Phase 3, Open-Label, Randomized Study of Gilteritinib and Azacitidine Vs Azacitidine for Newly Diagnosed FLT3-Mutated Acute Myeloid Leukemia in Patients Ineligible for Intensive Induction Chemotherapy
Authors: Wang Eunice S. , Montesinos Pau , Minden Mark D. , Lee Je-Hwan , Heuser Michael , Naoe Tomoki , Chou Wen-Chien , Laribi Kamel , Esteve Jordi , Altman Jessica K. , Havelange Violaine , Watson Anne-Marie , Patkowska Elzbieta , Liu Shufang , Wu Ruishan , Philipose Nisha , Hill Jason E. , Gill Stanley , Rich Elizabeth Shima , Tiu Ramon V. 
Published: November 2021

Abstract
Background: Gilteritinib (GIL), a FLT3 inhibitor, shows efficacy/safety in patients (pts) with FLT3mut+ relapsed/refractory (R/R) AML. For pts with newly diagnosed (ND) AML with FLT3 mutations unable to receive intensive induction chemotherapy (IIC), survival is limited, and therapy options are few. In preclinical studies, GIL plus azacitidine (AZA) impeded tumor growth and induced apoptosis/differentiation of FLT3-ITD AML cell lines. Antitumor effects appeared synergistic in xenografted mouse models (data on file). We investigated GIL+AZA vs AZA in adults with ND FLT3mut+ AML ineligible for IIC (NCT02752035).

Aim/Objective: To compare efficacy and safety/tolerability of GIL+AZA and AZA in pts with ND FLT3mut+ AML ineligible for IIC.

Methods: Pts were initially randomized (1:1:1) to GIL (120 mg/day orally on Days 1-28) plus AZA (75 mg/m 2/day SC/IV on Days 1-7), AZA (same regimen), or GIL (same regimen) during 28-day cycles. The GIL arm was removed due to preferred therapy changes. Pts were then randomized (2:1) to GIL+AZA or AZA alone. The primary endpoint was overall survival (OS) and key secondary endpoint was event-free survival (EFS). Treatment failure date was randomization date if complete remission (CR) was not achieved after 6 cycles. Subgroup/sensitivity analyses were prespecified. Response rates, safety/tolerability, and pharmacokinetic endpoints were analyzed. Data from long-term follow-up ≤3 yrs were obtained, including subsequent AML therapy. These results are from an interim analysis at 70 deaths (~50% of total deaths).

Results: As of August 26, 2020, 123 pts were randomized to GIL+AZA (n=74) and AZA (n=49); 39 (52.7%) and 31 (63.3%) deaths, respectively, occurred. Median age was 78 yrs with GIL+AZA and 76 yrs with AZA; ECOG PS ≥2 was 47.3% and 32.7%, and FLT3-ITD alone was in 78.4% and 81.6% of pts, respectively (TKD alone 18.9% vs 14.3%; ITD with TKD 2.7% vs 4.1%). Median follow-up was 9.76 mo for GIL+AZA and 17.97 mo for AZA. Median exposure duration was 112 days for GIL in the GIL+AZA arm (n=73); AZA exposure was 98 and 99 days in the GIL+AZA and AZA (n=47) arms, respectively. Subsequent AML therapy was received by 20.3% pts on GIL+AZA and 44.9% pts on AZA; median time to first subsequent therapy was 8.2 and 4.5 mo, respectively. In the AZA arm, 22 pts received subsequent AML therapy, including 10 pts on GIL and 4 pts on other FLT3 inhibitors. Median OS was 9.82 mo for GIL+AZA and 8.87 mo for AZA (HR 0.916 [95% CI 0.529, 1.585]; P=.753). Patient subgroups with improved OS with GIL+AZA vs AZA included pts with ECOG PS 0-1 (HR 0.811 [95% CI 0.409, 1.608]) and high FLT3-ITD allelic ratio ≥0.5 (HR 0.580 [95% CI 0.285, 1.182]). Median EFS was 0.03 mo in both arms (HR 1.175 [95% CI 0.764, 1.807]; P=.459). In sensitivity analyses, median EFS with events based on composite CR (CRc; CR+CRi+CRp) was 5.03 mo for GIL+AZA and 3.29 mo for AZA (HR 0.924 [95% CI 0.576, 1.482]; P=.767). Although CR rates for both arms were similar (16.2% vs 14.3%), CRc rates were significantly higher for GIL+AZA vs AZA (58.1 vs 26.5%, difference 31.4% [95% CI 13.1, 49.7]; P&lt;.001). Overall adverse event (AE; GIL+AZA, 100% and AZA, 95.7%) and grade ≥3 AE rates (95.9% and 89.4%) were similar in both arms. Treatment-related AEs led to death in 4 pts in each arm. Common AEs with GIL+AZA were pyrexia (47.9%) and diarrhea (38.4%). Potential confounding factors contributing to OS findings were subsequent AML therapy, more pts with baseline ECOG PS ≥2 in the GIL+AZA arm, and study design change.
No substantial differences in GIL trough concentrations at steady state (C trough) were seen between GIL+AZA and GIL alone (prior to arm removal). However, on Cycle 1 Day 15, median GIL C trough was 579 ng/mL (GIL+AZA and GIL arms) in contrast to C trough of 279 ng/mL observed with GIL monotherapy in the ADMIRAL trial in pts with R/R AML. Reasons for this difference are being evaluated. No apparent relationship was seen between C trough and response rates/grade of thrombocytopenia or neutropenia.

