Gilteritinib Yields Comparable Efficacy vs Midostaurin in Newly Diagnosed FLT3-Mutated AML but Fails to Meet Phase 3 Primary End Point

Treatment with gilteritinib (Xospata) elicited overall survival (OS) outcomes that were comparable with those with midostaurin (Rydapt) in patients with newly diagnosed, FLT3-mutated acute myeloid leukemia (AML), although the primary end point was missed in the phase 3 HOVON156/AMLSG28-18/PASHA trial (NCT04027309), data from which were presented at the 2026 EHA Congress.¹

At a median follow-up of 43.2 months (95% CI, 42.6-44.1), the median OS was not reached (NR) in either arm (HR, 1.02; 95% CI, 0.81-1.28; P = .864). The 48-month OS rate was 59% with gilteritinib (n = 384) vs 60% with midostaurin (n = 384). OS outcomes were comparable across patient subgroups, including age and type of FLT3 mutation.

“The HOVON156/AMLSG28-18/PASHA trial represents the first phase 3, randomized, head-to-head comparison between first- vs second-generation FLT3 inhibitors in combination with intensive chemotherapy in FLT3-mutated AML,” Marc H. G. P. Raaijmakers, MD, said in the presentation. “We observed a consistent trend toward improved event-free survival [EFS] and relapse-free survival [RFS] in favor of gilteritinib, suggesting greater biological activity of gilteritinib. Increased post-relapse survival in the midostaurin arm was associated with a higher percentage of [patients] receiving salvage with gilteritinib and/or allogeneic transplant compared with the gilteritinib arm.”

Raaijmakers is a professor of hematology in the Department of Hematology at the Erasmus MC Cancer Institute in Rotterdam, Netherlands.

What was the rationale for investigating gilteritinib in newly diagnosed, FLT3-mutated AML?

FLT3 mutations are present in approximately 30% of patients with newly diagnosed AML.² Furthermore, approximately 20% to 25% of adult patients with AML harbor FLT3-ITD mutations, and approximately 7% to 8% of adult patients with AML have FLT3-TKD mutations.

“These mutations are a driver of disease biology, and therefore, inhibitors have been developed,” Raaijmakers explained.¹

Currently, first-line FLT3-mutated AML is managed with the first-generation inhibitor midostaurin or the second-generation inhibitor quizartinib (Vanflyta). Midostaurin was FDA approved in 2017 in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation for the treatment of adult patients with newly diagnosed FLT3-mutated AML, based on data from the phase 3 RATIFY trial (NCT00651261), in which the addition of midostaurin to standard chemotherapy reduced the risk of death by 23% vs chemotherapy alone (HR, 0.77; 95% CI, 0.63-0.95; 2-sided P = .016).³

Quizartinib was FDA approved in 2023 in combination with standard cytarabine and anthracycline induction and cytarabine consolidation, and as maintenance monotherapy following consolidation chemotherapy, for the treatment of adult patients with newly diagnosed FLT3-ITD–mutated AML, based on data from the phase 3 QuANTUM-First trial (NCT02668653), in which quizartinib plus chemotherapy elicited a statistically significant OS improvement vs placebo plus chemotherapy (HR, 0.78; 95% CI, 0.62-0.98; 2-sided P = .0324).⁴

Gilteritinib is a potent, highly selective second-generation FLT3 inhibitor that is active against both the ITD and TKD variations of FLT3. It is the current standard of care for patients with relapsed/refractory FLT3-mutated AML, having been FDA approved for this indication in 2018, based on data from the phase 3 ADMIRAL trial (NCT02421939), in which gilteritinib generated an OS benefit vs salvage chemotherapy (HR, 0.64; 95% CI 0.49-0.83; P = .0004).⁵

What was the design of the HOVON156/AMLSG28-18/PASHA trial?

The multicenter, open-label HOVON156/AMLSG28-18/PASHA was conducted at 193 sites across 12 countries in Europe, as well as Australia.¹ It enrolled adult patients with FLT3-mutated newly diagnosed AML or myelodysplastic syndrome with excess of blasts 2; notably, the latter were excluded from the present analysis. Patients needed to have FLT3-ITD– or -TKD–mutated disease, an ECOG performance status of 0 to 2, and be eligible for intensive chemotherapy.

