FDA: Data not up to snuff
But as FDA staff member Kunthel By, PhD, a statistical reviewer in the Office of Biostatistics, pointed out, the upper limit of the hazard ratio favoring quizartinib over chemotherapy was 0.99, and the difference in median overall survival was just 6.5 weeks.
Additionally, the trial data lacked internal consistency, showing no benefits for the drug in either event-free survival (EFS) or in completer response rates.
There were also imbalances in the number of patients with subsequent HSCT between the arms, with more patients on quizartinib undergoing HSCT despite not having a complete remission, than in the chemotherapy group. Also, there were differences in the number of patients who were randomized but not treated and in those censored early. And statistical stress tests indicated “a lack of robustness in the estimated treatment effect,” he said.
Safety issues raised in QuANTUM-R included slow potassium channel (IKs) blockade and related cardiac toxicitites, as well as the differentiation syndrome, acute febrile neutrophilic dermatosis, and cytopenias, said Aviva Krauss, MD, a clinical reviewer in the FDA’s Office of Hematology and Oncology Products.
“Quizartinib therapy is associated with significant and unique safety concerns in the [proposed population], including the risk of fatal cardiac events that cannot be predicted with certainty using routine QTc measurements,” she said.
She noted that the events occurred in QuANTUM-R despite dose modifications and concomitant medications guidelines in the study protocol.
Reviewers recommended that should the drug receive approval, the package labeling should include contraindication for use with other QT-prolonging agents, and a recommendation for prophylactic beta blockage, although the panelists in general felt that the latter recommendation was not necessary.