Conclusions: In this trial of pts with ND FLT3mut+ AML ineligible for IIC, GIL+AZA led to significantly higher CRc rates but similar OS vs AZA alone. Pts with ECOG PS 0-1 and high FLT3-ITD allelic ratio appeared to have greater benefit with GIL+AZA. No new safety signals were seen. Curiously, C trough values in pts with ND FLT3mut+ AML ineligible for IIC were 2-fold greater than in pts with R/R FLT3mut+ AML. These results support the safety, tolerability, and activity of GIL+AZA vs AZA.

Disclosures
Wang: GlaxoSmithKline: Consultancy, Honoraria, Other: Advisory Board; Genentech: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Other: Advisory Board; Jazz Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; Pfizer: Consultancy, Honoraria, Other: Advisory Board, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Advisory board; Mana Therapeutics: Consultancy, Honoraria; Kite Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; Kura Oncology: Consultancy, Honoraria, Other: Advisory board, steering committee, Speakers Bureau; Stemline Therapeutics: Consultancy, Honoraria, Other: Advisory board, Speakers Bureau; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy, Speakers Bureau; Rafael Pharmaceuticals: Other: Data safety monitoring committee; Gilead: Consultancy, Honoraria, Other: Advisory board; Daiichi Sankyo: Consultancy, Honoraria, Other: Advisory board; PTC Therapeutics: Consultancy, Honoraria, Other: Advisory board; Genentech: Consultancy; MacroGenics: Consultancy. Montesinos: Stemline/Menarini: Consultancy; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Forma Therapeutics: Consultancy; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Glycomimetics: Consultancy; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Tolero Pharmaceutical: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Agios: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astellas Pharma, Inc.: Consultancy, Honoraria, Other: Advisory board, Research Funding, Speakers Bureau. Minden: Astellas: Consultancy. Lee: Korean Society of Hematology: Membership on an entity's Board of Directors or advisory committees; Astellas Pharma, Inc.: Consultancy, Honoraria, Other: Advisory board; AbbVie: Honoraria, Other: Advisory board. Heuser: Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees, Research Funding; BergenBio: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Tolremo: Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer Pharma AG: Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Research Funding. Naoe: Fuji Film: Other: Study funding for JAGSE; Astellas Pharma, Inc.: Consultancy, Other: Study funding for JAGSE; Bristol-Myers: Honoraria; Nippon Shinyaku: Honoraria; Daichi Sankyo: Other: Study funding for JAGSE; Otsuka Pharma: Honoraria. Chou: Abbvie: Honoraria, Other: Advisory Board, Research Funding; Celgene: Honoraria, Other: Advisory Board, Research Funding; IQVIA: Honoraria, Other: Advisory Board; Pfizer: Honoraria, Other: Advisory Board; Novartis: Honoraria, Other: Advisory Board; Bristol Myers Squibb: Honoraria, Research Funding; Kirin: Honoraria, Research Funding. Laribi: IQONE: Other: Personal Fees; Takeda: Other: Personal Fees, Research Funding; AstraZeneca: Other: Personal Fees; BeiGene: Other: Personal Fees; Astellas Phama, Inc.: Other: Personal Fees; Jansen: Research Funding; AbbVie: Other: Personal Fees, Research Funding; Le Mans Hospital: Research Funding; Novartis: Other: Personal Fees, Research Funding. Esteve: Jazz: Consultancy; Novartis: Research Funding; Bristol Myers Squibb/Celgene: Consultancy; Pfizer: Consultancy; Abbvie: Consultancy; Novartis: Consultancy, Research Funding; Astellas: Consultancy. Altman: ALZ Oncology: Research Funding; Amgen: Research Funding; Biosight: Consultancy, Other: Travel fees, Research Funding; Kartos: Research Funding; Boehringer Ingelheim: Research Funding; Daiichi Sankyo: Consultancy; Syros: Consultancy; BMS: Research Funding; GlycoMimetics: Other: Participation on an advisory board; Aprea: Research Funding; Kura: Research Funding; Kura Oncology: Consultancy; AbbVie: Consultancy, Other: Advisory Board, Research Funding; Theradex: Consultancy, Other: Advisory boards; Fujifilm: Research Funding; Astellas: Consultancy, Other: Advisory Board, Research Funding; Immunogen: Research Funding. Havelange: Astellas Pharma, Inc.: Consultancy; Novartis: Honoraria, Other: Travel fees, Participation on an advisory board; BMS: Other: Travel fees, Participation on an advisory board; Incyte: Other: Advisory board; Abbvie: Other: Advisory board. Watson: Astellas Pharma, Inc.: Consultancy; Roche, Amgen: Other: Travel support. Patkowska: Astellas Pharma, Inc.: Consultancy, Other: Travel fees; Pfizer: Other: Travel fees; Jazz Pharmaceuticals: Other: Travel fees; Angelini Pharma: Honoraria, Other: Travel fees; Novartis: Honoraria, Other: Travel fees; Bristol-Myers Squibb: Other: Travel fees; AMGEN: Honoraria; Servier: Honoraria, Other: Travel fees; KCR US, Inc.: Consultancy. Liu: Astellas Pharma, Inc.: Current Employment. Wu: Astellas: Current Employment. Philipose: Astellas Pharma Global Development: Current Employment. Hill: Astellas Pharma Global Development: Current Employment; Ligacept, LLC: Current holder of individual stocks in a privately-held company, Other: Stockholder. Gill: Astellas Pharma Global Development: Current Employment. Rich: Astellas Pharma Global Development, Inc.: Current Employment. Tiu: Astellas Pharma, Inc.: Current Employment.