Patients were randomly assigned 1:1 to receive induction therapy with cytarabine plus daunorubicin for 2 cycles plus either gilteritinib or midostaurin, followed by consolidation therapy with 1 of the following regimens:

• Idarubicin plus cytarabine (IDAC) or mitoxantrone/etoposide (ME) plus either gilteritinib (for those in the gilteritinib arm) or midostaurin (for those in the midostaurin arm)
• Autologous hematopoietic stem cell transplant (auto-HSCT)
• Allogeneic HSCT (allo-HSCT)

Then, patients received up to 1 year of maintenance therapy with either gilteritinib (for those in the gilteritinib arm) or midostaurin (for those in the midostaurin arm).

Gilteritinib was administered orally at 120 mg daily on days 8 through 21 in the induction/consolidation phases and daily at this dose level in 28-day cycles during the maintenance phase. Midostaurin was administered orally at 50 mg twice daily on days 8 through 21 in the induction/consolidation phases and daily at this dose level in 28-day cycles during the maintenance phase.

Patients were stratified by age (≤ 60 years vs ≥ 61 years), mutation status (FLT3-TKD vs FLT3-ITD allelic ratio < 0.5 vs FLT3-ITD allelic ratio ≥ 0.5), and chemotherapeutic consolidation policy (ME vs IDAC).

OS served as the primary end point. Key secondary end points included EFS, complete response (CR) rate after induction, and modified EFS. Selected additional secondary end points included RFS, hematological count recovery, and safety.

What were the characteristics of the patients enrolled in the HOVON156/AMLSG28-18/PASHA trial?

“The demographic and disease characteristics…were well balanced between arms and generally reflective of what you would expect from this population,” Raaijmakers noted.

The median age was 59 years (range, 18-78) in the gilteritinib arm vs 58 years (range, 18-78) in the midostaurin arm. FLT3 mutation status in these respective arms included FLT3-ITD allelic ratio less than 0.5 (30.5%; 31.0%), FLT3-ITD allelic ratio of at least 0.5 (49.0%; 46.9%), and FLT3-TKD (20.6%; 22.1%). The highest proportion of patients in each arm had intermediate-risk disease (37.0%; 37.2%). Most patients in each arm received the AMLSG consolidation chemotherapy policy (65.1%; 64.6%).

What additional efficacy data were seen with gilteritinib in newly diagnosed, FLT3-mutated AML?

CR rates after induction therapy were comparable between the 2 arms, at 78.9% (95% CI, 74.5%-82.9%) with gilteritinib vs 83.3% (95% CI, 79.2%-86.9%) with midostaurin (treatment difference, –4.4%; 95% CI, –10.0 to 1.1; P = .128). The rates of CR with incomplete count recovery and morphologic leukemia-free state were 2.9% and 3.9%, respectively, in the gilteritinib arm vs 3.6% and less than 0.1%, respectively, in the midostaurin arm.

Evaluable patients in the gilteritinib arm (n = 303) had a numerically longer median RFS and lower relapse rate vs those in the midostaurin arm (n = 320). The median RFS was NR (95% CI, NR-NR) with gilteritinib vs NR (95% CI, 24.7 months-NR) with midostaurin (HR, 0.68; 95% CI, 0.54-0.88; P = .003), and the relapse rates were 21.5% vs 35.9% in these respective arms.

A post hoc analysis showed that among patients in the midostaurin arm who experienced disease relapse (n = 115), gilteritinib was the most frequently used subsequent therapy (50%). Overall, in these patients, subsequent FLT3 inhibition was used in 55%. Use of a FLT3 inhibitor other than gilteritinib (15%), allo-HSCT (34%), and other treatment (70%) were also reported. Among patients in the gilteritinib arm who experienced disease relapse (n = 65), gilteritinib was less frequently used as subsequent therapy (17%). In these patients, the rate of subsequent FLT3 inhibition was 25%. Use of a FLT3 inhibitor other than gilteritinib (12%), allo-HSCT (22%), and other treatment (75%) were also reported.

Of patients in the gilteritinib arm who experienced disease relapse, the median OS after first relapse was 7.2 months (95% CI, 5.6-11.2); this value was 10.2 months (95% CI, 7.5-18.0) in the midostaurin arm. The 24-month OS rates after first relapse in these respective arms were 17.8% (95% CI, 8.6%-29.6%) and 37.3% (95% CI, 28.1%-46.4%).

What was the safety profile of gilteritinib in newly diagnosed, FLT3-mutated AML?

“Grade 3 [adverse effects (AEs)], as to be expected, were observed in most patients without differences between the arms, but there were more serious AEs in the gilteritinib arm…and 30- and 60-day morality [rates] were modestly increased in the gilteritinib arm,” Raaijmakers said in the presentation.

