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Clinical Trial
. 2022 Oct 27;140(17):1845-1857.
doi: 10.1182/blood.2021014586.

Phase 3 trial of gilteritinib plus azacitidine vs azacitidine for newly diagnosed FLT3mut+ AML ineligible for intensive chemotherapy

Eunice S Wang  1 , Pau Montesinos  2 , Mark D Minden  3 , Je-Hwan Lee  4 , Michael Heuser  5 , Tomoki Naoe  6 , Wen-Chien Chou  7 , Kamel Laribi  8 , Jordi Esteve  9 , Jessica K Altman  10 , Violaine Havelange  11 , Anne-Marie Watson  12 , Carlo Gambacorti-Passerini  13   14 , Elzbieta Patkowska  15 , Shufang Liu  16 , Ruishan Wu  16 , Nisha Philipose  16 , Jason E Hill  16 , Stanley C Gill  16 , Elizabeth Shima Rich  16 , Ramon V Tiu  16
Affiliations
Clinical Trial

Phase 3 trial of gilteritinib plus azacitidine vs azacitidine for newly diagnosed FLT3mut+ AML ineligible for intensive chemotherapy

Eunice S Wang et al. Blood. .

Abstract

Treatment results for patients with newly diagnosed FMS-like tyrosine kinase 3 (FLT3)-mutated (FLT3mut+) acute myeloid leukemia (AML) ineligible for intensive chemotherapy are disappointing. This multicenter, open-label, phase 3 trial randomized (2:1) untreated adults with FLT3mut+ AML ineligible for intensive induction chemotherapy to receive gilteritinib (120 mg/d orally) and azacitidine (GIL + AZA) or azacitidine (AZA) alone. The primary end point was overall survival (OS). At the interim analysis (August 26, 2020), a total of 123 patients were randomized to treatment (GIL + AZA, n = 74; AZA, n = 49). Subsequent AML therapy, including FLT3 inhibitors, was received by 20.3% (GIL + AZA) and 44.9% (AZA) of patients. Median OS was 9.82 (GIL + AZA) and 8.87 (AZA) months (hazard ratio, 0.916; 95% CI, 0.529-1.585; P = .753). The study was closed based on the protocol-specified boundary for futility. Median event-free survival was 0.03 month in both arms. Event-free survival defined by using composite complete remission (CRc) was 4.53 months for GIL + AZA and 0.03 month for AZA (hazard ratio, 0.686; 95% CI, 0.433-1.087; P = .156). CRc rates were 58.1% (GIL + AZA) and 26.5% (AZA) (difference, 31.4%; 95% CI, 13.1-49.7; P < .001). Adverse event (AE) rates were similar for GIL + AZA (100%) and AZA (95.7%); grade ≥3 AEs were 95.9% and 89.4%, respectively. Common AEs with GIL + AZA included pyrexia (47.9%) and diarrhea (38.4%). Gilteritinib steady-state trough concentrations did not differ between GIL + AZA and gilteritinib. GIL + AZA resulted in significantly higher CRc rates, although similar OS compared with AZA. Results support the safety/tolerability and clinical activity of upfront therapy with GIL + AZA in older/unfit patients with FLT3mut+ AML. This trial was registered at www.clinicaltrials.gov as #NCT02752035.

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Conflict of interest statement

