Gilteritinib Succeeds in Chinese Confirmatory Trial for FLT3-Mutated AML

Gilteritinib (Xospata) was found to result in a significant improvement in overall survival (OS) when used in patients with FLT3-mutated, relapsed/refractory acute myeloid leukemia (AML), meeting the primary end point of the confirmatory phase 3 COMMODORE trial (NCT03182244) in China.¹

In February 2021, the China National Medical Products Administration (NMPA) granted a conditional approval to gilteritinib for use in adult patients with relapsed/refractory AML harboring a FLT3 mutation detected by a fully validated test.² The designation was granted under an expedited pathway following the agent’s priority review designation in July 2020.

The decision was based on data from the phase 3 ADMIRAL trial (NCT02421939), which showed that gilteritinib resulted in a significant improvement in OS vs salvage chemotherapy in this population.³ The median OS in the investigative arm vs control arm was 9.3 months vs 5.6 months, respectively (HR, 0.64; 95% CI, 0.49-0.83; P = .0004); this translated to a 36% reduction in the risk of death.

The open-label, confirmatory phase 3 COMMODORE trial set out to examine gilteritinib vs salvage chemotherapy in adult patients with relapsed/refractory AML in China and other countries. Based on the positive findings from the planned interim analysis, pharmaceutical company has stopped enrollment to the trial and patients who are on the chemotherapy arm will be offered the chance to receive the FLT3 inhibitor.

Astellas announced that they will submit the results from the trial to the NMPA to support the full approval of the agent, and detailed findings will also be submitted for publishing in a peer-reviewed journal and/or to be presented at an upcoming medical meeting.

“In COMMODORE, patients receiving gilteritinib lived longer than those receiving salvage chemotherapy, confirming the OS benefit seen in the phase 3 ADMIRAL trial,” Andrew Krivoshik, MD, PhD, senior vice president and global therapeutic area head of Oncology Development at Astellas Pharma, Inc., stated in a press release. “For these patients, who have limited treatment options, the new findings provide additional evidence supporting gilteritinib as a treatment option.”

The objective of the COMMODORE trial was to identify the clinical benefit of gilteritinib over salvage chemotherapy in patients with FLT3-mutated AML who are refractory to, or who have relapsed after, frontline treatment.⁴

To be eligible for enrollment, patients had to have a diagnosis of primary AML or AML secondary to myelodysplastic syndrome, be refractory to or relapsed after frontline treatment, be positive for a FLT3 mutation, have an ECOG performance status of 0 to 2, and be candidates for salvage chemotherapy. If they had a diagnosis of acute promyelocytic leukemia, had BCR-ABL–positive leukemia, had AML secondary to previous chemotherapy for other neoplasms, were in second or later hematologic relapse or had received salvage treatment for refractory disease, or had clinically active central nervous system leukemia, they were excluded.

The primary end point of the trial was OS, although investigators also evaluated the safety, event-free survival, and complete remission rate of the FLT3 inhibitor vs salvage chemotherapy.

In the trial, study participants were randomized in a 1:1 fashion to receive either gilteritinib at 120 mg or salvage chemotherapy, which could have included low-dose cytarabine twice daily for 10 days; mitoxantrone, etoposide, cytarabine administered for days 1 through 5 and also recommended 7 days following completion of chemotherapy; and fludarabine and cytarabine given for days 2 through 6.

The safety of gilteritinib was examined in 319 patients with relapsed/refractory AML who were given at least 1 daily dose of gilteritinib at 120 mg.3 The most commonly experienced toxicities of any grade included increased alanine aminotransferase (ALT; 25.4%), increased aspartate aminotransferase (AST; 24.5%), anemia (20.1%), thrombocytopenia (13.5%), febrile neutropenia (12.5%), decreased platelet counts (12.2%). Additionally, 12.2% of patients experienced diarrhea, 11.3% had nausea, 11.0% had increased blood alkaline phosphatase, 10.3% had fatigue, 10.0% reported decreased white blood cell count, and 10.0% experienced increased blood creatinine phosphokinase.

Notably, 1 fatal adverse reaction of differentiation syndrome was reported in the arm of patients who received the FLT3 inhibitor.

The most common serious toxicities reported with gilteritinib comprised febrile neutropenia (7.5%), increased ALT (3.4%), and increased AST (3.1%).

References

1. Astellas’ XOSPATA (gilteritinib) meets overall survival endpoint in COMMODORE trial of patients with relapsed or refractory acute myeloid leukemia with a FLT3 mutation. News release. Astellas Pharma Inc. March 29, 2021. Accessed March 30, 2021. https://bit.ly/2OcsKc8
2. Astellas’ XOSPATA (gilteritinib) receives conditional approval by China’s National Medical Products Administration for relapsed or refractory acute myeloid leukemia with a FLT3 mutation. News release. Astellas Pharma, Inc. February 3, 2021. Accessed March 30, 2021. http://prn.to/3tn37VP.
3. Perl AE, Martinelli G, Cortes JE, et al. Gilteritinib or chemotherapy for relapsed or refractory FLT3-mutated AML. N Engl J Med. 2019;381(18):1728-1740. doi:10.1056/NEJMoa1902688
4. A study of ASP2215 versus salvage chemotherapy in patients with relapsed or refractory acute myeloid leukemia (AML) with FLT3 mutation. ClinicalTrials.gov. Updated March 16, 2021. Accessed March 30, 2021. https://clinicaltrials.gov/ct2/show/NCT03182244