with relapsed/refractory AML.

"I believe in this drug, I think it works, I believe it benefits patients, and I think it should be approved," said Sung. "The question is whether I think the benefits outweigh the risks ... I think this should help patients to transplant, and I think it has potential for quality of life ... My main concern is that women who may be at higher risk for adverse events ... I'm not convinced that the benefits outweigh the risks."

Jorge Cortes, MD, who spoke on behalf of the agent's sponsor, Daiichi-Sankyo, focused on quality-of-life issues.

"With standard chemotherapy, patients are usually hospitalized, sometimes for weeks ... ," said Cortes, of the University of Texas MD Anderson Cancer Center in Houston. "With quizartinib, patients can be mostly at home, taking a daily medication and coming to [the] clinic as needed."

"We have shown you today that patients with very aggressive disease experience clinical benefit with quizartinib," he added. "They can receive outpatient therapy and can expect a longer survival, a better probability of responding, a longer response duration, and a better chance of getting to transplant and the potential for a cure."

Supporting data for FDA approval came primarily from a single randomized trial comparing quizartinib and standard chemotherapy. The trial had a primary endpoint of OS, and the results demonstrated a statistically significant improvement in favor of the quizartinib arm (26.9 vs 20.4 weeks, HR 0.77, P=0.019). The median EFS did not differ between treatment groups (6.0 vs 3.7 weeks, P=0.114).

Additionally, differences in the rate of complete response and transfusion independence were modest, according to a report submitted by FDA staff.

The "FDA identified multiple issues that challenge the credibility, interpretation, and generalizability of the results," authors of the staff report stated.

Concerns include:

  • Lack of statistical robustness of the OS difference, including imbalances in censoring and the proportion of patients randomized but not treated
  • OS results driven by patients who received low-intensity chemotherapy
  • Imbalance in post-randomized therapy, including stem-cell transplant
  • Lack of benefit for key secondary endpoints, such as EFS

Differences in cardiac safety posed a major issue for members of the panel. Patients randomized to quizartinib had increased rates of ECG-confirmed prolonged QT interval (26.6% vs 2.1%), falls (4.6% vs 2.1%), and syncope (5.0% vs 2.1%).

The FDA is scheduled to make a final decision on the New Drug Application for quizartinib by August 2019. Although the agency is not required to follow its advisory committees' recommendations, it typically does.

FDA, panel, gives, thumbs, down to, spine Device



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