Conflict-of-interest disclosure: E.S.W. has received honoraria from Stemline, Kura, Pfizer, and DAVA Oncology; participated in advisory boards with AbbVie, Astellas, BMS/Celgene, Genentech, Gilead, GlaxoSmithKline, Jazz, Kite Pharmaceuticals, Kura Oncology, Novartis, Pfizer, Stemline, and Takeda; and participates in data monitoring committees for AbbVie and Rafael Pharmaceuticals. P.M. has participated in advisory boards and received honoraria from Astellas. M.D.M. has participated in advisory boards for Astellas, AbbVie, Trillium Therapeutics, Celgene, and Bristol Myers Squibb; and has received research funding from AbbVie. J.-H.L. has received honoraria from AbbVie Korea and Astellas Korea; and has participated in advisory boards for Astellas and AbbVie. M.H. has received honoraria from Jazz Pharmaceuticals, Janssen, and Novartis; participated in advisory boards for AbbVie, BMS/Celgene, Daiichi Sankyo, Jazz Pharmaceuticals, Novartis, Pfizer, Roche, and Tolremo; and has received research funding from Astellas, Bayer Pharma AG, BerGenBio, Daiichi Sankyo, Jazz Pharmaceuticals, Karyopharm, Novartis, Pfizer, and Roche. T.N. has received honoraria from Nippon Shinyaku, Bristol Myers Squibb, and Otsuka Pharma; and reports study funding from Astellas, Daiichi Sankyo, and Fujifilm. K.L. has received grants from Novartis, Takeda, Janssen, and AbbVie; and consulting fees from Novartis, Takeda, AbbVie, iQone, Astellas, Astra, and BeiGene. J.E. has received a grant from Novartis; honoraria from Astellas; and participated in advisory boards for Novartis, AbbVie, Jazz Pharmaceuticals, Pfizer, Celgene, and Daiichi Sankyo. J.K.A. has received advisory or consulting fees from AbbVie, Amgen, Astellas, bluebird bio, Curio Science, Daiichi Sankyo, Kura Oncology, Stemline, Syros, and Theradex; research funding at an institutional level for the conduct of trials from ALX Oncology, Amgen, Aptos, Astellas, Aprea, BioSight, BMS, Boehringer Ingelheim, Celgene, Fujifilm, ImmunoGen, Kartos, Kura Oncology, Loxo, and Takeda; reimbursement for travel from BioSight; and serves on a data monitoring committee for GlycoMimetics. V.H. has received honoraria fees from Novartis; travel support from Novartis and BMS; and participated in advisory boards for Incyte, Novartis, BMS, and AbbVie. E.P. has received consulting fees from KCR US, Inc.; honoraria from Amgen, Novartis, Servier, and Angelini Pharma; and travel support from Novartis, Servier, Angelini Pharma, Bristol Myers Squibb, Jazz Pharmaceuticals, Pfizer, and Astellas Pharma. J.E.H. reports holding stock for Ligacept, LLC. S.L., N.P., J.E.H., S.C.G., E.S.R., and R.V.T. are employees of Astellas. The remaining authors declare no competing financial interests.

The current affiliation for R.V.T. is Takeda Pharmaceutical Company, Boston, MA.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Randomization and treatment. GIL, gilteritinib.
Figure 2.
Figure 2.
OS. (A) Kaplan-Meier estimates show the primary end point of OS for the intention-to-treat population. Tick marks indicate censored data. (B) Forest plot for OS in prespecified subgroups. Data represent unstratified analyses. NE, not estimable.
Figure 3.
Figure 3.
Survival status, follow-up, and use of FLT3 inhibitors by individual patients among treatments. Follow-up, including survival status and treatment and follow-up periods, is shown for individual patients in the (A) AZA alone and (B) GIL + AZA groups who received subsequent AML therapy with FLT3 inhibitors.
Figure 4.
Figure 4.
EFS. (A) EFS based on CR, treatment failure, or all-cause death. (B) EFS based on CRc, treatment failure, or all-cause death. Tick marks indicate censored data. EFS is defined as the time from the date of randomization until the date of documented relapse from CR (panel A) or CRc (panel B), treatment failure (failure to achieve CR within 6 cycles of treatment), or all-cause death, whichever occurred first. NE, not estimable.
Figure 5.
Figure 5.
Comparison of CRc between treatment groups. A graphical depiction of the incidence of CRc in patients with ND FLT3mut+ AML ineligible for IIC who received GIL + AZA and AZA is shown.
Figure 6.
Figure 6.
OS according to gilteritinib Ctrough at steady state. OS is shown in patients stratified according to high (≥617 ng/mL) or low (<617 ng/mL) gilteritinib serum Ctrough at steady state. Tick marks indicate censored data. mOS, median OS.
See this image and copyright information in PMC

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