Among safety-evaluable patients in the gilteritinib arm (n = 384), grade 2 or higher treatment-emergent AEs (TEAEs; 99.5%), grade 3 or higher TEAEs (96.9%), serious AEs (68.2%), and treatment-related serious AEs (51.0%) were reported. These rates were 99.2%, 96.6%, 59.4%, and 40.6% among safety-evaluable patients in the midostaurin arm (n = 382). The most common grade 2 or higher TEAEs in these respective arms were febrile neutropenia (55.7%; 56.5%), diarrhea (49.5%; 50.3%), sepsis (49.0%; 38.2%), oral mucositis (33.6%; 38.0%), lung infection (33.1%; 30.6%), and hypokalemia (29.2%; 31.2%). The rates of treatment-related grade 2 or higher and grade 3 or higher AEs were 94.5% and 87.2%, respectively, in the gilteritinib arm vs 94.8% and 88.2%, respectively, in the midostaurin arm. The most common serious AEs in these respective arms were infections and infestations (43.2%; 35.6%); gastrointestinal disorders (8.3%; 9.4%); respiratory, thoracic, and mediastinal disorders (7.0%; 7.6%), cardiac disorders (6.8%; 6.8%), blood and lymphatic system disorders (6.0%; 5.5%), and immune system disorders (6.0%; 3.9%).

TEAEs led to death in 15.9% of patients in the gilteritinib arm vs 11.8% of those in the midostaurin arm, including infections and infestations (9.4%; 5.8%); general disorders and administration (1.6%; 1.6%); and respiratory, thoracic, and mediastinal disorders (1.8%; 0.8%). The respective 30-day mortality rates were 5.5% and 3.1%, and causes of death included pneumonia (4.8%; 8.3%), other infection (52.4%; 41.7%), hemorrhage (4.8%; 0%), and other reasons (38.1%; 50.0%). The respective 60-day mortality rates were 8.9% and 6.0%, and causes of death included leukemia (2.9%; 8.7%), pneumonia (5.9%; 4.3%), other infection (44.1%; 39.1%), hemorrhage (2.9%; 0%), other reasons (41.2%; 47.8%), and unknown reasons (2.9%; 0%).

Delayed hematologic recovery was observed with gilteritinib compared with midostaurin. The median time to absolute neutrophil count recovery of greater than 1.0 was 33 days among evaluable patients in the gilteritinib arm (n = 383) vs 28 days among those in the midostaurin arm (n = 379). The median time to platelet count recovery of greater than 100 was 31 days among evaluable patients in the gilteritinib arm (n = 383) vs 27 days among those in the midostaurin arm (n = 380).

Disclosures: Raaijmakers reported serving on advisory boards for Daiichi Sankyo and Astellas Pharma Inc., and receiving research funding to his institution from Daiichi Sankyo. Additionally, the HOVON156/AMLSG28-18/PASHA study was sponsored by Stichting Hemato-Oncologie voor Volwassenen Nederland (HOVON). Deutsch-Österreichische Studiengruppe Akute Myeloische Leukämie (AMLSG) and Astellas Pharma Inc. were collaborators on the study. Medical writing support for the study was provided by Pedro de Campos Silva, PhD, of Lumanity Scientific Inc., and was funded by Astellas Pharma Inc.

References

1. Raaijmakers MHGP, Ossenkoppele GJ, Gradowska PL, et al. Gilteritinib versus midostaurin in patients with newly diagnosed FLT3-mutated acute myeloid leukemia eligible for intensive therapy: results from the phase 3 HOVON156/AMLSG28-18/PASHA trial. Presented at: 2026 EHA Congress; June 11-14, 2026; Stockholm, Sweden. Abstract LB5005.
2. Bullinger L, Döhner K, Döhner H. Genomics of acute myeloid leukemia diagnosis and pathways. J Clin Oncol. 2017;35(9):934-946. doi:10.1200/JCO.2016.71.2208.
3. Rydapt. Prescribing information. Novartis; May 2023. Accessed June 14, 2026. https://www.novartis.com/us-en/sites/novartis_us/files/rydapt.pdf
4. FDA approves quizartinib for newly diagnosed acute myeloid leukemia. FDA. July 20, 2023. Accessed June 14, 2026. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-quizartinib-newly-diagnosed-acute-myeloid-leukemia
5. U.S. FDA approves supplemental new drug application adding overall survival data for Xospata (gilteritinib). News release. Astellas. May 30, 2019. Accessed June 14, 2026. https://newsroom.astellas.com/2019-05-30-U-S-FDA-Approves-Supplemental-New-Drug-Application-Adding-Overall-Survival-Data-for-XOSPATA-R-gilteritinib