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FDA Approves Update to Gilteritinib AML Label to Include OS Data

Gina Columbus
Published Online:2:08 PM, Thu May 30, 2019
A supplemental new drug application has been approved by the FDA to update the label for gilteritinib (Xospata) to include final analysis data from the phase III ADMIRAL trial, which demonstrated an improvement in overall survival with the FLT3 inhibitor compared with salvage chemotherapy in adult patients with relapsed/refractory FLT3-mutant acute myeloid leukemia (AML).1

Results from the phase III trial showed the median OS in patients who were treated with gilteritinib was 9.3 months (95% CI, 7.7-10.7) compared with 5.6 months in those who received salvage chemotherapy (95% CI, 4.7-7.3), which led to a 36% reduction in the risk of death (HR, 0.637; 95% CI, 0.490-0.830; P = .007).2

Moreover, at the interim analysis, the complete remission (CR)/complete remission with partial hematologic recovery (CRh) in the gilteritinib arm was 21% (95% CI, 14.5-28.8).

"The ADMIRAL trial's overall survival findings are encouraging for patients and families impacted by relapsed/refractory FLT3 mutation-positive AML,” said Alexander Perl, MD, Abramson Cancer Center, University of Pennsylvania. “The data underscore the importance of single-agent Xospata for this patient population that, until recently, had few remaining treatment options.”

The FDA reviewed the sNDA under the Oncology Center of Excellence Real-Time Oncology Review pilot program, which is designed to expedite a more efficient review process by allowing the agency to evaluate clinical data once trial results become available. Gilteritinib was initially approved by the FDA in November 2018; the decision was based on an interim analysis of CR/CRh rate, duration of CR/CRh, and rate of conversion from transfusion dependence to transfusion independence.

In the international, phase III ADMIRAL study, 371 adult patients with FLT3-mutant relapsed/refractory AML were randomized 2:1 to receive gilteritinib at 120 mg daily (n = 247) or salvage chemotherapy (n = 124). Patients in both arms then underwent HSCT, but only patients in the gilteritinib arm then resumed treatment with the FLT3 inhibitor; crossover was not permitted. Additionally, salvage chemotherapy was selected prior to randomization and could be one of the following regimens: mitoxantrone, etoposide, and cytarabine; fludarabine, cytarabine, idarubicin, and G-CSF; low-dose cytarabine; and azacitidine.

To be eligible for enrollment, patients with AML must have also harbored a FLT3-ITD or FLT3-TKD mutation, a mean of triplicate Fridericia-corrected QT interval <450 milliseconds at screening based on central reading, and be refractory to induction chemotherapy or in untreated first relapse.

Baseline characteristics were comparable between arms. Overall, the median age was 62 (range, 19-85) and 54% of patients were female. The majority of patients had intermediate-risk cytogenetics (73%) and 88% of patients had FLT3-ITD mutations. Additionally, 20% of patients had underwent prior HSCT, and 82% had received upfront intensive chemotherapy. Thirty-nine percent of patients had primary refractory AML without HSCT and 27% relapsed ≤6 months after composite complete remission (CRc).

The coprimary endpoints were OS and CR/CRh rate; secondary endpoints were event-free survival, CR rate, leukemia-free survival, duration of remission, CRc rate, transplantation rate, brief fatigue inventory, CRh rate, transfusion conversion rate, and transfusion maintenance rate.

In updated findings presented at the 2019 AACR Annual Meeting, data showed that the 1-year OS rates were doubled with gilteritinib at 37% (95% CI, 31%-44%) compared with salvage chemotherapy at 17% (95% CI, 10%-25%) in the intent-to-treat population (n = 371).

Results also showed that the CR, CRh, CR with incomplete hematologic recovery, and CR with incomplete platelet recovery rates with gilteritinib compared with salvage chemotherapy were 21% versus 11%, 13% versus 5%, 26% versus 11%, and 8% versus 0%, respectively. Additionally, the CRc rate was 54% with gilteritinib and 22% with salvage therapy.

The overall response rates were 26% with salvage chemotherapy and 68% with gilteritinib, which comprised a 13% partial response rate.

Moreover, the median duration of gilteritinib exposure was significantly longer than that of salvage therapy, at 4.1 months (range, 0.1-29.1) and 0.9 months (range, 0.2-7.1), respectively. The median time to achieve CRc was 1.8 months (95% CI, 0.9-9.95) with gilteritinib and 1.1 months (95% CI, 0.8-2.9) with salvage treatment. The median DOR with gilteritinib was also significantly longer at 11.0 months compared with 1.8 months with salvage therapy.

Regarding safety, gilteritinib's tolerability profile is based on 319 patients with relapsed/refractory AML in 3 clinical trials: NCT02421939, NCT02014558, and NCT02181660. Adverse events (AEs) that led to death occurred in 2% of patients on gilteritinib, which included cardiac arrest (1%) and differentiation syndrome and pancreatitis (n = 1 case each). The most frequent (≥5%) nonhematological serious AEs were fever (13%), dyspnea (9%), renal impairment (8%), transaminase increased (6%) and noninfectious diarrhea (5%). Moreover, the most frequent (≥5%) grade ≥3 nonhematological AEs reported in patients were transaminase increased (21%), dyspnea (12%), hypotension (7%), mucositis (7%), myalgia/arthralgia (7%), and fatigue/malaise (6%).

"Delivering innovation and value to address the unmet medical needs of patients is at the core of everything we do," said Bernhardt G. Zeiher, MD, chief medical officer, Astellas. “The FDA's approval of the sNDA based on overall survival data further highlights the strong potential gilteritinib has to help patients suffering from FLT3 mutation-positive AML, a life-threatening disease.”

Gilteritinib was initially approved by the FDA in November 2018; the decision was based on an interim analysis of CR/CRh rate, duration of CR/CRh, and rate of conversion from transfusion dependence to transfusion independence.
  1. U.S. FDA Approves Supplemental New Drug Application Adding Overall Survival Data for XOSPATA® (gilteritinib). Astellas Pharma. Published May 30, 2019. https://prn.to/2HKD05m. Accessed May 30, 2019.
  2. Perl AE, Martinelli G, Cortes JE, et al. Gilteritinib significantly prolongs overall survival in patients with FLT3-mutated (FLT3mut+) relapsed/refractory (R/R) acute myeloid leukemia (AML): Results from the Phase III ADMIRAL trial. Presented at: 2019 AACR Annual Meeting; March 29 to April 3, 2019; Atlanta, GA. Abstract CTPL04.

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