Oncologic Committee Votes Against Quizartinib
Committee: Oncologic Drugs Advisory Committee
Indications: the treatment of adults with relapsed or refractory acute myeloid leukemia which is FLT3-ITD positive, as detected by an FDA-approved test
Drug/Device: Drug - quizartinib
Sponsor: Daiichi Sankyo Inc.
Question 1: Do the results of Study AC220-007 demonstrate that treatment with quizartinib provides for a benefit that outweighs the safety risks for patients with relapsed or refractory FLT3-ITD-positive AML?
Vote Results: Yes 3 No 8 Abstain 0
FDA Documents:
Background:
Patients with acute myeloid leukemia (AML) that is refractory to or relapsed after a first-line regimen have a poor prognosis. The usual approach to treatment of such patients is with intensive combination cytotoxic chemotherapy or off-label use of low-intensity chemotherapy; gilteritinib is also approved for relapsed or refractory AML with a FLT3 mutation in particular. For patients who achieve a second complete remission (CR), allogeneic stem cell transplantation (HSCT) is considered the optimal approach to extend survival.
The applicant submitted the results of Study AC220-007 to support marketing application for quizartinib. Study AC220-007 was a randomized trial comparing quizartinib to standard-of-care (SOC) chemotherapy for the treatment of adult patients with FLT3-ITD positive relapsed or refractory AML.
Randomization was stratified by the type of preselected chemotherapy (intensive cytotoxic vs low-dose cytarabine) and response to prior therapy. The primary endpoint of the study was Overall Survival (OS). Event-free survival (EFS) and complete remission (CR) or CR with partial hematologic recovery (CR/CRh) were designated as secondary efficacy endpoints. The applicant seeks to use the OS results to provide evidence of efficacy for quizartinib based on a HR of 0.77 (95% CI 0.59, 0.99) with a 1.5 months difference in median OS between arms (median OS 6.2 months for the quizartinib arm and 4.7 months for the chemotherapy arm).
Unique Challenges:
Efficacy
The analysis of OS on the ITT population showed a statistically significant improvement with a hazard ratio (HR) of 0.77 (95% CI 0.59, 0.99; p=0.019), but the significance was marginal, the OS results were not robust, and analysis of the secondary endpoint, event-free survival (EFS), did not show a statistically significant improvement (HR 0.9; 95% CI 0.71, 1.16; p=0.114). Complete remission (CR) rates were similar between the arms (4% on the quizartinib arm vs 1% on the SOC arm). As a single trial to constitute substantial evidence of efficacy, the Study AC220-007 results were not consistent across the efficacy endpoints.
Furthermore, the credibility of the results of the primary efficacy endpoint analysis in Study AC220-007 were challenged by multiple findings, such as patients randomized not treated, early censoring etc., imbalanced in two arms, which raised the concerns on the robust of observed OS results. Additionally, subgroup analyses for OS by investigator-preselected chemotherapy group (high-intensity vs low-intensity), a stratification factor for the study, revealed a HR of 0.59 (95% CI 0.36, 0.97) for the low-intensity subgroup, compared to a HR of 0.83 (95% CI 0.62, 1.11) for the high-intensity subgroup, such that the results appear to be driven by the low-intensity stratum. Differences between the study arms in subsequent poststudy therapies were also noted, including a much higher rate of allogeneic hematopoietic stem cell transplantation (HSCT) in the quizartinib arm (23%) than in the chemotherapy control arm (0%) in the low-intensity stratum. The OS treatment effect may have been confounded by imbalances in poststudy therapy, including allogeneic HSCT.
Safety
The adverse events of special interest identified by the Applicant included infection, hemorrhage, hepatic disorders, QT prolongation, cardiac arrhythmias, and cardiac failure. In Study AC220-007, 27% of patients experienced at least one event of QT-prolongation. When compared to intensive chemotherapy or LDAC, the risk of cardiac events was substantially higher with quizartinib. Across the quizartinib clinical development program, the risk of on-treatment deaths due to cardiac events was estimated as 1-2%. Another key issue is that Quizartinib causes delayed cardiac repolarization by inhibition of IKs, a mechanism unique among non-antiarrhythmic drugs. Potential strategies to manage the risk of life-threatening or fatal cardiac events might include a contra-indication for use with drugs that prolong QT via the complementary IKr channel and a recommendation for administration of beta-blockers to prevent arrhythmias.