The recent US Food and Drug Administration (FDA) approval of gilteritinib (Xospata), in addition to final trial data from the phase 3 ADMIRAL trial, makes it the new standard of care for acute myeloid leukemia (AML).
On November 28, 2018, the FDA approved gilteritinib for the treatment of adult patients who have relapsed or refractory AML with a FLT3 mutation per an FDA-approved test. Furthermore, the FDA approved an expanded indication for a companion diagnostic, which was included with the drug. The LeukoStrat CDx FLT3 Mutation Assay is employed to detect FLT3 mutations in AML patients. The approval of gilteritinib was based on an interim analysis of the phase 3 ADMIRAL trial.
Final Results of the ADMIRAL Trial
In patients with FLT3 mutation-positive relapsed/refractory acute myeloid leukemia (AML), the potent, selective FLT3 inhibitor gilteritinib yielded significantly longer overall survival (OS), according to study findings presented at the American Association of Cancer Research 2019 Annual Meeting. Gilteritinib also yielded higher response rates vs chemotherapy and was safe.
“These results change the treatment paradigm for salvage therapy of relapsed/refractory FLT3mut+ AML and establish gilteritinib as the new standard of care,” wrote authors led by Alexander E. Perl, MD, a member of the leukemia program in the Abramson Cancer Center and an associate professor in the Division of Hematology/Oncology at the Perelman School of Medicine at the University of Pennsylvania.
In the study, adults with confirmed FLT3 mutation-positive relapsed/refractory AML (FLT3-ITD and/or FLT3-TKD D835/I836 mutations) refractory to induction chemotherapy or in untreated first relapse were randomized (2:1) to receive continuous 28-day cycles of 120 mg/d gilteritinib or prerandomization selected salvage chemotherapy, including low-dose cytarabine, azacitidine, mitoxantrone/etoposide/cytarabine, or fludarabine/cytarabine/granulocyte colony-stimulating factor/idarubicin.
Perl et al excluded previous FLT3 inhibitor use with the exception of midostaurin or sorafenib. Primary outcomes were OS and the combined rate of complete remission/complete remission with partial hematologic recovery (CR/CRh).
In total, 371 patients (39.4% refractory AML; 60.6% relapsed AML) were included, with 247 on gilteritinib and 124 on salvage chemotherapy. Patients in the experimental group had significantly longer OS (9.3 months) vs salvage chemotherapy (5.6 months; hazard ratio for death, 0.637; P = .0007). Furthermore, 1-year survival rates were 37.1% in the gilteritinib group vs 16.7% in the salvage chemotherapy group. The CR/CRh rates for gilteritinib were 34.0% vs 15.3% with salvage chemotherapy (P = .0001). Of note, CR rates were 21.1% and 10.5%, respectively (2-sided P = .0106).]3]).
“This is a change in terms of how we approach patients with aggressive relapsed/refractory disease, because we can get better results from less toxic, mutation-targeted therapy,” Dr. Perl said. He also noted that testing for FLT3 mutations should become standard for all patients with relapsed/refractory AML.
In an interview with Cancer Discovery, Ross Levine, MD, an oncologist at Memorial Sloan Kettering Cancer Center in New York, gave his take on the study: “Gilteritinib went up against investigator/patient’s choice—which included many patients receiving intensive chemotherapy—in the second line and won on all fronts: survival, response rate, toxicity. I think these data and the approval establish this as the treatment of choice for FLT3-mutant AML in the relapsed/refractory setting.”
More About the Drug
According to the manufacturer, gilteritinib is a kinase inhibitor used to treat adult patients who have relapsed or refractory AML along with a FLT3 mutation as detected via an FDA-approved test. Dosage for the drug is 120 mg orally once daily, and it comes in 40-mg tablets.
Gilteritinib is a pyrazinecarboxamide derivative that has demonstrated potency, selectivity, and activity against both FLT3-ITD and FLT3-TKD mutations. Gilteritinib also inhibits EML4-ALK and AXL, which is an oncogenic receptor tyrosine kinase believed to play a role in the maintenance of constitutive FLT3-ITD phosphorylation. The activation of AXL has been suggested as a mechanism of secondary resistance to FLT3 inhibitors.
Notably, in vivo models have demonstrated that AXL inhibition diminishes FLT3 phosphorylation and permits myeloid differentiation in FLT3-AML cell lines. In the phase I/II CHRYSALIS trial, investigators studied gilteritinib in patients with relapsed/refractory AML and reported potent FLT3 inhibition with doses 80 mg or more. Antileukemic activity was exhibited regardless of prior tyrosine kinase inhibitor treatment.
During clinical trials, unique adverse effects have been observed including a dose-dependent prolongation of the QTc interval, elevation in creatine kinase, and elevations in liver transaminases. Moreover, a handful of posterior reversible encephalopathy syndrome cases have transpired.
In FLT3-positive patients receiving gilteritinib—including those who were heavily pretreated—administration of the drug led to an OS of about 31 weeks. The single-agent antileukemic activity of gilteritinib has even more potential in patients with FLT3 mutations, according to experts, including those acquired at the FLT3-D835 tyrosine kinase domain.
In clinical trials, the most common adverse reactions (≥ 20%) were myalgia/arthralgia, transaminase increase, fatigue/malaise, fever, noninfectious diarrhea, dyspnea, edema, rash, pneumonia, nausea, stomatitis, cough, headache, hypotension, dizziness, and vomiting.
Med-med interactions for the drug occur with combined P-gp and strong CYP3A inducers. Additionally, it’s best to find alternative treatments to strong CYP3A inhibitors. Per the manufacturer, if the concomitant use of strong CYP3A inhibitors is absolutely necessary, patients should be checked more frequently for adverse reactions.
Certain warnings and precautions should be heeded when using gilteritinib. First, the drug should be discontinued in patients who develop posterior reversible encephalopathy syndrome. Second, with prolonged QT interval, drug dosage should be interrupted and reduced in patients who have a QTcF greater than 500 msec. Of note, it’s important to correct hypokalemia or hypomagnesemia prior to and during drug administration. Finally, the dose should also be interrupted and reduced in patients who develop pancreatitis
Financial Disclosure: Dr. Saleh and Dr. Copur have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.
1. Gilteritinib likely new standard care for AML. Cancer Discov. 2019;9:OF6.
2. U.S. Food and Drug Administration. FDA approves gilteritinib for relapsed or refractory acute myeloid leukemia (AML) with a FLT3 mutation. Available at: https://www.fda.gov/drugs/fda-approves-gilteritinib-relapsed-or-refractory-acute-myeloid-leukemia-aml-flt3-mutatation. Accessed July 29, 2019.
3. 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. American Association of Cancer Research (AACR) Annual Meeting, April 2, 2019. Abstr CT184. Available at: https://www.abstractsonline.com/pp8/#!/6812/presentation/9835. Accessed July 29, 2019.
4. XOSPATA (gilteritinib) [prescribing information]. Northbrook, IL: Astellas Pharma US; 2018. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211349s000lbl.pdf. Accessed July 29, 2019.
5. Weis TM, Marini BL, Bixby DL, Perissinotti AJ. Clinical considerations for the use of FLT3 inhibitors in acute myeloid leukemia. Crit Rev Oncol Hematol. 2019;141:125-38.