Updated Results from a Phase I/II Study of the Triplet Combination of Azacitidine, Venetoclax and Gilteritinib for Patients with FLT3-Mutated Acute Myeloid Leukemia

Background:FLT3 mutations are associated with a poor prognosis in both newly diagnosed (ND) and relapsed/refractory (R/R) acute myeloid leukemia (AML). Gilteritinib is a potent oral FLT3 inhibitor that improves response rates and overall survival (OS) in R/R FLT3-mutated AML. While a hypomethylating agent (HMA) plus venetoclax is standard of care for older/unfit patients (pts) with ND FLT3-mutated AML, remission durations are relatively short and FLT3-driven relapses are common. We therefore designed a phase I/II study to evaluate the triplet regimen of azacitidine, venetoclax and gilteritinib in pts with FLT3-mutated AML.

Methods: In this phase I/II study, pts with either R/R FLT3-mutated AML or ND FLT3-mutated AML who were unsuitable for intensive chemotherapy were eligible. Either FLT3-ITD and/or TKD mutations were allowed. Pts were required to have a performance status ≤3, total bilirubin ≤2.5 x ULN, ALT/AST ≤3 x ULN, and creatinine clearance ≥30 mL/min. In cycle 1, pts received azacitidine 75 mg/m² SC/IV on days 1-7, venetoclax on days 1-28, and gilteritinib on days 1-28. Gilteritinib dose ranged from 80mg to 120mg daily during the phase I dose escalation (3+3 design). Bone marrow was performed on day 14 and if blasts were <5% or the marrow was insufficient/aplastic, then both venetoclax and gilteritinib were held (ND cohort) or only venetoclax was held (R/R cohort). For cycles 2 and beyond, azacitidine 75 mg/m² SC/IV was given for 5 days, venetoclax was given for 7 days and gilteritinib was given continuously.

Results: Between 12/2019 and 6/2022, 40 pts were treated (21 ND pts and 19 R/R pts). Baseline characteristics of the 2 cohorts are shown in Table 1. The median age for both the ND and R/R cohorts was 68 years (range, 18-82 for ND cohort; 19-90 for R/R cohort). One pt <60 years of age (age 18) was enrolled in the ND cohort due to severe COVID-19 pneumonia at the time of AML diagnosis. In the ND cohort, 14 (67%) had a FLT3-ITD and 7 (33%) had a FLT3 TKD mutation; in the R/R cohort, 8 (42%) had a FLT3-ITD, 7 (37%) had a FLT3-TKD, and 4 (21%) had both mutations. In the R/R cohort, the median number of prior therapies was 2 (range, 1-5), 8 (42%) had received prior HMA plus venetoclax, 5 (26%) had received prior FLT3 inhibitor (including 1 pt who had received prior gilteritinib), and 5 (26%) had undergone prior hematopoietic stem cell transplant (HSCT).

Ten R/R pts were treated in the phase I cohort (6 at 80mg of gilteritinib and 4 at 120mg). Based on a superior safety and efficacy profile, the 80mg daily dose was chosen as the phase II dose for further study.

In the ND cohort, all pts responded, with 20 (95%) achieving CR and 1 (5%) achieving MLFS as best response. On the day 14 bone marrow, all pts achieved either morphologic remission with <5% blasts (n=15) or had an insufficient/aplastic marrow (n=6). Seventeen pts (81%) achieved flow measurable residual disease (MRD) negativity and 19 pts (90%) cleared the FLT3 mutation using a PCR assay with sensitivity of 10^-2. Four pts (19%) proceeded to HSCT in first remission. No pts died in the first 60 days of treatment. Overall, 3 pts have relapsed (1 FLT3-positive at relapse, 1 FLT3-negative at relapse, and 1 who relapsed with extramedullary-only disease) after a median response duration of 6.8 months, and 3 pts have died (1 after relapse, 1 from post-HSCT complications, and 1 due to sepsis while in CR). With a median follow-up of 10.0 months, the 6-month OS rate is 95% and the estimated 1-year OS rate is 80% (Figure 1A).

In the R/R cohort, 14 pts (74%) responded: 4 (21%) achieved CR, 3 (16%) achieved CRi, and 7 (37%) achieved MLFS. Among responders, 43% achieved MRD negativity by flow and 50% achieved FLT3 clearance by PCR. Four pts (29% of responding pts) proceeded to HSCT. Among the 14 responding pts, 7 relapsed (3 after HSCT and 4 who were not transplanted), 3 died in remission, 1 is alive and in remission post-HSCT, and 3 are alive in ongoing remission without HSCT. With a median follow-up of 24.1 months, the median OS is 5.8 months and the 1-year OS rate is 27%. Outcomes were superior for those who had not received prior HMA plus venetoclax or gilteritinib (median OS: 10.5 months vs. 4.8 months; 1-year OS rate: 41% vs. 11%; P=0.11) (Figure 1B).

Conclusions: The combination of azacitidine, venetoclax and gilteritinib is effective in pts with FLT3-mutated AML. OS in the ND cohort compares favorably with historical expectations of FLT3-mutated AML treated with HMA plus venetoclax without a FLT3 inhibitor.

Short:Stemline Therapeutics: Research Funding; Takeda Oncology: Consultancy, Research Funding; Pfizer: Consultancy; Novartis: Consultancy; AstraZeneca: Consultancy; Astellas: Research Funding; Amgen: Consultancy, Honoraria. DiNardo:Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; ImmuneOnc: Honoraria, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding; GenMab: Membership on an entity's Board of Directors or advisory committees; Foghorn: Honoraria, Research Funding; Takeda: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; Forma: Research Funding; Novartis: Honoraria; Astex: Research Funding; Cleave: Research Funding; Bluebird Bio: Honoraria; Servier: Consultancy, Honoraria, Research Funding; Kura: Honoraria, Membership on an entity's Board of Directors or advisory committees; LOXO: Research Funding; Jazz: Honoraria; Gilead: Honoraria; Astellas: Honoraria. Daver:Agios, Celgene, SOBI and STAR Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kartos and Jazz Pharmaceuticals: Other: Data monitoring committee member; Karyopham Therapeutics and Newave Pharmaceutical: Research Funding; Astellas, AbbVie, Genentech, Daiichi-Sankyo, Novartis, Jazz, Amgen, Servier, Karyopharm, Trovagene, Trillium, Syndax, Gilead, Pfizer, Bristol Myers Squibb, Kite, Actinium, Arog, Immunogen, Arcellx, and Shattuck: Consultancy, Other: Advisory Role; Astellas, AbbVie, Genentech, Daiichi-Sankyo, Gilead, Immunogen, Pfizer, Bristol Myers Squibb, Trovagene, Servier, Novimmune, Incyte, Hanmi, Fate, Amgen, Kite, Novartis, Astex, KAHR, Shattuck, Sobi, Glycomimetics, Trillium: Research Funding. Yilmaz:Daiichi-Sankyo: Research Funding; Pfizer: Research Funding. Borthakur:Catamaran Bio, Abbvie, PPD Development, Protagonist Therapeutics, Janssen: Consultancy; Pacylex, Novartis, Cytomx, Bio Ascend: Membership on an entity's Board of Directors or advisory committees; Astex Pharmaceuticals, Ryvu, PTC Therapeutics: Research Funding. Garcia-Manero:Genentech: Honoraria, Research Funding; Astex: Consultancy, Honoraria, Research Funding; Aprea: Honoraria; BMS: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Curis: Honoraria, Research Funding; Acceleron Pharma: Consultancy; Gilead Sciences: Research Funding; Novartis: Honoraria, Research Funding. Issa:Celgene, Kura Oncology, Syndax, Merck, Novartis: Research Funding; Novartis, Kura Oncology: Consultancy. Sasaki:Otsuka Pharmaceuticals: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, 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. Thompson:Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; AbbVie, Pharmacyclics, Adaptive Biotechnologies, Genentech: Research Funding; AbbVie, Gilead, Janssen, Pharmacyclics, Adaptive Biotechnologies, Genentech: Consultancy; AbbVie, Gilead, Janssen, Pharmacyclics, Adaptive Biotechnologies, Genentech, Amgen: Honoraria. Burger:TG Therapeutics: Consultancy; Gilead: Consultancy; Janssen: Consultancy, Speakers Bureau; BeiGene: Consultancy, Research Funding; Pharmacyclics LLC: Consultancy, Research Funding; Novartis: Consultancy. Alvarado:Daiichi-Sankyo/Lilly: Research Funding; Sun Pharma: Research Funding; FibroGen: Research Funding; BerGenBio: Research Funding; Astex Pharmaceuticals: Research Funding; Jazz Pharmaceuticals: Research Funding. Kadia:Astex: Honoraria; Astellas: Research Funding; PinotBio: Consultancy; Delta-Fly: Research Funding; Amgen: Research Funding; BMS: Consultancy, Research Funding; Genfleet: Research Funding; Regeneron: Research Funding; Glycomimetics: Research Funding; cyclacel: Research Funding; Iterion: Research Funding; Ascentage: Research Funding; Genentech: Consultancy, Research Funding; cellenkos: Research Funding; JAZZ: Consultancy, Research Funding; Servier: Consultancy; Pfizer: Research Funding; Novartis: Consultancy; AstraZeneca: Research Funding; Agios: Consultancy; Abbvie: Consultancy, Research Funding. Konopleva:Sanofi: Other: grant support, Research Funding; Novartis: Patents & Royalties, Research Funding; Rafael Pharmaceutical: Other: grant support, Research Funding; AstraZeneca: Other: grant support, Research Funding; Ascentage: Other: grant support, Research Funding; Agios: Other: grant support, Research Funding; Ablynx: Other: Grant support, Research Funding; Calithera: Other: Grant Support, Research Funding; Cellectis: Consultancy, Other: Grant support, Research Funding; Eli Lilly: Consultancy, Patents & Royalties, Research Funding; Reata Pharmaceuticals: Current equity holder in private company, Patents & Royalties; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kisoji: Consultancy, Honoraria; Amgen: Consultancy; Forty-Seven: Consultancy, Honoraria, Other: Grant support; Stemline Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffman La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grant support, Research Funding; Genentech: Consultancy, Other: grant support, Research Funding; AbbVie: Consultancy, Other: grant support, Research Funding. Kantarjian:AbbVie: Honoraria, Research Funding; KAHR Medical Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees; ImmunoGen: Research Funding; NOVA Research: Honoraria; Novartis: Honoraria, Research Funding; Jazz Pharmaceuticals: Research Funding; Astellas Health: Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Research Funding; Ascentage: Membership on an entity's Board of Directors or advisory committees, Research Funding; Ipsen Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Takeda: Honoraria. Ravandi:Xencor: Research Funding; Prelude: Research Funding; Astex/Taiho: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy; Amgen: Honoraria, Research Funding; Novartis: Consultancy; BMS/Celgene: Consultancy, Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Syos: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Biomea Fusion, Inc.: Research Funding.